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Introduction

THE MAJOR DEGENERATIVE DISEASES of the nervous system—Alzheimer, Parkinson, and the triplet repeat diseases (Huntington disease and the spinocerebellar ataxias)—afflict more than six million people in the United States and more than 25 million throughout the world. Although this is a relatively small percentage of the population, these diseases bring a disproportionate amount of suffering and economic hardship, not only to their victims but also to the families and friends of the afflicted.

Most of these disorders strike in mid-life or later. Aging itself may contribute to susceptibility. The first symptoms to appear often involve loss of fine motor control. Huntington disease can first manifest itself in cognitive deficits, and this is certainly the case for Alzheimer disease. Nevertheless, the end result is the same: A period of slow deterioration, usually 10 to 20 years, robs afflicted patients of their abilities and eventually their lives.

The late-onset neurodegenerative diseases can be divided into two categories: inherited and sporadic (ie, of unknown etiology). Alzheimer and Parkinson diseases are predominantly sporadic; nevertheless, inherited forms, which afflict only a small number of patients, have provided some insight into the pathophysiology of these diseases. Huntington disease, the spinocerebellar ataxias, dentatorubropallidoluysian atrophy, and spinobulbar muscular atrophy are inherited, the result of polyglutamine or CAG triplet repeat diseases.

The triplet repeat diseases are notable for being caused by a “dynamic” mutation: The disease proteins contain a CAG repeat tract that codes for glutamine and can undergo expansion during DNA replication. Unfortunately, the longer the CAG tract, the more likely it is to further expand, which accounts for the striking phenomenon of anticipation: Younger generations within a family have longer repeats and develop more severe symptoms at an earlier age than their parents. Identification of the molecular basis of these disorders has facilitated diagnosis and provides hope for eventual treatment.

Huntington Disease Involves Degeneration of the Striatum

Huntington disease usually strikes in early or middle adulthood and affects 5 to 10 people per 100,000. Symptoms include loss of motor control, cognitive impairment, and affective disturbance. Motor problems most commonly manifest first as chorea (involuntary, jerky movement that involves the small joints at first but then gradually affects the legs and trunk, making walking difficult). Fast, fluid movements are replaced by rigidity and bradykinesia (unusually slow movements).

Cognitive impairment—especially difficulty in planning and executing complex functions—may be detected by formal neuropsychological testing even prior to motor dysfunction. Affected individuals may also have disordered sleep and affective disturbances such as depression, irritability, and social withdrawal. About 10% of patients experience hypomania (increased energy), and a smaller percentage experience frank psychosis.

In adult patients, the disease progresses inexorably to death some 17 to 20 years after onset. Juvenile-onset patients suffer a more rapid course and typically develop bradykinesia, dystonia (spasms of the neck, shoulders, and trunk), ...

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