{{2011ProjectsMH}}

='''Friedreich’s Ataxia'''=

==Introduction==
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" />

FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref>

The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref>

==History==

Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" />

In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia.

===Timeline===

{|style= border="0"
|- bgcolor="LightSeaGreen"
| '''Date'''
| '''Significance'''
|- bgcolor="Azure"
| '''1863'''
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref>
|- bgcolor="Azure"
| '''1882'''
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref>
|- bgcolor="Azure"
| '''1907'''
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>
|- bgcolor="Azure"
| '''1976'''
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref>
|- bgcolor="Azure"
| '''1980'''
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref>
|- bgcolor="Azure"
| '''1988'''
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref>
|- bgcolor="Azure"
| '''1989'''
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>
|- bgcolor="Azure"
| '''1990'''
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref>
|- bgcolor="Azure"
| '''1995'''
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>
|- bgcolor="Azure"
| '''1996'''
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref>
|- bgcolor="Azure"
| '''1997'''
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref>
|-bgcolor="Azure"
|
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>
|- bgcolor="Azure"
| '''2002'''
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref>
|- bgcolor="Azure"
| '''Current'''
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>
|
|}

==Epidemiology==
{|align="right"
|-
|[[File:GAA Frequency in FRDA.jpg|370px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]
|-
|[[File:Symptoms and signs in FRDA patients.jpg|370px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]
|}

'''Distribution'''

FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" />

'''Populations'''

It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India.

Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref>

Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref>

'''Gender'''

There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" />

'''Age'''

Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref>

''' Morbidity & Mortality'''

FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref>
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref>

==Aetiology==
===Genetic Component===
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.

The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.

'''Evolution'''

FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.

'''Genetic Instability'''

Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.

===Inheritance===

Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>

{|align="center"
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]
|}

===Genetic Expression===
{|align="right"
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]
|}
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development.

In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.

Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.

===Silencing of the frataxin gene (consequences of the mutation)===

In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure.

It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref>
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref>

In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>

The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.

==Pathogenesis==

{|align="left"
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]
|}

As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>.

Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.

{|align="right"
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]
|}
===Cardiomyopathy===
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.

The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.

Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.

===Neuropathology===
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref>

FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.

'''The Dorsal Root Ganglia'''

The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref>

The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref>

When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>

{|align="center"
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]
|}

'''The Dorsal Nuclei of Clarke'''

The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum.

When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>

'''The Spinocerebellar Tract'''
{|align="right"
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]
|}

This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.

Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref>

Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as:
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref>
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )
* Intention tremor nearing target.
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )

'''The Cerebellum'''

{|align="right"
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]
|}

The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.
* Producing projections into the descending motor pathways.

The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

'''The Dentate Nucleus'''

Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas.
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given.

The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref>
{|align="right"
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]
|}

'''The Corticospinal Tract'''

This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles.
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles.

It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

Results of lesion of the corticospinal tract can produce:
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref>
* Positive Babinski reflex indicate involvement of the corticospinal tracts.

==Clinical Presentation==
{|align="right"
|-
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]
|-
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]
|}
===Symptoms===

Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.

As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.

For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.

The table below summarises symptoms of FRDA as primary or secondary.

{| style= "width:60%; height:100px" align="center" border="0"
|-bgcolor="LightSeaGreen"
| '''Classification of symptom'''
| '''Type of symptom'''
|-bgcolor="Azure"
| '''Primary'''
| Ataxia of limb and gait
Absent reflexes in lower limbs

Onset before 25 years of age

Loss of peripheral sense (proprioception)
|-bgcolor="Azure"
| style="white-space: nowrap" | '''Secondary'''
| Scoliosis
Pes Cavus

Extensor plantar responses (Babinski's sign)

Dysarthria
|}

===Complications===

Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.

Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.

==Diagnosis==

As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.

In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>.

Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.

===Diagnostic Tools===

The table below shows common diagnostic tools employed in the diagnosis of FRDA:

{|style= border="0"
|- bgcolor="LightSeaGreen"
| '''Diagnostic tool'''
| '''What it does'''
| '''How it diagnoses FRDA'''
| '''Image (if available)'''
|- bgcolor="Azure"
| '''Electromyogram''' (EMG)
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]
|- bgcolor="Azure"
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)
| Provides graphic presentation of the electrical activity or beat pattern of the heart
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]
|- bgcolor="Azure"
| '''Echocardiogram''' (ECHO)
| Records the position and motion of the heart muscle
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]
|- bgcolor="Azure"
| '''Blood tests'''
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]
|- bgcolor="Azure"
| '''Magnetic resonance imaging''' (MRI)
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]
|- bgcolor="Azure"
| '''Computed tomography scans''' (CT scan)
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]
|- bgcolor="Azure"
| '''Nerve conduction studies''' (NCS)
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]
|- bgcolor="Azure"
| '''Genetic Testing'''
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]
|- bgcolor="Azure"
| '''Prenatal Testing'''
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.
| Same as in '''Genetic Testing'''.
|
|}

===Prenatal Diagnosis===

Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.

