Dyt1 Dystonia

The most common type of early-onset generalized dystonia is DYT1 dystonia. The DYT1 mutation consists of a

3-bp deletion (GAG) in the DYT1 (TOR1A) gene that encodes the protein, torsinA (1). Symptoms of this disorder typically present before the age of twenty-one with involuntary sustained muscle contractions that cause posturing of a foot, leg, or arm. The contractions frequently, but not invariably, generalize to other body regions. No other neurological abnormalities are usually present, except for postural arm tremor. Disease severity can vary considerably within the same family. Isolated writer's cramp may be the only sign of dystonia in one family member, whereas another relative may exhibit multifocal or generalized dystonia (2). The lifespan of affected individuals is not shortened and no evidence exists of other medical problems that can be attributed to the DYT1 mutation. Rarely does onset of symptoms occur after the age of twenty-eight, suggesting a window of susceptibility during postnatal development.

DYT1 is inherited in an autosomal dominant manner (3). Offspring of a mating between a carrier and noncarrier have a 50% chance of inheriting the disease-causing mutation, but only a 30-40% chance of developing abnormalities that are detected on clinical exam. The lack of phenotypic expression in 60-70% of those who carry the DYT1 mutation is referred to as reduced penetrance. Thus, although the DYT1 mutation is necessary, it is not sufficient to cause disease. Secondary factors (environmental or genetic) must operate in conjunction with the DYT1 mutation. Numerous reports suggest the role of a modifying gene(s) or environmental agent in variable disease expression in individuals who share the same disease mutation. For example, adult and childhood forms of adrenoleukodystrophy can be caused by the same mutations in the X-ALD gene (4) (5). Three families with severe cases of autosomal recessive limb-girdle muscular dystrophy have the same mutation in the g-sarcoglycan gene as a family with much milder symptoms (6). Sex-of-affected-parent may play a role in determining severity of disease in affected offspring, in that maternally transmitted DYT1 dystonia tends toward somewhat later onset and milder expression (7). Environmental factors, specifically childhood infection and peripheral trauma, have been posited as triggers in the expression of DYT1 dysto-nia. One recent, retrospective study identified varicella or mumps infection prior to the age of six years as increasing the risk that a DYT1 carrier will develop dystonia (8). However, this epidemiologic study must be repeated in a larger cohort. In addition, the pathophysiologic mechanism by which a viral infection prior to the age of six years precipitates the expression of dystonia is not clear.

In the few cases examined, no evidence exists of significant neuropathology in DYT1 dystonia. Two recent reports, utilizing different antibodies against torsinA, characterized torsinA expression in the brains of individuals with DYT1 dystonia and control brains. Both reports did not reveal any differences in the pattern of torsinA immunoreactivity with the brains of individuals with DYT1 dystonia (9) (10). However, Rostasy et al. did report a trend toward larger size of nigral dopaminergic neurons in dystonia brains versus normal brains (10).

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