2011 Group Project 4

From Embryology
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

Huntington's Disease

Introduction

HD patients.jpg

Huntington’s disease (HD) is an autosomal dominant disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.[1]

HD is characterised by degeneration and dysfunction of the cerebral cortex and striatum causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as chorea.[2][3] HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.[4]

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in alleles with no relation to inheritance.[5]

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.[6]

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.[7]

History

George Huntington

Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in The Medical and Surgical Reporter: A Weekly Journal.[8] Huntington’s disease was initially known as chorea, derived from the Greek word khoreia which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."[4]

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.


TIMELINE OF HUNTINGTON'S DISEASE RESEARCH [9]

Year Milestones
1842 Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." [10]
1846 Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.[10]
1860 Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.[11]
1872 George Huntington’s paper, "On Chorea" was published.[4]
1888 Hoffman describes juvenile Huntington's disease.[12]
1900 Mendel’s work on inheritance patterns of certain traits was rediscovered.[13]
1908 Punnett cites Huntington's disease as autosomal dominant.[14]
1978 Restriction fragment-length polymorphisms (RFLPs) were first described. This was used to locate the gene associated with Huntington's disease in 1983.[15]
1981 The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.[16]
1983 The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.[17]
1989 Linkage disequilibrium between HD gene and the loci D4S95 and D4S98 indicated a 2 Mb candidate region for localisation of HD gene near the loci.[18][19][20]
1993 The HD gene was isolated and a CAG repeat mutation was identified.[21]
1994 The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.[22]
1995 A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.[23]
1996 The first mouse model for Huntington's disease was described.[24]
1997 Aggregates were described in mouse [25] and patient brains with Huntington's disease.[26]
2000 An inducible mouse model of Huntington's disease was described.[27]
2001 The first phase-III clinical trials for Huntington's disease were published.[28]
2001 Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.[29]
2002 The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.[30][31]
2004 A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.[32]
2004 Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.[33][34]
2006 The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.[35]
2009 Gene therapy stalls development of Huntington's disease in mice.[36]

Epidemiology

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.[37] Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela[38] and Northern Ireland.[39] The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.[40].


Country/Region Prevalence of HD (individuals per 100,000)
Venezuela 700 [41]
Tasmania (Australia) 12.1 [42]
Northern Ireland 6.4 [39]
South East Wales (UK) 6.2 [43]
Olmsted County, Minnesota (US) 6 - 6.6 (1960) & 1.8 - 2 (1990) [44]
Valencia Region (Spain) 5.38 [45]
Slovenia 5.16 [46]
Oxford Region (UK) 4.0 [47][48]
New South Wales (Australia) 0.65 [49]
Japan 0.65 [50]
Finland 0.5 [51]
Taiwan 0.42 [52]
Hong Kong 0.37 [53]
Table 1: Prevalence of Huntington's Disease in various parts of the world


Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is. Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.[54] For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. [55]


In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).[56] Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.[57]


HD Halotypes General Population HD Chromosomes
East Asia Europe East Asia Europe
A1 0.00 0.07 0.00 0.50
A2 0.00 0.13 0.00 0.29
B 0.16 0.04 0.10 0.00
C 0.40 0.47 0.77 0.02
Table 2: HTT haplotype frequency in East Asia and Europe [56]


The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.[52] This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.[39] Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

Genetics

Inheritance

Inheritance pattern in Huntington's Disease


Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females. [58]

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected. In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. [59]


Huntingtin Gene

Huntingtin gene on fourth chromosome

Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

HTT & normal functions:

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.[60] The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic reticulum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia). [1]

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

  • HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. [60]
  • It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.
  • Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.
  • A recent study has shown that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. [61]

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).


HTT & Huntington’s Disease:

Comparison between healthy huntingtin gene & huntingtin gene in Huntington's disease

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. [62] In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.[60]

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. [63] CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.[1]

Molecular Mechanisms & Pathogenesis

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.

