Huntington’s disease (HD) is a late-onset neurodegenerative disorder which is



characterized by presence of hyperkinetic motor disturbances, neurological abnormalities and progressive dementia. The prevalence rate of HD in the U.S and Europe is approximately 5 cases per 100,000 individuals (Margolis & Ross, 1276). Though the age of onset of HD can vary from anywhere between childhood to 80 years of age, the disease typically manifests itself between the ages of 35 to 50 years (Margolis & Ross, 1276). HD is a genetic disease with an autosomal dominant mode of inheritance (Meiser & Dunn, 575). Patients with HD vary greatly in the age of onset of the disease and various behavioural and clinical manifestations of the disease. Though the exact genetic defect underlying HD has been identified, its relationship with the clinical manifestations of the disease have yet not been properly determined. This paper aims at reviewing the genetic defect underlying HD and its relationship with the behavior abnormalities produced by the disease.

The gene which undergoes mutation resulting in HD was mapped on the tip

of short arm of chromosome 4 in 1983, by Gusella et al (qtd. in Vuillaume, Vermersch, Destee, Petit & Sablonniere, 758) using recombinant DNA technology. The exact causative mutation in HD was identified in 1993 by ‘The Huntington’s Disease Collaborative Research Group’ (qtd. in Vuillaume, et al, 758) in the first exon of the IT15 gene on chromosome 4(4p16.3). The normal gene is actually a segment of DNA which contains a strip of trinucleotide sequences usually of the type cytosine-adenine-guanine (CAG) at one end and expresses a protein called Huntington protein or huntingtin (htt) (Walker 220). Mutation of this gene results in expansion of these unstable trinucleotide CAG repeat sequences. Everyone has two copies of the normal gene. The patients with HD have mutation in one of these genes. The mutation results in abnormal production of huntingtin (htt). This is so as expansion of CAG trinucleotide repeats in HD results in over expression of glutamine (amino acid represented by CAG), which can aggregate to form polyglutamine chains (Walker 222).

Development of HD depends on number of CAG repeats contained within the copies of

the HD genes. When the number of these CAG repeats is 41 or more, the disease is fully penetrant (i.e. the disease expresses itself completely). Incomplete penetrance is observed in people who have between 36-40 CAG repeats (U.S.-Venezuela Collaborative Research Project & Wexler, 3500). If number of these CAG repeats is 35 or less, the disease does not manifest itself (U.S.-Venezuela Collaborative Research Project & Wexler, 3500). The number of CAG repeats may change as the gene passes from parent to child. Thus the child may show slightly fewer or slightly more repeats compared to the parent. The tendency for a child to inherit the disease is more when the gene is passed to him from father rather than from his mother (Walker, 220).