ADVANCES IN SMA RESEARCH - REVIEW OF GENE DELETIONS

The term spinal muscular atrophy (SMA) is used to encompass a group of inherited disorders in which the striking pathological feature is los s of the cell bodies of alpha motor neurons in the anterior horn cell of the spinal cord and, in some cases, of the bulbar motor nuclei. Alt hough the pathological features of these disorders have been well char acterized, the nature of the primary underlying biochemical abnormalit y remains to be determined. In the 1990s genetic linkage was establish ed for the childhood onset recessive forms of SMA (types I, II and III ) to markers mapping to the chromosomal region 5q11.2-13.3. Physical m aps of the region were then constructed, several candidate genes isola ted and in 1995 deletions in two genes, the survival motor neuron (SMN ) gene and the neuronal apoptosis inhibitory protein (NAIP) gene, were identified in significant numbers of patients. Already the impact of the characterization of these deletions is being seen in clinical prac tice in terms of aiding diagnosis in symptomatic cases and in prenatal diagnosis. As discussed in this review however, several questions rem ain unresolved. It is unclear whether deletions in one or both of thes e genes, or indeed in other, as yet unidentified, genes are important in generating the SMA phenotype. The function of the protein product o f the SMN gene is unknown. The NAIP gene encodes a protein which inhib its apoptosis in a mammalian cell line: is it disruption of this funct ion which is relevant in SMA? What underlies the variation in disease severity evident both between and within families? Resolution of such issues is of crucial importance if the identification of these deleted gene sequences is to lead to the development of rational therapies fo r motor neuron diseases.