INTRO DUCTION

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

HISTORY
George Huntington

Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntingtons disease was first documented with great details by George Huntington in On Chorea, a paper published in The Medical and Surgical Reporter: A Weekly Journal. Huntingtons disease was initially known as chorea, derived from the Greek word khoreia which means dancing in unison. George Huntington described the disease as an heirloom from generations away back in the dim past as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, On Chorea, he described: "Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."

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

EPIDEMIOLOGY
There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.Two of the most well-known populations in which high prevalence of HD is found 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 Venezuela Tasmania (Australia) Northern Ireland South East Wales (UK) Olmsted County, Minnesota (US) Valencia Region (Spain) Slovenia Oxford Region (UK) New South Wales (Australia) Japan Finland Taiwan Hong Kong

Prevalence of HD (individuals per 100,000) 700 12.1 6.4 6.2 6 - 6.6 (1960) & 1.8 - 2 (1990) 5.38 5.16 4.0 0.65 0.65 0.5 0.42 0.37

Prevalence of Huntington's Disease in various parts of the world

The Table 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 2835 CAG repeats in Europeans and the fact the disease is autosomal dominant. In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntingtons disease). Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.

General HD Population Chromosomes HD Halotypes 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 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.