However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.

Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.

Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref>

===Postnatal Diagnosis===

Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.

{|style= "width:60%; height:100px" align="center" border="0"
|-bgcolor="LightSeaGreen"
| '''Availability of genetic testing'''
| '''Diagnostic symptoms'''
|-bgcolor="Azure"
| '''Prior to genetic testing availability'''
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref>
|-bgcolor="Azure"
| style="white-space: nowrap" | '''After genetic testing is available'''
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).
|}

==Treatment==

Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:

{|align="right"
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]
|}
*Iron chelators
* Histone deacetylase inhibitors(HDACI)
* Antioxidant

'''Iron-chelation'''

Treating with iron chelators is very effective in delaying the progress of FRDA. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.

As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.

{|align="Right"
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]
|}

'''Histone deacetylase inhibitors(HDACI)'''

The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']]. More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']], which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']], and thus preventing hypoacetylation<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.
Histone deacetylase inhibitors (HDACI) have been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI returned the levels of genetic expression of the frataxin gene, responsible for the production of the frataxin protein, to normal. HDACI is able to cross the blood brain barrier and acetylate histones, furthermore tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.

'''Antioxidants'''

Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.

*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.

*Treatment with idebenone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.

{|align="center"
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]
|}

==Current Research==

{|
|-bgcolor="LightSeaGreen"
| '''Area of research'''
| '''What it is about'''
| '''Recent publications'''
|-bgcolor="Azure"
| style="width:20%" |A lot of the current research is looking at the potential of idebenone, an iron chelator as a treatment for FRDA.
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebenone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref>

Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref>

Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref>

Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref>
|-bgcolor="Azure"
| Recent publication providing an overview of the current therapeutic perspective for FRDA.
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref>
|-bgcolor="Azure"
| Evaluation criteria of FRDA in children.
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref>
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref>
|-bgcolor="Azure"
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref>
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref>
|-bgcolor="Azure"
| Improvements in genetic counseling for FRDA patients.
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref>
|}

==Related Links==

* [[Cardiac Embryology]] - Development of heart.

* [[Magnetic Resonance Imaging]] - More on MRI including imaging.

* [[Molecular Development - Genetics]] - The genetics and molecular mechanisms of development.

* [[Musculoskeletal System - Abnormalities]] - More details about scoliosis and other musculoskeletal abnormalities.

* [[Neonatal Diagnosis]] - More on genetic screening and neonatal diagnosis.

* [[Neural - Cerebellum Development]] - This page relates the development of the cerebellum, in addition to some of the cellular origins.

==External Links==
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]

Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]

Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]

Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]

Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]

Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]

Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]

Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]

Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]

Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]

Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]

==Glossary==

[[#Introduction | '''Back to top''']]

'''Acetylation''' - The process of adding an acetyl group into a compound. Acetylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.

'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.

'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.

'''Apoptosis''' - Programmed cell death.

'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement.

'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body.

'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.

'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia).

'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.

'''Cardiomyocytes''' - Specialised muscle cells of the heart.

'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])

'''CNS''' - Central Nervous System.

'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.

'''Cortical''' - Of or relating to the cortex.

'''Deacetylation''' - The removal of an acetyl group to a compound.

'''Demyelination''' - The loss of the myelin sheath surrounding an axon.

'''DNA''' - Deoxyribonucleic Acid.

'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.

'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.

'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain.

'''DRG''' - Dorsal Root Ganglion.

'''Dysarthria''' – A motor speech disorder causing slurring of words.

'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results.

'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia.

'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).

'''Erythropoietin''' - A hormone that stimulates red blood cell production.

'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans

'''FRDA''' - Friedreich's Ataxia.

'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.

'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.

'''Gene silencing''' - Inhibition of the gene expression.

'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.

'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.

'''Hematocrit''' - Measures the volume of red blood cells in blood.

'''Histone''' - A protein around which DNA coils to form chromatin.

'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.

'''Heterozygous''' - Possessing two different variants of a gene.

'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.

'''Homozygous''' - Possessing two identical variants of a gene.

'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements

'''Hypertrophy''' - Increasing in size of a organ or tissue.

