Chapter 34

Huntington's disease (HD) is a neurodegenerative disorder related to a mutation occurring in the coding region of the IT15 gene on chromosome 4. The average age of onset is about 40 years; however, the range is extremely broad, with pediatric and late-life onsets not infrequent. The genetic mutation consists of expansion of a polymorphic trinucleotide (CAG) repeat, near the 5′ end of the gene, that normally ranges from about 17 to 30 copies. Individuals with more than 37 repeats develop HD, with the largest numbers (greater than 60) correlating with juvenile onset of HD. Genetic anticipation occurs such that the affected offspring of males have an increased probability of developing the disease at an earlier age than their fathers. The IT15 gene codes for a protein named huntingtin, which is highly interactive with many other proteins and may have many functions, including new ones conferred by the repeat expansion. In individuals heterozygous for HD, both normal huntingtin and huntingtin containing an expanded polyglutamine tract, transcribed by the CAG expansion, are expressed. The relationship between this abnormal protein and neuropathology and pathogenesis has been studied extensively since the gene was discovered and evidence points to complex contributions from the mutant protein, its proteolytic fragments, and dysfunction of the normal protein in neuronal degeneration and death. The mutation is thus considered to lead to both gain of function and loss of function alterations in cellular biochemistry, which lead progressively to neurodegeneration and cell death. A hallmark of HD is the presence of insoluble aggregates of huntingtin,1 which can occur in neuronal nuclei, cytoplasm, and processes2 and which consists of heterogeneous mixtures of mutant and normal huntingtin and a variety of other proteins. Most evidence suggests that the toxicity of mutant huntingtin resides in its soluble interactions as a holoprotein, as fragments, or as soluble oligomers. While much has been learned, many questions remain, particularly which interactions of mutant huntingtin and which of its forms are most important for pathogenesis. The clinical expression of HD is characteristic, though variable, and consists of progressively disordered movement, behavior, and cognition. The specific symptoms and progression of HD can be related directly to its neuropathology (Fig. 34–1), which is characterized by relatively selective loss of specific neuronal populations in a variety of brain regions. Basal ganglia pathology has been the most thoroughly characterized and has been central to the development of animal models and hypotheses about the circuitry involved in chorea and about potential mechanisms of neuronal death in HD. Pathology in other brain regions has not been studied as extensively but is very widespread and more significant than the customary focus on basal ganglia might suggest and contributes importantly to the clinical phenotype of HD. Outside the brain, molecular and biochemical alterations have been identified; however, their clinical significance is unknown. This review focuses on research occurring in the last 25 years, during which the identification of the causative genetic mutation, the development of many genetic cellular and ...

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