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.
There seem to be an increased prevalence of Huntington's disease among white people 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 with a prevalence of 6.4 individuals per 100,000. A fairly recent study in Slovenia showed that the prevalence of HD in the country was estimated to be 5.16 individuals per 100,000. The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations. An epidemiologic study in Taiwan showed that the prevalence was 0.42 individuals per 100,000 in 2007. Hong Kong had a reported prevalence of 0.37 per 100,000 while Japan had a prevalence of 0.37 per 100,000 individuals. This indicates the lower prevalence of HD in Asia as compared to that in European populations.
The difference in prevalence of HD between European and East Asian populations is due to HTT haplotypes. It was hypothesised that different HD haplotypes have different mutation rates. 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.
For those areas where there are intermarriages with white people, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in white individuals and the fact the disease is autosomal dominant. 
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
HD is an autosomal dominant disease. It is localised to the 4th chromosome where one gene of its gene pair is not functioning correclty. In unaffected individuals the CAG segemnt is repeated up to 26 times. Howver in HD patients this segment can be repeated from 40-100 times.
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 counselling 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. 
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. They also provide biological, histopathological and cell-to-cell evidence which allow for the basis of finding treatment options as well as allowing us to see the effects of gene modification.
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.
Neuropathological: The pathology of the nervous system
- Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. 
- 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