'''Hypoacetylation''' - Less acetylated than in normal circumstances.

'''Hypotonia''' - Decrease in muscle tone.

'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.

'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.

'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.

'''Methylation''' - Enzymatic transfer of methyl groups to biological molecules, such as RNA and DNA. Methylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.

'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.

'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.

'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.

'''Neurological''' - Pertaining to the nervous system or nerves.

'''Neuron''' - The excitable cell of the nervous system.

'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.

'''Oligodendrocytes''' - Are the supporting cells in the CNS.

'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.

'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)

'''Pes cavus''' - Feet with abnormally high arches.

'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.

'''Phenotype''' - Traits or characteristics that are observable externally.

'''Pneumonia''' - Inflammatory condition of the lungs.

'''PNS''' - Peripheral Nervous System.

'''Point mutation''' - A mutation affecting a single nucleotide.

'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease.

'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.

'''Purine''' - One of the two chemical classes to which nucleotides belong.

'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.

'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.

'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.

'''Replication''' - The process whereby DNA is duplicated.

'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.

'''Schwann Cells''' - Are the supporting cells of the PNS.

'''Sepsis''' - Infection of the blood, generally bacterial.

'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.

'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.

'''Tachycardia''' - A resting heart rate that exceeds the normal range.

'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.

'''T-wave''' - On an ECG, it represents the recovery of the ventricles.

==References==
<references/>

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'''Gene expression responses of Friedreich's ataxia'''
----
==Analogous gene expression responses in blood from children and adults with FRDA.==

(A) A common gene signature is representative of a genotoxic stress response found by Gene Set Analysis. Twenty-three genotoxic stress response gene sets were searched for common genes. This heat map, generated by unsupervised clustering, displays the genes present in at least 6 of the 23 gene sets and compares transcript levels between FRDA patients, the adult and children cohorts, and controls. Yellow=upregulated; Blue=downregulated. C=Control; P=Patient. Note that while three patients and one control did not segregate with their respective groups, all adult patients and controls clustered in two separate groups in this unsupervised clustering. (B) Heat-map generated by unsupervised clustering of FRDA and control samples, which displays the overlap of significantly differentially expressed genes (SAM FDR<0.023%; n=228) in the FRDA children and FRDA adults (overlap p≤0.007). C=control; P=patient. (C) A selected list of significant GO groups representing the overlap gene list described in (B). All controls used for comparison to the FRDA children are young adults (see Table S1). The percent of total (displayed with a gray ball) is based on the number of significantly changed genes out of the total number of genes assigned to each gene ontology term. The gene number for each GO group is shown with a blue bar, the intensity of which is indicative of the p-value.
----
'''Reference'''

<pubmed>20090835</pubmed>| [http://www.ncbi.nlm.nih.gov/pubmed/20090835/]

Copyright This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

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'''Gene expression responses of Friedreich's ataxia'''
----
==Analogous gene expression responses in blood from children and adults with FRDA.==

----
(A) A common gene signature is representative of a genotoxic stress response found by Gene Set Analysis. Twenty-three genotoxic stress response gene sets were searched for common genes. This heat map, generated by unsupervised clustering, displays the genes present in at least 6 of the 23 gene sets and compares transcript levels between FRDA patients, the adult and children cohorts, and controls. Yellow=upregulated; Blue=downregulated. C=Control; P=Patient. Note that while three patients and one control did not segregate with their respective groups, all adult patients and controls clustered in two separate groups in this unsupervised clustering. (B) Heat-map generated by unsupervised clustering of FRDA and control samples, which displays the overlap of significantly differentially expressed genes (SAM FDR<0.023%; n=228) in the FRDA children and FRDA adults (overlap p≤0.007). C=control; P=patient. (C) A selected list of significant GO groups representing the overlap gene list described in (B). All controls used for comparison to the FRDA children are young adults (see Table S1). The percent of total (displayed with a gray ball) is based on the number of significantly changed genes out of the total number of genes assigned to each gene ontology term. The gene number for each GO group is shown with a blue bar, the intensity of which is indicative of the p-value.
----
'''Reference'''

<pubmed>20090835</pubmed>| [http://www.ncbi.nlm.nih.gov/pubmed/20090835/]

Copyright This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

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'''Figure 5'''

Model of Friedreich's ataxia pathology based on this study.
Data presented in this study are consistent with a dysregulation of mitochondrial function, decreased oxidative phosphorylation, increased ROS production, and subsequent mitochondrial and nuclear DNA damage. These factors contribute to decreased signaling and altered DNA transactions, which are likely to result in subsequent loss of protein synthesis and decreased protein degradation, as suggested in the transcription profiling. These alterations may cause tissue damage, altered immune response, and the clinical pathology associated with FRDA.

