The Neurobiology of Childhood Spinal Muscular Atrophy

Abstract

Almost to the century after the initial clinical description of childhood spinal muscular atrophy (SMA) (Werdnig, 1891) a new era of investigation into the nature of SMAwas inaugurated when Conrad Gilliam and his group at Columbia University established genetic linkage for this autosomal recessive disorder to chromosome 5q (Brzustowicz et al., 1990). In 6 years the pace of research has accelerated markedly: an extensive international effort to identify the gene is documented in over 50 papers by 240 authors at a dozen centers. One early by-product of this search was the discovery that the SMA-critical region of chromosome 5q is unusually unstable and that this genetic instability is likely responsible for the high incidence and worldwide distribution of SMA (Carpten et al., 1994; Theodosiou et al., 1994; Thompson et al., 1995; Crawford, 1996). By early 1995, the search had narrowed sufficiently for two neighboring but unrelated candidate genes to be proposed for the disorder (Lefebvre et al., 1995; Roy et al., 1995a). The arguments buttressing the candidacy of each of these two genes contrast strong biologic plausibility against high genetic probability. The plausible candidate gene, neuronal apoptosis inhibitory protein (NAIP), has displayed anti-apoptotic function—an activity that matches closely a standing hypothesis that SMA is a disorder of development. The probable candidate gene, survival motor neuron (SMN), is deleted in over 95% of patients with SMA and disabling point mutations have been found in a number of the remaining patients where they were pursued. Investigations into the pathogenesis of SMAare now turning to the cellular biology of NAIP and SMN and to the generation of gene-targeted animal models. Meanwhile, available animal models of motor neuron degeneration raise new questions about the multiple pathways of selective motor neuron vulnerability. New clinical insights and findings also raise some unexpected questions. The current vigor of SMA research stands as an outstanding illustration of how insight frommultiple levels—from epidemiology, clinical trials, and individual patient investigations to pathology, biochemistry, classic genetics, and now molecular genetics and cell biology—contribute to and draw strength from one another.