2011 Group Project 4: Difference between revisions

From Embryology
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==History==
==History==


[[Image:George_Huntington.jpg|thumb|right|George Huntington|150px]] 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” <ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref>. 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 HD 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:
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” <ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref>. 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 HD 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:


{| style="border: solid 1px #a0a0ff"
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|- align="center" style="background:#eeeeff"
|"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.".<ref><pubmed>11232352</pubmed></ref>  
|"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.".<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>  
|}
|}


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'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>
'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>


'''1842''': Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
{| style="border: solid 1px #a0a0ff"
 
|- align="center" style="background:#8eb2ec"
'''1846''': Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. HD is observed as being localised.<ref name="OxfordMonographHistory"/>  
|style="width:50px"|'''Year'''
 
|'''Milestones'''
'''1860''': Johan Christian Lund produced the first description of the illness while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.
|-
</ref>
|align="center"|'''1842'''
 
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
'''1872''': George Huntington’s paper was published.<ref><pubmed>11232352</pubmed></ref>
|- style="background:#eeeeff"
 
|align="center"|'''1846'''  
'''1888''': Hoffman describes juvenile HD.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. HD is observed as being localised.<ref name="OxfordMonographHistory"/>
 
|-
'''1900''': Mendel’s work was rediscovered.<ref>On the Origin of Mendelian Genetics  Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|align="center"|'''1860'''  
 
| Johan Christian Lund produced the first description of the illness while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
'''1908''': Punnett cites HD as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
 
|align="center"|'''1872'''  
'''1978''': Restriction fragment-length polymorphisms (RFLPs) were first described.<ref><pubmed>281713</pubmed></ref>
| George Huntington’s paper was published.<ref name="PMID11232352"/>
 
|-
'''1981''': The Venezeula Project was initiated.<ref><pubmed>2881213</pubmed></ref>
|align="center"|'''1888'''  
 
| Hoffman describes juvenile HD.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
'''1983''': The HD gene was mapped to the short arm of chromosome 4.<ref><pubmed>6316146</pubmed></ref>
|- style="background:#eeeeff"
 
|align="center"|'''1900'''
'''1989''': Linkage disequilibrium indicated a 2 Mb candidate region.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>  
| Mendel’s work was rediscovered.<ref>On the Origin of Mendelian Genetics  Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
 
|-
'''1993''': The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|align="center"|'''1908'''  
 
| Punnett cites HD as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
'''1994''': The Working Group on HD of the WFN/IHA published guidelines on counseling for predictive testing.<ref><pubmed>7966192</pubmed></ref>  
|- style="background:#eeeeff"
 
|align="center"|'''1978'''  
'''1996''': The first mouse model for HD was described.<ref><pubmed>9267033</pubmed></ref>
| Restriction fragment-length polymorphisms (RFLPs) were first described.<ref><pubmed>281713</pubmed></ref>
 
|-
'''1997''': Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains.<ref><pubmed>9302293</pubmed></ref>
|align="center"|'''1981'''  
 
| The Venezeula Project was initiated.<ref><pubmed>2881213</pubmed></ref>
'''2000''': An inducible mouse model of HD was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
 
|align="center"|1983
'''2001''': The first phase-III clinical trials for HD were published.<ref><pubmed>11502903</pubmed></ref>
| The HD gene was mapped to the short arm of chromosome 4.<ref><pubmed>6316146</pubmed></ref>
 
|-
'''2002''': The first high-throughput screen was published.<ref><pubmed>12200548</pubmed></ref>
|align="center"|'''1989'''  
| Linkage disequilibrium indicated a 2 Mb candidate region.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''  
| The Working Group on HD of the WFN/IHA published guidelines on counseling for predictive testing.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1996'''
| The first mouse model for HD was described.<ref><pubmed>9267033</pubmed></ref>
|-
|align="center"|'''1997'''  
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains.<ref><pubmed>9302293</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2000'''
| An inducible mouse model of HD was described.<ref><pubmed>10778856</pubmed></ref>
|-
|align="center"|'''2001'''  
| The first phase-III clinical trials for HD were published.<ref><pubmed>11502903</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published.<ref><pubmed>12200548</pubmed></ref>
|}


==Epidemiology==
==Epidemiology==

Revision as of 10:37, 2 October 2011

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

--Mark Hill 14:58, 8 September 2011 (EST) Good sub-heading structure, as I have discussed this will be postnatal rather than prenatal effects, so diagnosis should be covered in some depth. Content in some sections is still very light and not researched. Currently there is not a single figure on the project page.

