Genetics of childhood spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a disease, or group of diseases, of the anterior horn cells of the spinal cord, in which there is widespread atrophy of muscles secondary to anterior horn cell degenera- tion. Though the characteristic neuronal degeneration can be determined directly only by necropsy, the secondary changes in the skeletal muscle de- tectable by electromyography and muscle biopsy are so specific that the diagnosis poses no serious problem. However, the classification and genetics of SMA are still under discussion (Research Group on Neuromuscular Diseases, 1968; Zellweger et al, 1969). Though most authors agree that all SMA is genetically determined, it is not yet clear whether it is a single entity, in which action of the same mu- tant gene or gene pair against a variety of genetic backgrounds produces the variability observed in onset age, clinical course, and life span, or whether there is genetic heterogeneity (several diseases with similar or overlapping phenotypes, determined by different mutant genes). In particular, doubt re- mains as to whether the two main forms presenting in childhood, the infantile Werdnig-Hoffmann form (Werdnig, 1891; Hoffmann, 1892) and the juvenile, clinically milder Kugelberg-Welander form (Kugelberg and Welander, 1956), represent different expressions of the same mutant gene or are genetically distinct. The question as to whether all cases are autosomal recessive or whether some are autosomal dominant with reduced penetrance, or even nongenetic phenocopies, is also unresolved.