===Reference===

<pubmed>20090835</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799513 PMC2799513]

Copyright This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

{{Template:2011 Student Image}}

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='''Friedreich’s Ataxia'''=

==Introduction==
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" />

FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref>

The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref>

==History==

Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" />

In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia.

===Timeline===

{|style= border="0"
|- bgcolor="LightSeaGreen"
| '''Date'''
| '''Significance'''
|- bgcolor="Azure"
| '''1863'''
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref>
|- bgcolor="Azure"
| '''1882'''
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref>
|- bgcolor="Azure"
| '''1907'''
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>
|- bgcolor="Azure"
| '''1976'''
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref>
|- bgcolor="Azure"
| '''1980'''
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref>
|- bgcolor="Azure"
| '''1988'''
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref>
|- bgcolor="Azure"
| '''1989'''
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>
|- bgcolor="Azure"
| '''1990'''
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref>
|- bgcolor="Azure"
| '''1995'''
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>
|- bgcolor="Azure"
| '''1996'''
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref>
|- bgcolor="Azure"
| '''1997'''
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref>
|-bgcolor="Azure"
|
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>
|- bgcolor="Azure"
| '''2002'''
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref>
|- bgcolor="Azure"
| '''Current'''
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>
|
|}

==Epidemiology==
'''Distribution'''

FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" />

'''Populations'''

It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India.

Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref>

Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref>

'''Gender'''

There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" />

'''Age'''

Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref>

''' Morbidity & Mortality'''

FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref>
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref>

==Aetiology==
===Genetic Component===

[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.

The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a '''missense''' or '''nonsense point mutation''' on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>

'''Evolution'''

FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 '''carriers''' in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>

'''Genetic Instability'''

Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.

===Inheritance===

Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.
As already mentionned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases.

{|align="center"
|[[File:Friedreich's Ataxia Pedigree.jpg|450px|thumb|Friedreich's Ataxia Pedigree]]
|}

===Genetic Expression===

[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development.

In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.

Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the '''periventricular''' zone, the '''cortical''' plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.

===Silencing of the frataxin gene (consequences of the mutation)===

In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that '''splicing''' of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that '''mRNA''' levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are '''purines''' while T (thymine) and C (cytosine) are '''pyrimidines'''. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to '''gene silencing'''. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref>
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref>

In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>

The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.

==Pathogenesis==

{|align="right"
|[[File:Pathogenesis of Friedreich Ataxia.jpg|340px|thumb|A model of pathogenesis in Friedreich's Ataxia]]
|}

As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.

===Cardiomyopathy===
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.

Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.

===Neuropathology===
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref>

FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.

'''The Dorsal Root Ganglia'''

The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref>

The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref>

When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>

{|align="center"
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]
|}

'''The Dorsal Nuclei of Clarke'''

The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum.

When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>

'''The Spinocerebellar Tract'''
{|align="right"
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]
|}

This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.

Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref>

Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as:
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref>
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )
* Intention tremor nearing target.
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )

'''The Cerebellum'''
{|align="right"
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]
|}

The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.
* Producing projections into the descending motor pathways.

The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

'''The Dentate Nucleus'''

Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas.
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given.

The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref>
{|align="right"
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]
|}

'''The Corticospinal Tract'''

This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles.
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles.

It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

Results of lesion of the corticospinal tract can produce:
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref name="PMID20301458"><pubmed>20301458</pubmed></ref>
* Positive Babinski reflex indicate involvement of the corticospinal tracts.

==Clinical Presentation==
{|align="right"
|-
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]
|-
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]
|}
===Symptoms===

Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.

As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.

For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.

The table below summarises symptoms of FRDA as primary or secondary.

{| style= "width:60%; height:100px" align="center" border="0"
|-bgcolor="LightSeaGreen"
| '''Classification of symptom'''
| '''Type of symptom'''
|-bgcolor="Azure"
| '''Primary'''
| Ataxia of limb and gait
Absent reflexes in lower limbs

Onset before 25 years of age

Loss of peripheral sense (proprioception)
|-bgcolor="Azure"
| style="white-space: nowrap" | '''Secondary'''
| Scoliosis
Pes Cavus

Extensor plantar responses (Babinski's sign)

Dysarthria
|}

===Complications===

Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.

Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']]in islets<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.

==Diagnosis==

As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>.
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.

