Huntington's disease genetics

Abstract

Huntington's disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children of HD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. HD is a "trinucleotide repeat" disorder, which is caused by an increase in the number of CAG repeats in the HD gene. Repeats of 40 or larger are associated with disease expression, whereas repeats of 26 and smaller are normal. Intermediate numbers of repeats, between 27 and 35, are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendents. Repeats of 36-39 are associated with reduced penetrance whereby some develop HD and others do not. The identification of the genetic defect in HD permits direct genetic testing for the presence of the gene alteration responsible for the disease. Tests may be performed in three circumstances: (1) confirmation of diagnosis, (2) predictive testing of persons at genetic risk for inheriting HD, and (3) prenatal testing. Testing is widely available and much experience has been gained with protocols that assist the individual in making an informed choice about test options, and minimize the occurrence of adverse emotional outcomes.

FIG. 1.

Huntington’s disease onset ages. The age at onset distribution in Huntington’s disease is very broad and may vary ffrom as young as 3 or 4 years of age to as old as 85. Onset presented here represents initial signs of motor impairment.

FIG. 2.

Normal and expanded HD repeat sizes. The distribution of repeats for Huntington’s disease may be divided into four categories. Repeats of 26 or fewer are normal. Repeats between 27 and 35 are rare and are not associated with the expression of the disease, but occasionally fathers with repeats in this range will transmit a repeat to descendants that is expanded to the range for expression of the illness. Repeats between 36 and 39 are associated with reduced penetrance whereby some individuals will develop HD and others will not. Repeats of 40 or larger are associated with the expression of HD. Persons carrying repeats in this range will develop HD, assuming they do not die of other causes before onset.

FIG. 3.

HD repeat size and onset age. The relationship between the repeat size and the age at onset is presented. Persons with repeats of 60 or larger commonly have very young onset, before the age of 20, and among these large repeats there is a clear relationship between repeat size and onset age. For persons with 55 repeats or fewer, the relationship between repeat size and onset age is much weaker and the repeat size is not predictive of onset age.