// Huntington’s disease

Huntington’s disease was first described by George Huntington in 1872, and has since been understood to result from an unstable trinucleotide repeat sequence (CAG) on chromosome 4. Huntington’s disease is transmitted in an autosomal dominant pattern with complete penetrance. Damage occurs through neuronal loss in the caudate nucleus and putamen by a mechanism that remains unknown. Recent theories include mitochondrial dysfunction that results in neurotoxicity by the neurotransmitter glutamate. Other leading theories involve proposed abnormalities of protein metabolism and transcriptional dysregulation. The onset of Huntington’s disease typically occurs between the age of 25 and 50 years old. A greater number of trinucleotide repeats is correlated with more severe neuronal loss, earlier age of onset, and lower cognitive performance. A juvenile form of Huntington’s disease also exists, with a greater degree of motor impairment early in the course of the illness and a more rapid rate of disease progression.

Huntington’s disease is characterized by psychiatric symptoms and cognitive impairment followed by pronounced motor abnormalities, including the classic choreoathetoid movements. Psychopathology may include affective disturbance, psychotic phenomena, anxiety, and personality changes. Psychiatric symptoms do not necessarily occur, but when present, are typically evident early in the disease course. Depression is a common feature of Huntington’s disease and patients are at an increased risk of suicide. As the disease progresses, patients may become apathetic or minimize symptoms. Cognitive impairment is consistent across patients with Huntington’s disease, and follows a gradual, deteriorating course. Initial symptoms may include mild memory deficits with subtle difficulty in executive functioning (e.g., organizing, planning, and sequencing). Complex task performance worsens as the disease progresses, as do learning, verbal and visuospatial abilities. Eventually the cognitive symptoms of dementia in Huntington’s may be indistinguishable from AD. As the disease evolves the choreoathetoid movements develop into more dystonic motor abnormalities and bradykinesia. Patients eventually become severely dystonic and bedridden.

As progress is made in understanding the pathophysiology of Huntington’s disease, investigators have begun to develop new therapies, such as glutamate receptor antagonists, for potential use in future clinical trials aimed at slowing disease progression. Associated psychiatric features are treated symptomatically, although controlled trials are needed to assess the efficacy of antidepressants and neuroleptics. Psychotherapy may also play an important supportive role for both the patient and the family.