===Diagnostic Tools===

The table below shows common diagnostic tools employed in the diagnosis of FRDA:

{|style= border="0"
|- bgcolor="LightSeaGreen"
| '''Diagnostic tool'''
| '''What it does'''
| '''How it diagnoses FRDA'''
| '''Image (if available)'''
|- bgcolor="Azure"
| '''Electromyogram''' (EMG)
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]
|- bgcolor="Azure"
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)
| Provides graphic presentation of the electrical activity or beat pattern of the heart
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]
|- bgcolor="Azure"
| '''Echocardiogram''' (ECHO)
| Records the position and motion of the heart muscle
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]
|- bgcolor="Azure"
| '''Blood tests'''
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]
|- bgcolor="Azure"
| '''Magnetic resonance imaging''' (MRI)
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI heart]]]
|- bgcolor="Azure"
| '''Computed tomography scans''' (CT scan)
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]
|- bgcolor="Azure"
| '''Nerve conduction studies''' (NCS)
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]
|- bgcolor="Azure"
| '''Genetic Testing'''
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]
|- bgcolor="Azure"
| '''Prenatal Testing'''
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.
| Same as in [[#Glossary|'''Genetic Testing''']].
|
|}

===Prenatal Diagnosis===

Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent '''DNA markers''', MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.
Nevertheless, refinement of the genetic screens continued, especially after '''recombination''' events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.

Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. '''PCR''' and '''Southern Blot''' can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref>

===Postnatal Diagnosis===

Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.

{|style= "width:60%; height:100px" align="center" border="0"
|-bgcolor="LightSeaGreen"
| '''Availability of genetic testing'''
| '''Diagnostic symptoms'''
|-bgcolor="Azure"
| '''Prior to genetic testing availability'''
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref>
|-bgcolor="Azure"
| style="white-space: nowrap" | '''After genetic testing is available'''
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).
|}

==Treatment==

Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from [[#Glossary | '''FRDA''']] patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for [[#Glossary | '''FRDA''']]<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.

'''Iron-chelation'''

Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the [[#Glossary | '''Frataxin''']] deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential [[#Glossary | '''chelators''']] are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.

As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-[[#Glossary | '''chelation''']] had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated [[#Glossary | '''frataxin''']] gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.

{|align="center"
|[[File:Role of FXN Gene.jpg|350px|thumb|Role of FXN Gene]]
|}

'''Histone deacetylase inhibitors(HDACI)'''

Treatment of [[#Glossary | '''FRDA''']] through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of [[#Glossary | '''fractin''']] restoring to normal range within the nervous system and the heart, restoration of [[#Glossary | '''fractin''']] levels was achieved where acetylisation of [[#Glossary | '''histones''']] at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.

Positive effects of [[#Glossary | '''fractin''']] level restoration is signs of decrease in progression of [[#Glossary | '''FRDA''']]. Therapeutic use of HDACI led to the normalization of the genetic expression of [[#Glossary | '''FRDA''']] patients. Support of [[#Glossary | '''fractin''']] level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to [[#Glossary | '''histones''']] without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.

'''Antioxidants'''

The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.

*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of [[#Glossary | '''FRDA''']]<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.

*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.

{|align="center"
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]
|}

==Current Research==

A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:
* A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. <ref name="PMID20697044"><pubmed>20697044</pubmed></ref>
* Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. <ref name="PMID21779958"><pubmed>21779958</pubmed></ref>
* Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. <ref name="PMID20865357"><pubmed>20865357</pubmed></ref>
* Antioxidants and other pharmacological treatments for Friedreich ataxia. <ref name="PMID19821439"><pubmed>19821439</pubmed></ref>

The following recent publication provides an overview of the current therapeutic perspective:
* New advances in the treatment of Friedreich ataxia: promisses and pitfalls. <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref>

The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:
* In children with Friedreich ataxia, muscle and ataxia parameters are associated. <ref name="PMID21574990"><pubmed>21574990</pubmed></ref>
* Neurophysiological evaluation in children with Friedreich's ataxia. <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref>

Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:
* Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. <ref name="PMID20063431"><pubmed>20063431</pubmed></ref>
* Review: Evaluating the progression of Friedreich ataxia and its treatment. <ref name="PMID19283349"><pubmed>19283349</pubmed></ref>

Improvements in genetic counseling for FRDA patients are suggested by this recent study:
* Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling. <ref name="PMID20979606"><pubmed>20979606</pubmed></ref>

==External Links==
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]

Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]

Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]

Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]

Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]

Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]

Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]

Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]

Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]

Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]

Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]

==Glossary==

'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis

'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities

'''Apoptosis''' - Programmed cell death.

'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement.

'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body.

'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.

'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia).

'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.