  • Introduction - brief and to the point. There are some terms that may require clarification (cerebral cortex, striatum, chorea). There is no mention of it belonging to a group of known disease types.
  • History - This is a genetic disease, it probably had "existed" before the seventeenth century, this was when it was described. It appears that there is only a single time point (the discovery) in the history of this disease, fix this please.
  • Epidemiology - "white people as compared to Africans and Asians" is this the correct terminology? The country by country information would look better in the form of a table. "HTT haplotypes" without any explanation. Sub-headings would fix some of the disjointed feel to this section.
  • Pathogenesis and Genetics - same content, with typos. Typos suggest that you (or your group) have not reviewed the work. This is a very poor sub-section.
  • Diagnostic Tests - "the middle ages" as opposed to the medieval period? These "similar diseases, which mimic similar characteristics" need to be better organised to show how they are similar. Neuropathology, is this not a postmortem diagnosis?
  • Clinical Manifestations - no text here.
  • Treatment - a list of bullet points with no accurate descriptions of these treatments. Breakthroughs, is this not Current/Future Research?
  • Current/Future Research - Nothing here of interest nor referenced.


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

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” [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 HD 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.".[9]

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 [10]

Year Milestones
1842 Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." [11]
1846 Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. HD is observed as being localised.[11]
1860 Johan Christian Lund produced the first description of the illness while working at Jefferson Medical College.[12]
1872 George Huntington’s paper was published.[9]
1888 Hoffman describes juvenile HD.[13]
1900 Mendel’s work was rediscovered.[14]
1908 Punnett cites HD as autosomal dominant.[15]
1978 Restriction fragment-length polymorphisms (RFLPs) were first described.[16]
1981 The Venezeula Project was initiated.[17]
1983 The HD gene was mapped to the short arm of chromosome 4.[18]
1989 Linkage disequilibrium indicated a 2 Mb candidate region.[19][20][21]
1993 The HD gene was isolated and a CAG repeat mutation was identified.[22]
1994 The Working Group on HD of the WFN/IHA published guidelines on counseling for predictive testing.[23]
1996 The first mouse model for HD was described.[24]
1997 Aggregates were described in mouse [25] and patient brains.[26]
2000 An inducible mouse model of HD was described.[27]
2001 The first phase-III clinical trials for HD were published.[28]
2002 The first high-throughput screen was published.[29]

Epidemiology

There seem 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.[30] Two of the most well-known populations in which high prevalence of HD was notably in the state of Zulia, Venezuela[31] and Northern Ireland.[32] The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.[33].

Country/Region Prevalence of HD (individuals per 100,000)
Tasmania 12.1 [34]
Northern Ireland 6.4 [35]
South East Wales (UK) 6.2 [36]
Olmsted County, Minnesota (US) 6 - 6.6 (1960) & 1.8 - 2 (1990) [37]
Valencia Region (Spain) 5.38 [38]
Slovenia 5.16 [39]
Oxford Region (UK) 4.0 [40][41]
New South Wales (Australia) 0.65 [42]
Japan 0.65 [43]
Finland 0.5 [44]
Taiwan 0.42 [45]
Hong Kong 0.37 [46]
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.[47] 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 that the disease is autosomal dominant. [48]


In a paper by Warby et al. (2011), it was reported that HTT haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. Haplotypes are sets of single-nucleotide polymorphisms (SNPs) on a single chromosome of a chromosome pair that are statistically associated. Different HD haplotypes have different mutation rates, resulting in expansion of CAG tract (marker for HD).[49] 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 HD halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.[50]

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 [51]


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.[53] 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.jpeg

Huntington's Disease is an autosomal-dominant disorder, meaning that it is not inherited according to sex of the parent, rather the severity of the CAG repeat.

The offspring of one affected and one unaffected parent will have a 50% chance of inheriting HD. In rare cases where both parents are affected the child will have a 100% chance of inheriting the disease. [54]

Huntingtin Gene

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.[55]

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 retiniculum 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).

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. [56]
  • It has been shown to have a significant role in clathrin-mediated 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 study by Bates & Murphy, 2001 showed 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. [57]

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


HTT & Huntington’s Disease:

Healthy Huntingtin protein and Huntingtin gene mutated by 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 (i.e. CAGCAGCAG...). This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. [58] 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.[59]

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. [60] CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers. .[61]

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 unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation 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 basal ganglia forming the striatum region of the brain.[62] The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. [63]

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. [64] The striatum is the main target for glutamatergic output neurons from the thalamus and the cortex, making striatal cells highly sensitive to glutamate. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. [65]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 HD

Abnormal protein-protein interactions

HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, these interactions are altered. HTT is known to react with HTT-associated protein I (HAPI) and HTT-interacting protein (HIPI).[66] In HD, the HTT protein’s interaction with HAPI is increased, and interaction with HIPI is decreased with lengthening polyglutamine chains. An over-expression of HIPI is known to be neurotoxic , therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.[67]

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. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation. [68] HTT is cleaved by a different number of proteases such as caspases and calcium-dependent proteases such as calpain. However proteosome 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.[69]

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 proteosome activity and interfering with Ca2+ signaling. [70]

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. [71] 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; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).[72] BDNF belongs to the neutrophin 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.[73]

Clinical Manifestations

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:

Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender
  • 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 [74] [75]

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 [76] [77]. 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 –

1) motor, it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

2) cognitive, a progressive impairment in the brain that leads commonly to dementia;

3) behaviour/psychiatric, also caused by 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 [78] [79].


