This study proposes to investigate neurocognitive development by measuring neuropsychological and genetic profiles of boys diagnosed with Duchenne muscular dystrophy (DMD). DMD provides a unique opportunity to examine gene-cognition relationships. DMD is an X-linked disorder that causes progressive muscular atrophy and varying degrees of cognitive impairment; about 19 percent of boys with DMD are mentally retarded. It remains unclear whether a specific cognitive profile is associated with the disorder, but verbal and immediate memory skills may be selectively impaired. It has been hypothesized that mentally retarded boys with DMD may have mutations that disrupt the DMD gene's brain- dystrophin as well as muscle-dystrophin production; and that some regions of the gene may be necessary, but not sufficient, for normal cognitive development. At present, there are no studies documenting whether deletion positions are related to selective cognitive deficits (perhaps reflecting impaired function of brain areas where dystrophin is missing), or to general IQ. A thorough neuropsychological and genetic evaluation of DMD boys could therefore contribute both to clinical understanding of the disorder and to theoretical understanding of neurocognitive development. Specifically, the studies will determine: 1) what, if any, relationship exists between neuropsychological profile and deletion position; 2) whether cognitive profiles reflect underlying brain function presumed to be involved; and 3) if there is a progressive course to the cognitive impairment. Empirically driven, descriptive analyses of neuropsychological profile, developmental history and deletion position in 100 DMD boys and their unaffected siblings will be completed during the first two years. More finely honed neuropsychological testing in the second half of the grant period will be guided by initial findings. Focused developmental neuroscience hypotheses of presumed gene role on brain structure, and hence function, will be tested in restricted proband and IQ-matched comparison groups. Longitudinal assessment of DMD boys previously assessed on intellectual and muscle function will be continued through the five years.
