Dr Bishay is Professor of Anatomy and Physiology in the Department of Biology at North Park University, Chicago, IL, and Professor of Advanced Pharmacology in the School of Nursing at North Park University.
Huntington disease is an autosomal dominant neurological disorder characterized by neuron degeneration that results in progressive motor abnormality such as chorea, a decline in intellectual functions, and psychiatric conditions such as depression. Symptoms typically appear in the third to fifth decades.1 Thus, genetic determination becomes a preoccupation for many because of the consequences of knowing whether they will develop the disease later in life.
Previously, it was difficult to determine the pedigree of Huntington disease because of the late onset of symptoms and the need for a large number of individuals for the investigation. The diagnosis depended on enzymatic markers, which could exclude Huntington disease in 20% of the population.
In 1983, Gusella and colleagues1 discovered a closely related marker on chromosome 4 that could be used to localize the Huntington disease gene. The test, known as “presymptomatic testing,” relied on polymorphic DNA markers. The markers were obtained by recombinant DNA technology through restriction fragments length polymorphism (RFLP). Different-sized fragments on DNA were obtained, whether they encoded a protein or not (anonymous), and those fragments were free from repetition. Anonymous DNA fragments were found on chromosome 4. This marker showed a close linkage to Huntington disease in two separate families from the US and Venzuela; thus, the chromosome was identified despite the small sample size.
Another breakthrough occurred 10 years later. The previous technique required a sample of many family members, but in 1993 a specific mutation was discovered as a “trinucleotide repeat expansion” on the short arm of chromosome 4.2 Then a gene was targeted by cloned exons in that area. Known as IT15, the gene was composed of a trinucleotide repeat of sequence CAG: “A (CAG) repeat longer than the normal range was observed on HD chromosomes from all 75 disease families examined, comprising a variety of ethnic backgrounds and 4~16.3 haplotypes.”3
The trinucleotide repeat with at least 17 alleles in the normal population can range from 11 to 35 CAG sequence copies, but in patients with Huntington disease, the number of repeats increases to a range of 42 to 66 copies. The number shows a correlation with the age of onset: the younger the age, the larger the number of repeats. It was also found that earlier onset (before age 21) stems mainly from paternal gene transmission rather than maternal. Individuals with a larger number of normal repeats have a delayed onset of the disease; such a modifier of the gene may help in the future to counteract the mutation and possibly prevent the disease. The penetrance is full, which means that children of Huntington disease gene carriers have a 50% possibility of inheriting the gene, and those who do will eventually develop the disease.4
The Huntington disease mutation is related to an unstable gene, in a similar pattern to fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy. The tandem nucleotide repeat expansion is believed to code for RNA of a protein called huntingtin, resulting in neuronal cell death. The progressive neurodegeneration in Huntington disease mainly involves the basal ganglia and cerebral cortex.
Age of onset is usually in the 30s or 40s, but it can occur in those as young as 2 to 3 years and as old as 80 years.4 The clinical picture includes motor disturbances in the form of choreiform movements, cognitive impairment, mood disorders, and behavioral changes that are chronic and progressive.
Dr Bishay reports no conflicts of interest concerning the subject matter of this article.
1. Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983;306:234-238.
2. Harper PS, Lim C, Craufurd D. Ten years of presymptomatic testing for Huntington’s disease: the experience of the UK Huntington’s Disease Prediction Consortium. J Med Genet. 2000;37:567-571.
3. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72:971-983.
4. Myers RH. Huntington’s disease genetics. NeuroRx J Am Soc Experimental NeuroTherapeutics. 2004;1:255-262.
5. Brandt J, Quaid KA, Folstein SE, et al. Presymptomatic diagnosis of delayed-onset disease with linked DNA markers. The experience in Huntington’s disease. JAMA. 1989;261:3108-3114.
6. Codori AM, Slavney PR, Young C, et al. Predictors of psychological adjustment to genetic testing for Huntington’s disease. Health Psychol. 1997;16:36-50.
7. Meiser B, Dunn S. Psychological impact of genetic testing for Huntington’s disease: an update of the literature. J Neurol Neurosurgery Psychiatry. 2000;69:574-578.
8. Tibben A. Predictive testing for Huntington’s disease. Brain Res Bull. 2007;72:165-171.