There are key pathological mechanisms that has been used to explain the pathways by which a mutation
Regions of the brain significant in Huntington's disease
in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the striatum forming the basal ganglia region of the brain.[64] The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. [65]

Destruction of Striatal cells

The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.[62] The striatum is the main target for glutamatergic output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegeneration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions. [66]It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

Key cellular pathogenic mechanisms in Huntington's Disease

Aggregate formation

The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by proteasomes in the cytoplasm for degradation.[60] However proteasome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.[67] Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce apoptosis. The implication of proteasome in HD is further consolidated when proteasome inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of proteases such as caspases and calcium-dependent proteases such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. [68] [60]

Abnormal protein-protein interaction

HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered. HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).[69] In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neurotrophic factor. [70]

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.[71] [62]

Calcium Signalling

The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteasome activity and interfering with calcium signaling. [72]

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.[73] Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome c and apoptosis-inducing factor.[74]

Role in transcription inhibition

The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions. Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.[1] Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).[75] BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.[76]

Clinical Manifestations

Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features.

These are:

  • Chorea movements
  • Heritability; HD is autosomally dominant
  • Physical and behavioural disturbances; unbalanced stance and personality changes
  • Cognitive impairment; causes depression, dementia
  • Death common in 15-20 years after intial onset [77][78]


A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.[6][79] The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.



In the case of HD, symptoms are manifested in three classes:

Classes Effects
Motor it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea
Cognitive a progressive impairment in the brain that leads commonly to dementia
Behaviour/Psychiatric a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease. [5][1]


Motor movement Impairment

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.[5] The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.[80] Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.[81]


Cognitive Disorder

Being noted that HD causes a progressive cognitive decline in impairment, it was previously thought that this only began when or soon before the physical manifestations of HD was apparent. However in recent studies which observed the HD gene carrier patients, it was clear that subtle cognitive impairment was among the earlier forms of manifestations that was present even before the diagnosis of the disease was made, which could be found through neuropsychological testing. [82] [83] By the time of diagnosis, the early signs of cognitive impairment won’t significantly hinder daily activities however individuals who work demanding jobs may find it increasingly difficult and stressful in maintaining sustained periods of concentration. Cognitive impairment is slow in its progression but will gradually increase and become more noticeable over many years, which will ultimately lead to dementia. Dementia in HD patients is classified specifically through the subcortical regions of the brain and is characterised by delay in initiating thought processes, having problems with tasks involving sequence and concentration and executive functions. [84] HD disease patients will have an impairment in episodic memory however in general, as their cortex is relatively well preserved, they will have a fairly good memory.


Behavioural/Psychiatric Disorder

Behavioural changes in HD patients may be one of the most painful manifestations for the patient, family and friends to watch unfold. These changes may be caused by illnesses such as depression, apathy, obsessive-compulsive disorders and irritability.[85][86] Just like the other manifestations of HD, behavioural changes may progressively become worse overtime, however in most cases, HD gene carriers will start to experience behavioural symptom changes before their official diagnosis and is said to be one of the earliest symptoms that arise. [87] [88]

The severity of psychiatric disorders vary greatly between different patients with HD and is seen to have no correlation with dementia or chorea.[85] However in recent studies it was found that those with juvenile-onset cases of HD were found to be psychiatrically more problematic. [89]



Video of Huntington's disease patient

File:HD patient with no treatment.mov

Diagnostic Tests

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.[6] The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.[90] These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).[91] In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.[92] Huntington’s disease can also be diagnosed when a patient is asymptomatic, by genetic testing. This also enables detection of the disease in embryos.

Differential Diagnosis

Neuroacanthocytosis
Disease Characteristics
Huntington’s Disease Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements [90]
Tardive Dyskinesia Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements [93]
Chorea Gravidarum A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs [94]
Hyperthyroid Chorea Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine [95]
Neuroacanthocytosis Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures [96]

Neuropathology

Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)

Anton (1896) and Lannois (1897) were the first to observe neuropathological changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.[97] Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum [98] as well as the amygdala, dorsal striatum and globus pallidus.[99]

Other brain areas greatly affected include the substantia nigra [100] and the centromedial-parafascicular complex of the thalamus.[101] The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.[102]

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.[98]

Imaging

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of computed tomography (CT) scans, magnetic resonance images (MRIs), single-photon emission computed tomography (SPECT) as well as positron emission tomography (PET).[103]

SPECT scanner

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.[90] Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.[99] The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.[104] During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.[105] These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.[106]

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.[99]

MRI of patient with Huntington's disease

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.[107] Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.[103]

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.[108] They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.[109]

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum [110] which shows a strong correlation with verbal fluency, visuospatial skills and perceptual speed and reasoning.[111]







Genetic testing and prenatal diagnosis

Amniocentesis

After the Huntingtin gene’s discovery in 1983 [17], genetic testing first became available using linkage analysis. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.[112]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.[113]. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.[114]

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.[115] Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.[116]

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. Chorionic villus sampling can be carried out between the 10th and 12th week of pregnancy whereas amniocentesis is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.[117]

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.[118]

Treatment

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.[7]

Medications

Tetrabenazine

Chemical structure of Tetrabenazine

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.[119]

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.[120] Its role as a dopamine-depleting agent is achieved by inhibiting the vesicular monoamine transporters (VMAT).