'''Cardiomyocytes''' - Specialised muscle cells of the heart

'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])

'''CNS''' - Central Nervous System.

'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.

'''Cortical''' - Of or relating to the cortex.

'''Demyelination''' - The loss of the myelin sheath surrounding an axon.

'''DNA''' - Deoxyribonucleic Acid

'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.

'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.

'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain.

'''DRG''' -Dorsal Root Ganglion.

'''Dysarthria''' – A motor speech disorder causing slurring of words.

'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results.

'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia.

'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)

'''Erythropoietin''' - A hormone that stimulates red blood cell production.

'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans

'''FRDA''' - Friedreich's Ataxia.

'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.

'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.

'''Gene silencing''' - Inhibition of the gene expression.

'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.

'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.

'''Hematocrit''' - Measures the volume of red blood cells in blood.

'''Histone''' - A protein around which DNA coils to form chromatin.

'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.

'''Heterozygous''' - Possessing two different variants of a gene.

'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.

'''Homozygous''' - Possessing two identical variants of a gene.

'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements

'''Hypertrophy''' - Increasing in size of a organ or tissue.

'''Hypotonia''' - Decrease in muscle tone.

'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.

'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.

'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.

'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.

'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.

'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.

'''Neurological''' - Pertaining to the nervous system or nerves.

'''Neuron''' - The excitable cell of the nervous system.

'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.

'''Oligodendrocytes''' - Are the supporting cells in the CNS.

'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.

'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)

'''Pes cavus''' - Feet with abnormally high arches.

'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.

'''Phenotype''' - Traits or characteristics that are observable externally.

'''Pneumonia''' - Inflammatory condition of the lungs.

'''PNS''' - Peripheral Nervous System.

'''Point mutation''' - A mutation affecting a single nucleotide.

'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease.

'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.

'''Purine''' - One of the two chemical classes to which nucleotides belong.

'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.

'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.

'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.

'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.

'''Replication''' - The process whereby DNA is duplicated.

'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.

'''Schwann Cells''' - Are the supporting cells of the PNS.

'''Sepsis''' - Infection of the blood, generally bacterial.

'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.

'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.

'''Tachycardia''' - A resting heart rate that exceeds the normal range.

'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.

'''T-wave''' - On an ECG, it represents the recovery of the ventricles.

==References==
<references/>

2011 Group Project 8

2011-10-06T00:14:37Z

Z3329495: /* Friedreich’s Ataxia */

{{2011ProjectsMH}}

='''Friedreich’s Ataxia'''=

==Introduction==
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" />

FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref>

The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref>

==History==

Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" />

In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia.

===Timeline===

{|style= border="0"
|- bgcolor="LightSeaGreen"
| '''Date'''
| '''Significance'''
|- bgcolor="Azure"
| '''1863'''
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref>
|- bgcolor="Azure"
| '''1882'''
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref>
|- bgcolor="Azure"
| '''1907'''
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>
|- bgcolor="Azure"
| '''1976'''
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref>
|- bgcolor="Azure"
| '''1980'''
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref>
|- bgcolor="Azure"
| '''1988'''
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref>
|- bgcolor="Azure"
| '''1989'''
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>
|- bgcolor="Azure"
| '''1990'''
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref>
|- bgcolor="Azure"
| '''1995'''
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>
|- bgcolor="Azure"
| '''1996'''
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref>
|- bgcolor="Azure"
| '''1997'''
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref>
|-bgcolor="Azure"
|
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>
|- bgcolor="Azure"
| '''2002'''
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref>
|- bgcolor="Azure"
| '''Current'''
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>
|
|}

==Epidemiology==
'''Distribution'''

FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" />

'''Populations'''

It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India.

Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref>

Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref>

'''Gender'''

There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" />

'''Age'''

Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref>

''' Morbidity & Mortality'''

FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref>
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref>

==Aetiology==
===Genetic Component===

[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.

The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a '''missense''' or '''nonsense point mutation''' on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>

'''Evolution'''

FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 '''carriers''' in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>

'''Genetic Instability'''

Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.

===Inheritance===

Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.
As already mentionned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases.

{|align="center"
|[[File:Friedreich's Ataxia Pedigree.jpg|450px|thumb|Friedreich's Ataxia Pedigree]]
|}

===Genetic Expression===

[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development.

In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.

Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the '''periventricular''' zone, the '''cortical''' plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.

===Silencing of the frataxin gene (consequences of the mutation)===

In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that '''splicing''' of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that '''mRNA''' levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are '''purines''' while T (thymine) and C (cytosine) are '''pyrimidines'''. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to '''gene silencing'''. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref>
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref>

In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>

The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.