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 [80]. The juvenile cases, younger onset of HD individuals may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be manifested rather than chorea [81]. 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 [82].


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 [83]. 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 [84]. These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below) [85]. In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations [86]. 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 [87]
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 [88]
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 [89]
Hyperthyroid Chorea Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine [90]
Neuroacanthocytosis Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures [91]


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 [92]. 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 [93] as well as the amygdala, dorsal striatum and globus pallidus [94] .

Other brain areas greatly affected include the substantia nigra [95] and the centromedial-parafascicular complex of the thalamus [96]. 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 [97].

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) [99].

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.[100] Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus [101]. The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs [102]. 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 [103]. These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function. [104]

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. [105]

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. [106] 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. [107]

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

After the Huntingtin gene’s discovery in 1983 [112], 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. [113]


Amniocentesis

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested. [114]. 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. [115]

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. [116] 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. [117]

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.[118]

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. [119]

Treatment

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.[120]

Medications

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

(anticonvulsants)

Valproic acid [121] Depakene Depakote renal toxicity [122][123], hepatoxicity [124], hemorrhagic pancreatitis, coagulopathies, bone marrow suppression and encephalopathy [125]
Lorazepam Ativan sleepiness [126], withdrawal symptoms [127], memory impairment and confusion [128]
Lamotrigine Lamictal chorea [129], toxic epidermal necrolysis [130][131] and multiorgan failure [132]
Levetiracetam [133] Keppra somnolence, lethargy [134], rhinitis, asthenia [135], headache and dizziness [136]
Tetrabenazine [137] Xenazine drowsiness, depression, nausea, worsening of parkinsonism, xerostomia, hypotension [138]
Clonazepam Klonopin Rivotril drowsiness [139], depression, disinhibition and sexual dysfunction [140]
Antianxiety drugs Diazepam Valium Antenex rebound anxiety after withdrawal [141]
Psychiatric disorders Antidepressants Escitalopram Lexapro Lexamil Lexam insomnia, somnolence, dizziness, sweating, constipation, fatigue [142], sexual dysfunction [143], suicidal ideation [144]
Fluoxetine Prozac Sarafem Fontex mania [145], akathisia [146], asthenia, tremor, nausea [147]
Sertraline Zoloft Lustral similar effects to flouxetine and escitalopram: movement disorders and sexual dysfunction [148][149]
Nortriptyline Aventyl Noritren Sensoval Pamelor suicidal ideation [150], hepatic failure [151], dry mouth, sedation, constipation and increased appetite
Mirtazapine Remeron Avanza Zispin dry mouth, sedation, and increases in appetite and body weight [152], restless legs syndrome (RLS) [153]
Antipsychotic drugs Haloperidol Haldol Serenase Linton acute dystonia, akathisia, parkinsonism [154], cognitive decline & brain damage [155]
Clozapine Clozaril Clopine Zaponex agranulocytosis [156], myocarditis [157], gastrointestinal hypomotility [158]
Mood-stabilizing drugs Lithium Lithobid renal failure [159], nystagmus [160], teratogenicity [161]
Carbamazepine Tegretol Carbatol Sirtal congenital malformations [162], pitch perception deficit [163]

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.

Tetrabenazine

Chemical structure of Tetrabenazine

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.[164]

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).[165] 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.[166] 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

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.[167]

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.

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.

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.

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

  • 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

HD future research.jpg

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 [168] 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 [169]


Atrophy of the Caudate Heads
Atrophy in Huntington's disease
Seen in a 50yr old man with movement disorder


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. [170]


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. [171]


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. [172]


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. [173]


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.[174]


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

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.

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.

Coagulopathies: a disease or condition affecting the blood's ability to coagulate.

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.

Dopamine: A catecholamine neurotransmitter

Dystonia: A movement disorder which causes involuntary repetitive contractions of muscles.

Encephalopathy: diseases of the brain.

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.

Haplotypes: Sets of single-nucleotide polymorphisms (SNPs) on a single chromosome of a chromosome pair that are statistically associated.

Hemorrhagic pancreatitis: Inflammation of the pancreas accompanied by the formation of necrotic areas on the surface of the pancreas and in the omentum and, frequently, also accompanied by hemorrhages into the substance of the gland.

Hepatoxicity: Poisoning of the liver.

Hypotension: Low blood pressure.

Hyperkinetic disorder: characterised by excessive abnormal involuntary movements. Movements may be regular, irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

Linkage Analysis: Study aimed at establishing linkage between genes

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.

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.

Renal toxicity: Poisoning of the kidney.

Rhinitis: Irritation and inflammation of some internal areas of the nose, resulting in ‘stuffy nose’.

Single-photon emission computed tomography (SPECT): a nuclear medicine tomographic[1] 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.

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.

Visuospatial: pertaining to perception of the spatial relationships among objects within the field of vision.

Xerostomia: Dry mouth resulting from reduced or absent saliva flow.

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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