Huntington’s disease (HD) was described graphically, lucidly, and succinctly by George Huntington in 1872. Despite almost 150 years of research since his incisive description of its major clinical features, it remains, in his words, “one of the uncurables”. Huntington’s disease is a devastating, progressive neurodegenerative disease characterized by a constellation of motor, psychiatric, and cognitive dysfunctions. Huntington’s disease is an autosomal dominant inherited disorder with a typical onset in midlife. Median age of onset is 40 years, and onset before 20 or after 65 is rare. There are approximately 30,000 cases of HD in the US and Canada, with 150,000 more at-risk individuals. Death usually occurs within 15-20 years post-diagnosis. While psychiatric and cognitive dysfunctions often appear earlier than the onset of motor symptoms, diagnosis is not made until the appearance of motor disturbances. The typical midlife onset results in a significant loss of productivity and, when combined with the slow progressive nature of the disease, generally means a high cost of care which affects the patient and the entire family. Additionally, the dominant inheritance of the disease affects multiple generations and tends to pull the family down the social scale. These factors combined cause HD to have an impact disproportionate to its prevalence
Huntington’s disease is classically a striatal atrophy disorder and is characterized by significant dysfunction and degeneration of both the caudate and putamen. While striatal atrophy is a hallmark, careful analysis has revealed a much more widespread atrophy. Post-mortem analysis of HD patients show 21-29% loss of cerebral cortex, 29-34% loss of telencephalic white matter, 64% loss of putamen, and 57% loss of caudate as compared to age-matched individuals. The pattern of degeneration, most highly involving the striatum with a diffuse loss of cerebral white matter, is consistent with symptom development. Degeneration within the striatum typically progresses in caudal to rostral and dorsal to ventral gradients. Of the cellular populations present in the striatum, the medium spiny neurons (MSNs) are the earliest and most severely affected. Selective degeneration among the MSNs also correlates well with typical motor symptom onset. Subpopulations of MSNs have been identified and categorized based on their projections, the neuropeptides they express, and their neurotransmitter receptors. MSNs which project to the external segment of the globus pallidus (GPe) and express enkephalins, dopamine D2 receptors, and adenosine A2a receptors, are the earliest to be lost in the disease course of HD. In contrast, MSNs that project to the internal segment of the globus pallidus (GPi) and express substance P and dopamine D1 receptors tend to be spared until later in the disease course. In correlation with the presentation of HD symptoms, degeneration of striato-GPe MSNs leads to inhibition of the substantia nigra, which is associated with chorea. For many patients, as the disease progresses, symptoms transition to dystonia and bradykinesia which is characteristic of the loss of striato-GPi MSNs. Because of the highly specific pattern of degeneration observed in HD patients, it was believed that the discovery of the genetic cause would explain this pattern of neurodegeneration.
While the hereditary nature of HD was described by Huntington in 1872, it took over 100 years, vast improvements in positional cloning techniques, many dedicated research teams, and countless research hours to discover the genetic cause. HD is caused by a CAG repeat expansion in exon 1 of the huntingtin (HTT) gene on chromosome 4. HTT codes for huntingtin (htt), a large 350 kDa protein found in all metazoans, with the highest conservation among vertebrates. Structural studies suggest that htt forms an elongated superhelical solenoid structure that has several diverse cellular functions. The CAG repeat codes for a poly-Q tract expressed near the N-terminus of the protein. A repeat length of greater than 40 glutamines has a 100% penetrance, whereas 6-26 repeats are considered normal, and 36-39 cause incomplete penetrance. While repeat lengths of 27-35 usually do not cause HD, it is important to note that alleles with 27 repeats or higher are unstable and prone to expansion in subsequent generations, an inheritance pattern known as genetic anticipation. The htt protein is ubiquitously expressed throughout the body, with the highest levels in brain and testes, and throughout the central nervous system without significant regional differences in virtually all neurons and glial cells. While the discovery of the gene which causes HD in 1993 has led to an explosion of important findings and potential therapeutic targets, the ex
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