==Pathogenesis==

{|align="right"
|[[File:Pathogenesis of Friedreich Ataxia.jpg|340px|thumb|A model of pathogenesis in Friedreich's Ataxia]]
|}

As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.

===Cardiomyopathy===
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.

Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.

===Neuropathology===
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref>

FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.

'''The Dorsal Root Ganglia'''

The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref>

The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref>

When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>

{|align="center"
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]
|}

'''The Dorsal Nuclei of Clarke'''

The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum.

When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>

'''The Spinocerebellar Tract'''
{|align="right"
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]
|}

This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.

Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref>

Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as:
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref>
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref>
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )
* Intention tremor nearing target.
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref>
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )

'''The Cerebellum'''
{|align="right"
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]
|}

The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.
* Producing projections into the descending motor pathways.

The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

'''The Dentate Nucleus'''

Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas.
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given.

The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref>
{|align="right"
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]
|}

'''The Corticospinal Tract'''

This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles.
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles.

It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref>

Results of lesion of the corticospinal tract can produce:
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref name="PMID20301458"><pubmed>20301458</pubmed></ref>
* Positive Babinski reflex indicate involvement of the corticospinal tracts.

==Clinical Presentation==
{|align="right"
|-
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]
|-
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]
|}
===Symptoms===

Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.

As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.

For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.

The table below summarises symptoms of FRDA as primary or secondary.

{| style= "width:60%; height:100px" align="center" border="0"
|-bgcolor="LightSeaGreen"
| '''Classification of symptom'''
| '''Type of symptom'''
|-bgcolor="Azure"
| '''Primary'''
| Ataxia of limb and gait
Absent reflexes in lower limbs

Onset before 25 years of age

Loss of peripheral sense (proprioception)
|-bgcolor="Azure"
| style="white-space: nowrap" | '''Secondary'''
| Scoliosis
Pes Cavus

Extensor plantar responses (Babinski's sign)

Dysarthria
|}

===Complications===

Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.

Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']]in islets<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.

==Diagnosis==

As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>.
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.

===Diagnostic Tools===

The table below shows common diagnostic tools employed in the diagnosis of FRDA:

{|style= border="0"
|- bgcolor="LightSeaGreen"
| '''Diagnostic tool'''
| '''What it does'''
| '''How it diagnoses FRDA'''
| '''Image (if available)'''
|- bgcolor="Azure"
| '''Electromyogram''' (EMG)
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]
|- bgcolor="Azure"
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)
| Provides graphic presentation of the electrical activity or beat pattern of the heart
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]
|- bgcolor="Azure"
| '''Echocardiogram''' (ECHO)
| Records the position and motion of the heart muscle
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]
|- bgcolor="Azure"
| '''Blood tests'''
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]
|- bgcolor="Azure"
| '''Magnetic resonance imaging''' (MRI)
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI heart]]]
|- bgcolor="Azure"
| '''Computed tomography scans''' (CT scan)
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]
CT scan of lung cancer (video): [http://youtu.be/MLg-_fsaHso]
|- bgcolor="Azure"
| '''Nerve conduction studies''' (NCS)
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]
|- bgcolor="Azure"
| '''Genetic Testing'''
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]
|- bgcolor="Azure"
| '''Prenatal Testing'''
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.
| Same as in [[#Glossary|'''Genetic Testing''']].
|
|}

===Prenatal Diagnosis===

Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent '''DNA markers''', MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.
Nevertheless, refinement of the genetic screens continued, especially after '''recombination''' events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.

Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. '''PCR''' and '''Southern Blot''' can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref>

===Postnatal Diagnosis===

Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.

{|style= "width:60%; height:100px" align="center" border="0"
|-bgcolor="LightSeaGreen"
| '''Availability of genetic testing'''
| '''Diagnostic symptoms'''
|-bgcolor="Azure"
| '''Prior to genetic testing availability'''
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref>
|-bgcolor="Azure"
| style="white-space: nowrap" | '''After genetic testing is available'''
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).
|}

==Treatment==

Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from [[#Glossary | '''FRDA''']] patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for [[#Glossary | '''FRDA''']]<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.

'''Iron-chelation'''

Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the [[#Glossary | '''Frataxin''']] deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential [[#Glossary | '''chelators''']] are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.

As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-[[#Glossary | '''chelation''']] had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated [[#Glossary | '''frataxin''']] gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.

