2011 Group Project 8

Note - This page is an undergraduate science embryology student group project 2011. 2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

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Friedreich’s Ataxia

Introduction

Nikolaus Friedreich Portrait

Friedreich’s Ataxia (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 50000 people. 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 phenotypes become noticable, such as ataxic gait. 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. The disruption of the frataxin gene is often caused by a trinucleotide repetition of GAA, which is located on chromosome 9q13. The result of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron homeostasis. This causes major disabilities in the tissues containing the fraxtain deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and cardiac arrhythmia.

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. 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”. 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, scoliosis and cardiac abnormalities linking there cause to a common factor. Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia.

Timeline

1863	1882	1907	1988	1996
Friedreich describes the clinical presentation of patients and publishes his findings.	Brousse et al (1882) suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which calls for further investigation and classification techniques.	A study by Mott gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology.	The chromosomal locus for Friedreich’s ataxia was mapped to chromosome 9q13.	Frataxin the mutated gene responsible for FRDA was discovered, which allowed for molecular testing and full clinical classification of the disease.

Epidemiology

Distribution - FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people.

1. Populations - It has been noted that Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. Furthermore, Asian and African populations have a much lower prevalence of FDRA.
2. Gender - There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA.
3. 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. 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. Furthermore, there has been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40.

Morbidity & Mortality FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. Commonly, patients tend to lose the capability to walk nearing the age of 25. Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou et al, (2011) 59% of patients died due to cardiac dysfunction, such as congestive heart failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including pneumonia, sepsis and renal failure and the remaining patients died of unknown causes. 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.

Aetiology

Genetic Component

GAA expansion or point mutation in first intron of frataxin gene

most individuals homozygous for repeat expansion, some heterozygous for repeat expansion & piont mutation

Inheritance

GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat

Pathogenesis

As FA is a ‘neurodegenerative disorder’ patients with FA are normal at birth until the ‘age of onset’ where symptoms present due to (what is believed to be) iron build up in mitochondria. Studies on mouse models show that if the frataxin gene is totally knocked out, the embryo does not survive.

Cardiomyopathy

In the past, the pathogenesis of cardiomyopathy in FA patients was relatively unknown, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FA patients. 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 lot 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.

Neuropathology

FRDA produces a complex neuropathological phenotype within the central nervous system (CNS), as well as, the peripheral nervous system (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 (DRG), dorsal spinal roots, dorsal nuclei of Clarke, spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. 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 of Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic atrophy, and degeneration of the corticospinal tract.

Dorsal Root Ganglia (DRG)

The hallmark of FRDA involves atrophy of DRG and thinning of dorsal roots themselves within the PNS (figure...). 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 . Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes demyelination and unsuitable regeneration of myelin of the dorsal root. The study by Mott et al, (1907) 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 triplet-repeat sequence may contribute directly to disease pathogenesis and progression.” Furthermore, the experiment conducted by Lu et al, (2009) measured the significance of frataxin depletion in Schwann cell and oligodendrocyte cell lines. Schwann cells are the supporting cells of the PNS and oligodendrocytes serve the same function in the CNS. 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. When abnormalities arise in Schwann cells, due to injury or genetics, they can cause demyelination, inappropriate proliferating and phagocytosis of debris. The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. As the damage and/or loss of the neurons of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;

1. The depletion of the centrally projecting axons of the DRG into the dorsal root.
2. 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 gray matter of the dorsal horns.”

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 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 (figure...). 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.

Clinical Presentation

Symptoms

Friedreich's Ataxia (FA) often manifests before puberty to early adulthood. Physical complaints such as chest pains , progressive gait and limb ataxia, absent lower limb reflexes, extensor plantar responses (Babinski's sign), dysarthria, reduction in or loss of vibration sense and proprioception , . scoliosis, foot deformity (pes cavus, hammer toe) and cardiomyopathy are common but not symptoms which FA is often diagnosed by.

Schematic drawing of scoliosis

Complications

Cardiomyopathy

As cardiac involvement is high (>90%), it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular hypertrophy and tachycardia). Even in Friedreich's original description of his patients, 5 out of 6 had cardiac involvement. Although insight into cardiac involvement of FA discovered that compensation of the impaired cardiac function with increase oxygen consumption to myocardial blood flow, where high percentage of cardiomyopathy was due to left ventricular hypertrophy which resulted in most deaths due to heart failure. 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 .

Diabetes

Diabetes as a complication of FA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell apoptosis, loss of beta-cell proliferation and increased Reactive Oxygen Speices (ROS)in islets. It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001).

Diagnosis

Previous papers have set guidelines for the diagnosis of FRDA and was first established by Geffory et al. (1976) to include ataxia of limb and gait, absent reflexes in lower limbs, dysarthria, extensor plantar responses, muscle weakness and sensory loss on the back. It was then revised by Harding (1981) to exclude muscle weakness and sensory loss on the back, include the onset of FRDA before the end of puberty, ataxia of gait, dysarthria, loss of peripheral sense, and absent reflexes in the leg. As these diagnostic criteria were set before genetic screening was available, the diagnostic criteria was often split into two categories of 'primary' and 'secondary' symptoms. In a more recent review of FRDA diagnostic criteria, it is proposed that three categories (not using the dated categories) indicating the likelihood of FRDA should be used.

Prenatal Diagnosis

Genetic Screening

Tight linkage to an adjacent DNA marker (MCT112) provides reliable tool for genetic screening

Postnatal Diagnosis

Friedreich's Ataxia (FA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis.

Availability of genetic testing	Diagnostic symptoms
Prior to genetic testing availability	Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FA progression could identify it as FA.
After genetic testing is available	Physical complaints are used in conjunction with genetic testing to confirm FA. Due to genetic testing, it has been discovered that FA can occur in individuals older than the typical diagnostic age (first two decades of life).

A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia

Treatment

Iron-chelation

As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-chelation had been studied for it's therapeutic action on removing excess iron on mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This shows that chelation limits cardiomyopathy but it did not 'cure' the problem. While chelation did not lead to major iron depletion or toxicity reduction, it did prevent iron accumulation in mice with the mutated frataxin gene. This discovery is significant as 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. 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 hematocrit.

Idebenone

Alternative treatment of Friedreich ataxia (FA) is the use of Idebenone. Idebenone a new emerging treatment of FA reverses redox reactions, influencing the mitochondria electron balance preventing damage to the mitochondrial membrane . Usage of Idebenone has been proven to reduce cardiac hypertrophy in FA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy. Thus Idebenone has been strongly used a treatment method although other alternative are present including erythropoietin, histone deacetylase inhibitors and other gene-based strategies.

External Links

Video Showing Ataxic Gait [1]

Glossary

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.

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

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... (ASTM)

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

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.

FRDA - Friedreich's Ataxia.

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

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

Hypertrophy - Increasing in size of a organ or tissue.

Pes cavus - Feet with abnormally high arches.

Pneumonia - Inflammatory condition of the lungs.

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.

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

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

Sepsis - Infection of the blood, generally bacterial.

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