Dystrophin in the Nervous System

Duchenne Muscular Dystrophy and Cognitive Function Duchenne/Becker dystrophy (DMD/BMD), in common with many myopathies, affects the nervous system as well as muscle. In the discussion that follows it is assumed that the reader is already familiar with the biology of 427kD dystrophin, the truncated dystrophin isoforms, alternative splice forms, and the dystrophin-associated protein complex as they occur in muscle cells (see articles by Kunkel, Brown and Hoffman). From the earliest reports of Duchenne muscular dystrophy it was noted that in affected boys cognitive function was below normal (29, 30). Modern studies of Duchenne patients have shown that there is mild (mean IQ 85) cognitive deficit that is non-progressive (30). A multitude of subsequent studies have argued against the possibility that the disease is primarily neuropathic or that the mental deficiency is an environmental effect of the musculoskeletal impairment. Comparison with similarly severely affected individuals with other muscular dystrophies or spinal muscular atrophy indicates that the mental deficiency is not secondary to the musculoskeletal handicap (48, 95). Several studies find that verbal IQ is more affected than performance IQ or full scale IQ (12, 66) , but the correlates of these observations are not known at present. A milder degree of cognitive impairment is also associated with Becker dystrophy patients although at the time of the first studies the allelic relationship to Duchenne dystrophy was not recognized (48). The deficit associated with Becker dystrophy has been more difficult to establish since the incidence of Becker dystrophy is only one tenth that of Duchenne dystrophy and only recently have reasonably large cohorts of boys with Becker dystrophy been studied (13, 22). the epistemologically fastidious) that a second independent, immediately adjacent, or even intercalated gene is not likely to be responsible for the cognitive effect (21) but that the cognitive effect results from the same mutation that produces the myopathy. Behavioral studies of the mdx mouse, the most tvidely used model of Duchenne dystrophy, have shown a mild impairment in “learning” as tested in several paradigms (73, 105). The presence of a cognitive dysfunction raises the question of neuropathology, but an examination of a series of brains from patients with DMD failed to find any consistent abnormality (28). A CT study of a small cohort of DMD patients showed mild atrophy and white matter abnormality; both very non-specific findings (110). An intriguing report of mild macrocephaly (not hydrocephalus) in a large group of DMD patients by Gardner-Medwin and colleagues is also of unclear significance ( 3 ) . The absence of overt neuropathology in DMD is not in itself remarkable. Metabolic disorders such as the lysosomal storage diseases, leukodystrophies, and some aminoacidopathies are marked by significant pathology but they produce such a severe progressive cognitive decline they are best thought of as dementias. Trisomy 21 has a profound and less progressive cognitive impairment but has relatively subtle neuropathologic alterations ( 5 3 ) . There are relatively few models of mild non-progressive cognitive impairment bordering on the range of a “learning disability”; “minimal brain dysfunction” is not generally regarded as having well defined neuropathologic correlates. Thus the possibility of understanding the cognitive impairment associated with a molecularly characterized disease such as DMD, is exciting both in terms of the specific disease and more broadly as a model of a mild inherited mental retardation.