Huntington's disease (genetics and pathology)

Question 1

Genetics

Answer 1

Huntington’s disease is an autosomal dominant condition caused by a mutation in the Huntington gene which is located on the short arm of chromosome 4. It is one of several trinucleotide repeat disorders.

The Huntington gene contains a sequence of three bases (CAG), repeated multiple times. Normally CAG is repeated less than 27 times. In Huntington’s the number of repeats is increased, and the number of repeats is related to the severity of the illness and the age at which it presents. The condition shows anticipation meaning that it gets worse with progressive generations.
The CAG length is more unstable when inherited from the father which results in clinical disease 3 years earlier than when inherited from the mother.
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Question 2

Pathology

Answer 2

The symptoms typically begin in the third and fourth decades but with very high numbers of CAG repeats people younger than 20 can be affected (referred to as juvenile Huntington’s disease).

The chief pathological finding is gross bilateral atrophy of the head of the caudate and putamen (hence the chorea), usually associated with a degree of gyral atrophy of the frontal (hence problems with executive function) and temporal regions (so memory impairment).

The EEG of patients with Huntington’s demonstrates a flattened trace.

Macroscopic pathological findings include:-

Frontal atrophy
Marked atrophy of the caudate and putamen
Enlarged ventricles

Micrscopic findings include:-

Neuronal loss and gliosis in the cortex
Neuronal loss in the striatum
Inclusion bodies in the neurons of the cortex and striatum