Chapter 223

## Abstract

1. Huntington disease (MIM 143100) is a slowly progressive autosomal dominant neurodegenerative disease. Onset is usually in adult life, with a mean of around 40 years. However, onset before age 20 or after age 60 is well described. The disease progresses inexorably, with death occurring approximately 18 years from the time of onset. Prevalence is between 3 and 7 per 100,000 in populations of western European descent, but Huntington disease (HD) has been described in populations of many different ancestries.

2. The neuropathologic hallmark of the disease is neuronal loss and gliosis in the caudate nucleus and the putamen (the striatum), with resulting atrophy. Medium-sized striatal neurons that contain gamma-aminobutyric acid and enkephalin or gamma-aminobutyric acid and substance P as their neurotransmitters are selectively depleted. Other, neurochemically distinct striatal neuronal populations are spared, such as large aspiny acetylcholinesterase-containing neurons or NADPH-diaphorase neurons with somatostatin and neuropeptide Y. Apart from the striatum, the whole brain undergoes generalized atrophy. No specific pathologic changes have been found outside the central nervous system.

3. Clinical manifestations consist of gradually evolving involuntary movements, progressive dementia, and psychiatric disturbances, especially mood disorder and personality changes. Chorea is the most prominent abnormality, but parkinsonism, dystonia, and involuntary motor impairment all may be present. Minor motor abnormalities, including clumsiness, hyperreflexia, and eye movement disturbances, often appear as early manifestations of HD. Patients with onset before age 20 frequently have prominent bradykinesia, rigidity, epilepsy, severe dementia, and a shorter duration of illness. In contrast, cognitive decline is often less severe in patients with onset aftetr age 60.

4. In 1993, a novel gene containing a CAG trinucleotide repeat that is expanded on HD chromosomes was identified. This highly polymorphic CAG repeat located in the 5′ end of the gene has been shown to range between 10 and 29 copies on normal chromosomes, whereas it is expanded to a range of 36 to 121 on HD chromosomes. The vast majority of patients with the clinical diagnosis of HD have expansion of the CAG repeat. Age of onset shows a highly significant association with the length of the CAG repeat.

5. The biochemical defect underlying HD is unknown. Recent data suggest that cells die via apoptotic pathways. Cleavage of huntingtin, the polypeptide product of the HD gene, into a smaller fragment containing the expanded polyglutamine tract appears to be an important step in pathogenesis of the illness. There is no known treatment to retard disease progression. Neuroleptic medication is able to alleviate choreic movements to some extent, but side effects may be severe. Antidepressant therapy may be helpful in the early stages to alleviate the mood disorder.

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