Segregation analysis of chronic childhood spinal muscular atrophy.

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Abstract
A formal segregation analysis for the disease, chronic childhood spinal muscular atrophy, is presented. (This disease is also known as Kugelberg-Welander disease, arrested Werdnig-Hoffmann disease, and chronic proximal or generalized spinal muscular atrophy.) There were 124 index cases occurring in 115 families. Ascertainment of index patients was by incomplete multiple selection. Three types of segregation analysis were performed: Weinberg Proband, an improved Weinberg Proband with a variance corrected formula for differences both in family size and ascertainment probability, and a bracketing technique assuming the extremes of both single and of truncate selection. All 3 methods gave similar results. The improved Weinberg Proband method with corrections for differences in ascertainment and in family size gave a segregation ratio of 0.18 and a 95% confidence range of 0.11-0.25. The mid-point of the bracketing method assuming extremes of truncate and of single selection was 0.19. The segregation ratio of that group of children with clinical onset before 9 mo. of age was 0.21, which does not differ significantly from the 0.25 predicted on the basis of autosomal recessivity. Evidence is presented to indicate that 25% of index patients may be due to new dominant mutations, or phenocopies, or both, and that these occur particularly among sporadic cases with clinical onset over 2 yr of age. Empirical risk figures for use in genetic counseling are presented, and the literature of the subject is reviewed.

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