Huntington Disease

Contributed by: Yasmin Qaseem, Baylor College of Medicine, 1 Baylor Plaza, Houston, Tx 77030
Overview
  • Huntington Disease (HD) is an autosomal dominant neurodegenerative disorder with onset in middle age. It is characterized by atrophy of the basal ganglia's caudate nucleus and manifests with involuntary choreiform movements as well as progressive dementia.
Genetics
  • HD is an autosomal dominant disorder and is the prototype 'trinucleotide repeat' disease, where pathogenesis is due to abnormal expansion of a repeated three nucleotide region of a gene. In the case of HD, the trinucleotide repeat is 'CAG' within the huntingtin gene on chromosome 4. Normal individuals possess fewer than 34 repeats of CAG whereas in those affected, the repeat expands to greater than 40. The cause of the expansion is unknown but may be due to slippage of DNA polymerase. Importantly, in those with greater than 40 repeats, the penetrance of the disease is 100%, meaning development of disease is certain.
Morphology and Pathogenesis
  • Patients with HD show atrophy of the caudate nucleus and putamen of the basal ganglia as well as atrophy of the cerebral cortex. Functionally, there is loss of GABAergic neurons within the extrapyramidal motor system of the brain.
  • How expansion of CAG repeats in the huntingin gene are connected to loss of GABAergic neurons is not well-understood; however, given the autosomal dominant nature of the disease, the expanded huntingtin gene likely acts to disrupt normal cellular processes. This fits with another observed feature of HD known as anticipation, in which successive generations inherit a higher number of trinucleotide repeats and often have more severe or earlier onset disease.
Clinical Consequences
  • Age of onset is usually around 30 to 50 years and patients display an inexorable decline thereafter over the course of one to two decades. The disease initially manifests as a movement disorder with involuntary writhing movements, known as chorea, but in some cases rigidity or spasticity. Over time neuropsychiatric complications develop which include cognitive changes and dementia. Depression is common and suicide is often seen.
Further Reading
  • Davies, S., and D. B. Ramsden. "Huntington's disease." Molecular Pathology 54.6 (2001): 409.
  • Bates, Gillian, Sarah Tabrizi, and Lesley Jones, eds. Huntington's disease. Oxford University Press, 2014.


To cite this article
Qaseem, Y, “Huntington Disease” in Pathway Medicine: An Introduction to Clinical Medicine", PathwayMedicine.org (2015).