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).[121] Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.[122]

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

Mechanism of tetrabenazine inhibition


Other drugs

Types of symptoms Types of medications Active chemical ingredient Drugs Mechanism of action Possible negative side-effects
Movement disorders Antiseizure drugs

(anticonvulsants)

Valproic acid [123] Depakene Depakote It enhances gamma-aminobutyric acid (GABA)-mediated neurotransmission, which decreases the excitability of neurons and inhibits histone deacetylases.[124] renal toxicity [125][126], hepatoxicity [127], encephalopathy [128]
Lorazepam Ativan It increases the efficiency of GABA and has an inhibitory effect on the activity of the HPA axis. [129] sleepiness [130], withdrawal symptoms [131], memory impairment [132]
Lamotrigine Lamictal It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).[133] chorea [134], toxic epidermal necrolysis [135][136], multiorgan failure [137]
Levetiracetam [138] Keppra It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.[139] somnolence [140], asthenia [141], headache [142]
Clonazepam Klonopin Rivotril Refer to Lorazepam drowsiness [143], disinhibition, sexual dysfunction [144]
Antianxiety drugs Diazepam Valium Antenex Refer to Lorazepam rebound anxiety after withdrawal [145]
Psychiatric disorders Antidepressants Escitalopram Lexapro Lexamil It inhibits serotonin reuptake once released into the synapse, promoting serotonin transmission.[146] insomnia[147], sexual dysfunction [148], suicidal ideation [149]
Fluoxetine Prozac Sarafem Refer to Escitalopram mania [150], akathisia [151], nausea [152]
Sertraline Zoloft Lustral Refer to Escitalopram similar effects to flouxetine and escitalopram [153][154]
Nortriptyline Aventyl Noritren Norepinephrine (noradrenaline) as well as serotonin reuptake is inhibited.[155] suicidal ideation [149], hepatic failure [156], dry mouth
Mirtazapine Remeron Avanza It is associated with the antagonism of central presynaptic α2-adrenergic receptors.[157] dry mouth, increases in appetite [158], akathisia [159]
Antipsychotic drugs Haloperidol Haldol Serenase Its antidopaminergic action inhibits binding of dopamine to dopamine D(2) receptors.[160] acute dystonia, parkinsonism [161], cognitive decline & brain damage [162]
Clozapine Clozaril Zaponex It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.[163] agranulocytosis [164], myocarditis [165], gastrointestinal hypomotility [166]
Mood-stabilizing drugs Lithium Lithobid It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.[167] renal failure [168], nystagmus [169], teratogenicity [170]
Carbamazepine Tegretol Carbatol It potentiates GABA receptors [171] and stabilises voltage-gated sodium channels.[172] congenital malformations [173], pitch perception deficit [174]

Table 3 Symptomatic medications for Huntington's disease

Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.

Disclaimer: The table above is not a comprehensive reference. Please consult your doctor for further information.

Therapies

Psychotherapy: Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.[175]

Speech therapy: HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing Hence, this therapy addresses difficulties with muscles used in eating and swallowing.[176]

Physical Therapy: It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.[176]

Occupational Therapy: This therapy requires the use of assistive devices that improve functional abilities.[176]

  • Handrails at home
  • Assistive devices for activities such as bathing and dressing
  • Eating and drinking utensils adapted for people with limited capabilities

Current/Future Research

Atrophy of the Caudate Heads
Current is needed to help symptoms due to the atrophy
Future research is needed in hope to one day find a cure for this fatal disease


The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s [177] to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community [178]

Cholesterol metabolism in Huntington disease. (2011)

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. [179]


Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. [180]


Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. [181]


Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. [182]


Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.[183]

Related Links

  • Molecular Development - this page gives an explanation of the dominant inheritance nature of HD.
  • Prenatal Diagnosis - this page relates to the ethics and consequences of prenatal testing for Huntington's disease (HD).
  • Amniocentesis - More information about this procedure of prenatal testing for HD can be found here.
  • Chorionic villus sampling - More information about this procedure of prenatal testing for HD can be found here.
  • Computed Tomography - More information about this procedure of prenatal testing for HD can be found here.

