2011 Group Project 4
|Note - This page is an undergraduate science embryology student group project 2011.|
--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.
Huntington’s disease (HD) is an autosomal dominant disease that is established by the mutated huntingtin protein gene. HD is characterized by neuronal degeneration and dysfunction of the cerebral cortex and striatum which may be the cause of its clinical manifestations in jerky, involuntary movements such as chorea  .
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” . 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.".|
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 
1872: George Huntington’s paper was published.
1888: Hoffman describes juvenile HD.
1900: Mendel’s work was rediscovered.
1908: Punnett cites HD as autosomal dominant.
1978: Restriction fragment-length polymorphisms (RFLPs) were first described.
1981: The Venezeula Project was initiated.
1983: The HD gene was mapped to the short arm of chromosome 4.
1993: The HD gene was isolated and a CAG repeat mutation was identified.
1994: The Working Group on HD of the WFN/IHA published guidelines on counseling for predictive testing.
1996: The first mouse model for HD was described.
2000: An inducible mouse model of HD was described.
2001: The first phase-III clinical trials for HD were published.
2002: The first high-throughput screen was published.
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. Two of the most well-known populations in which high prevalence of HD was notably in the state of Zulia, Venezuela and Northern Ireland. The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations..
|Country/Region||Prevalence of HD (individuals per 100,000)|
|Northern Ireland||6.4 |
|South East Wales (UK)||6.2 |
|Olmsted County, Minnesota (US)||6 - 6.6 (1960) & 1.8 - 2 (1990) |
|Valencia Region (Spain)||5.38 |
|Oxford Region (UK)||4.0 |
|New South Wales (Australia)||0.65 |
|Hong Kong||0.37 |
- 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. 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. 
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). 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.
|HD Halotypes||General Population||HD Chromosomes|
|East Asia||Europe||East Asia||Europe|
- Table 2 HTT haplotype frequency in East Asia and Europe 
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. 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. 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.
Pathogenesis and Genetics
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.
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.
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 (Review 2), signifying a role in vesicle transport and cytoskeleton anchoring.
• 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.
HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).
HTT & 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. 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.
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.
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.
Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42 . 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 . These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below) . In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations . Huntington’s disease can also be diagnosed when a patient is asymptomatic, by genetic testing. This also enables detection of the disease in embryos.
|Huntington’s Disease||Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements |
|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 |
|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 |
|Hyperthyroid Chorea||Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine |
|Neuroacanthocytosis||Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures |
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 . 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  as well as the amygdala, dorsal striatum and globus pallidus  . Other brain areas greatly affected include the substantia nigra  and the centromedial-parafascicular complex of the thalamus . 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 .
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 .
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) .
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. Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus . The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs . 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 . These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function. 
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. 
PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.  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. 
Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.  They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients. 
PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum  which shows a strong correlation with verbal fluency, visuospatial skills and perceptual speed and reasoning 
Genetic testing and prenatal diagnosis
After the Huntingtin gene’s discovery in 1983 , 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. 
Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested. . 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. 
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.  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. 
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.
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. 
There is no cure for Huntington's disease. Similar to AIDS, only the symptoms can be treated to slow down the progression of the disease.
- Movement disorders
- Psychiatric disorders
- Speech Therapy
- Physical Therapy
- Occupational Therapy
Quite recently, there are a couple of breakthroughs for the treatment of Huntington's.
- Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients. 
- Using adult neurotrophic factor-secreting stem cells. 
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  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 
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. 
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. 
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. 
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. 
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.
Chorea: a disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word khoreia which means dance.
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.
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.
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
Positron Emission Tomography (PET): a nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.
Single-photon emission computed tomography (SPECT): a nuclear medicine tomographic imaging technique using gamma rays
Visuospatial: pertaining to perception of the spatial relationships among objects within the field of vision.
- Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. 
- Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)
- On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. 
- Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)
- Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.Epidemiology of Huntington’s disease in Slovenia. Acta Neurol Scand.: 2009 PMID:18976322 
- DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.
- C, Landles., & G, P. Bates. (2004). Huntingtin and the molecular pathogenesis of Huntington's disease. EMBO reports, 5, 958-963. doi:10.1038/sj.embor.7400250
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