To quote Huntington, the rule has been that “When either or both of the parents have shown manifestations of the disease, one or more of the offspring invariably suffer of the disease, if they live to adult life. 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 disease.” Vessie in a review of 962 patients with Huntington chorea, found only 5 who had descended from unaffected parents. Possibly, in these 5 patients, a parent had the trait, in very mild form, or parentage was in question, because spontaneous mutations are rare.
In university hospital centers, this is a regularly observed type of hereditary nervous system diseases and the main cause of progressive chorea at most ages. Its overall frequency is estimated at 4 to 5 per million, and 30 to 70 per million among whites of northern European ancestry. The usual age of onset is in the fourth and fifth decades, but 3 to 5 percent begin before the 15th year and some even in childhood, where it takes on special form. In approximately 30 percent, symptoms become apparent after 50 years. The progression of the disease is generally slower in older patients for reasons noted below. Once begun, the disease progresses relentlessly, until only a restricted existence is possible and a medical disease terminates life.
Exhaustive genealogic documentation many years ago established the cause to be an autosomal dominant gene with complete penetrance. Koller and Davenport made the observation that young patients usually inherit the disease from their fathers and older patients from their mothers. It has been observed beginning at almost the same age in identical twins.
The first important achievement in respect to the biologic understanding of Huntington disease was the discovery by Gusella and colleagues of a marker linked to what is now termed the huntingtin gene (also termed HTT) and localized to the short arm of chromosome 4. Subsequently, these investigators and others identified the mutation as an excessively long repeat of the trinucleotide CAG within the gene, the length (number) of which determines not only the presence of the disease, but also the age of onset, longer repeat lengths being associated with an earlier appearance of signs. The result of the expansion is the accumulation of abnormal protein also termed huntingtin. At the Huntington gene locus there are normally 11 to 34 (median: 19) consecutive repetitions of the CAG triplet, each coding for glutamine. Individuals with 35 to 39 triplets may eventually manifest the disease but it tends to be late in onset and mild in degree, or limited to the below-mentioned “senile chorea.” Those with more than 42 repeats almost invariably acquire the signs of disease if they live long enough. The rare alternative mutation, termed HDL2 (Huntington disease-like-2), is associated with CATCG repeat expansion of the juntophilin-3 gene, but it is so infrequent that few clinicians will encounter it (Margolis et al).
These discoveries have made possible the development of a genetic test for the measurement of the repeat length that confirms the diagnosis in symptomatic patients and allows screening of asymptomatic individuals. Because there is no treatment for the disease, testing raises certain ethical considerations that must be resolved before its utilization.