Glossary

Agranulocytosis: Failure of the bone marrow to make enough white blood cells (neutrophils).
Akathisia: Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.
Allele: One part of a pair of genes.
Amniocentesis: A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.
Antibody: Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.
Apoptosis:Programmed cell death. Natural process by which the organism discards unwanted or damaged cells.
Asthenia: The lack of strength or energy.
Asymptomatic: Showing no evidence of disease.
Atrophy: A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.
Autosomal dominant: An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.
Catecholamines: "Fight-or-flight" hormones released by the adrenal glands in response to stress.
Cerebral Cortex: Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.
Chorea: A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word khoreia which means dance.
Chorionic villus sampling: A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.
Cognitive: Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.
Computed tomography (CT): A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.
Degeneration: A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.
Dendrite: Projective protoplasmic processes that carry out impulses toward the main organisation of a nerve cell.
Dopamine: A catecholamine neurotransmitter.
Dystonia: A movement disorder which causes involuntary repetitive contractions of muscles.
Encephalopathy: Diseases of the brain.
Endocytosis: Cellular absorption of external substances by the process of phagocytosis or pinocytosis.
Endoplasmic reticulum: Cellular organelle consisting of vesicular and cytoplasmic membranes that are involved in cellular transport.
Episodic memory: Memory in autobiographical events such as time, date, emotions felt in the past etc.
Excitotoxin: class of substances that damage neurons.
Executive function: Umbrella term for cognitive processes which include functions involved with concentration, problem solving, planning, working memory, multi-tasking, initiation of actions and monitoring actions.
Exon: Sequence of amino acids in DNA that codes the information required for cellular protein production.
Gamma-aminobutyric acid (GABA): The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.
Gastrointestinal hypomotility: A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.
Glutamate: A salt of glutamic acid that is involved in neurological signal transmission pathways as a neurotransmitter.
Glutamatergic: Relative to the function of glutamate as a neurotransmitter or its involvement in metabolic pathways.
Haplotype: A group of genes within an organism that was inherited together from a single parent. [6]
Hepatoxicity: Poisoning of the liver.
Histone deacetylases (HDAC): A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.
HPA axis: Hypothalamic-pituitary-adrenal axis.
Hyperkinetic disorder: This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.
Juvenile-onset: Individuals who develop Huntington’s Disease symptoms before the age of 20.
Linkage Analysis: Study aimed at establishing linkage between genes.
Linkage disequilibrium: The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.
Magnetic Resonance Images (MRI): A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.
Mania: A state of abnormally elevated or irritable mood, arousal or energy levels.
Motor impersistence: Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.
Myocarditis: Inflammation of the heart muscle.
Neuronal: A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.
Neuropathological: The pathology of the nervous system.
Neurodegeneration: Selective degeneration of neurons.
Standard definition given to a group of molecules that are involved in neuronal survival and protection.
Norepinephrine (noradrenaline): A catecholamine, which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.
Nystagmus: Involuntary eye movements.
Parkinsonism: A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.
Polymorphisms: The existence of two or more clearly different phenotypes in the same population of a species.
Positron Emission Tomography (PET): A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.
Protease: Enzymes that catalyse the proteolytic breakdown of proteins to smaller proteins or it’s component amino acids.
Proteasome: A group of large proteins located in eukaryotic cells and archae which are involved in protein degradation.
Renal toxicity: Poisoning of the kidney.
Restriction fragment-length polymorphisms (RFLPs): Genetic variations that can be detected by emzymatic digestion.
Serotonin: A monoamine neurotransmitter involved in the transmission of nerve impulses.
Single-photon emission computed tomography (SPECT): A nuclear medicine tomographic imaging technique using gamma rays.
Somnolence: Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.
Striatum: A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.
Subcortical dementia: Impairment in parts of the brain that are beneath the cortex. Usually includes changes in personality and attention span and a delay in initiation process of thinking.
Teratogenicity: The capability of inducing fetal malformations.
Toxic epidermal necrolysis: A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.
Transcription factor: A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.
Vesicular monoamine transporters (VMAT): A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.
Visuospatial: Pertains to perception of the spatial relationships among objects within the field of vision.

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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