Pathology and genetics

The earliest visible neuropathology is in the striosomes of the caudate/putamen,(4) followed by a dorsal-to-ventral progressive loss of almost all striatal output neurones. There can also be milder neuronal loss in some brainstem nuclei and the deep layers of cortex.

The disorder, with a point prevalence of about 6/100 000,(5) is caused by the expansion of an unstable triplet repeat sequence (CAG) in the first exon of a gene near the telomere of chromosome 4p.(6) Normally, this triplet sequence contains from about 7 to 30 repeats; when the number rises above 37, Huntington' disease occurs. The abnormal gene is transcribed and appears to function abnormally, causing a 'gain of function' (see ChapteĀ£.2.4.2). It is transmitted as an autosomal dominant trait; if one parent is affected, each offspring (regardless of sex) has an independent 50 per cent chance of having inherited the abnormal gene. Those who inherit the gene will almost certainly develop Huntington' disease. The mutation rate is low, so that most patients will have an affected parent. However, it can be difficult to obtain an accurate family history. The pathophysiology may be related to the accumulation of fragments of the abnormal huntington protein (called 'huntingtin') in the nucleus of striatal neurones or the protein' abnormal interaction with other proteins. (7)

Like most disorders caused by the expansion of unstable trimeric repeat sequences, the number does not remain stable at meiosis. In Huntington' disease, the number of CAG repeats is more likely to increase when the gene is transmitted by fathers. As the number of repeats increases, the age at onset is earlier. Thus paternal transmission is often associated with 'anticipation', earlier onset in subsequent generations, and most cases with childhood onset have affected fathers. (8)

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