{|align="center"
|[[File:Role of FXN Gene.jpg|350px|thumb|Role of FXN Gene]]
|}

'''Histone deacetylase inhibitors(HDACI)'''

Treatment of [[#Glossary | '''FRDA''']] through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of [[#Glossary | '''fractin''']] restoring to normal range within the nervous system and the heart, restoration of [[#Glossary | '''fractin''']] levels was achieved where acetylisation of [[#Glossary | '''histones''']] at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.

Positive effects of [[#Glossary | '''fractin''']] level restoration is signs of decrease in progression of [[#Glossary | '''FRDA''']]. Therapeutic use of HDACI led to the normalization of the genetic expression of [[#Glossary | '''FRDA''']] patients. Support of [[#Glossary | '''fractin''']] level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to [[#Glossary | '''histones''']] without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.

'''Antioxidants'''

The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.

*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of [[#Glossary | '''FRDA''']]<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.

*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.

{|align="center"
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]
|}

==Current Research==

A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:
* A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. <ref name="PMID20697044"><pubmed>20697044</pubmed></ref>
* Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. <ref name="PMID21779958"><pubmed>21779958</pubmed></ref>
* Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. <ref name="PMID20865357"><pubmed>20865357</pubmed></ref>
* Antioxidants and other pharmacological treatments for Friedreich ataxia. <ref name="PMID19821439"><pubmed>19821439</pubmed></ref>

The following recent publication provides an overview of the current therapeutic perspective:
* New advances in the treatment of Friedreich ataxia: promisses and pitfalls. <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref>

The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:
* In children with Friedreich ataxia, muscle and ataxia parameters are associated. <ref name="PMID21574990"><pubmed>21574990</pubmed></ref>
* Neurophysiological evaluation in children with Friedreich's ataxia. <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref>

Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:
* Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. <ref name="PMID20063431"><pubmed>20063431</pubmed></ref>
* Review: Evaluating the progression of Friedreich ataxia and its treatment. <ref name="PMID19283349"><pubmed>19283349</pubmed></ref>

Improvements in genetic counseling for FRDA patients are suggested by this recent study:
* Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling. <ref name="PMID20979606"><pubmed>20979606</pubmed></ref>

==External Links==
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]

Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]

Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]

Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]

Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]

Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]

Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]

Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]

Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]

Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]

Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]

==Glossary==

'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis

'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities

'''Apoptosis''' - Programmed cell death.

'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement.

'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body.

'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.

'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia).

'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.

'''Cardiomyocytes''' - Specialised muscle cells of the heart

'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])

'''CNS''' - Central Nervous System.

'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.

'''Cortical''' - Of or relating to the cortex.

'''Demyelination''' - The loss of the myelin sheath surrounding an axon.

'''DNA''' - Deoxyribonucleic Acid

'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.

'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.

'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain.

'''DRG''' -Dorsal Root Ganglion.

'''Dysarthria''' – A motor speech disorder causing slurring of words.

'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results.

'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia.

'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)

'''Erythropoietin''' - A hormone that stimulates red blood cell production.

'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans

'''FRDA''' - Friedreich's Ataxia.

'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.

'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.

'''Gene silencing''' - Inhibition of the gene expression.

'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.

'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.

'''Hematocrit''' - Measures the volume of red blood cells in blood.

'''Histone''' - A protein around which DNA coils to form chromatin.

'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.

'''Heterozygous''' - Possessing two different variants of a gene.

'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.

'''Homozygous''' - Possessing two identical variants of a gene.

'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements

'''Hypertrophy''' - Increasing in size of a organ or tissue.

'''Hypotonia''' - Decrease in muscle tone.

'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.

'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.

'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.

'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.

'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.

'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.

'''Neurological''' - Pertaining to the nervous system or nerves.

'''Neuron''' - The excitable cell of the nervous system.

'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.

'''Oligodendrocytes''' - Are the supporting cells in the CNS.

'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.

'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)

'''Pes cavus''' - Feet with abnormally high arches.

'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.

'''Phenotype''' - Traits or characteristics that are observable externally.

'''Pneumonia''' - Inflammatory condition of the lungs.

'''PNS''' - Peripheral Nervous System.

'''Point mutation''' - A mutation affecting a single nucleotide.

'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease.

'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.

'''Purine''' - One of the two chemical classes to which nucleotides belong.

'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.

'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.

'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.

'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.

'''Replication''' - The process whereby DNA is duplicated.

'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.

'''Schwann Cells''' - Are the supporting cells of the PNS.

'''Sepsis''' - Infection of the blood, generally bacterial.

'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.

'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.

'''Tachycardia''' - A resting heart rate that exceeds the normal range.

'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.

'''T-wave''' - On an ECG, it represents the recovery of the ventricles.

==References==
<references/>