Spinal muscular atrophy—clinical and genetic correlations

Abstract

A clinical and molecular genetic study of nearly 500 patients with proximal spinal muscular atrophy (SMA) was undertaken. On the basis of defined achieved milestones, survival probabilities in type I (never able to sit), type II (able to sit but not to walk) and the probability of being ambulatory in type III (achieved ability to walk) SMA for a total of 445 patients with SMA are given. Specific deletions of the survival motor neuron (SMN) gene were found in 96% type I, 94% type II and 82% type III in a total of 191 patients, while four SMA type IV patients with an age of onset beyond 30 years were not deleted. The SMN gene obviously plays an important role in the pathogenesis of SMA but there is evidence that the SMN gene is not the SMA gene itself. The demonstration of SMN deletions in healthy siblings of affected persons, the high intrafamilial similarity of the clinical course on the background of a broad clinical spectrum of proximal SMA and the demonstration of different mutations causing different clinical manifestations in single pedigrees indicate that additional genetic factors might be relevant. Linkage studies, as well as the analysis of the SMN gene, recognised that SMA variants (with severe arthogryposis or cerebellar or diaphragmatic involvement) are not linked to chromosome 5q markers.