CORRELATION OF SMNT AND SMNC GENE COPY NUMBER WITH AGE-OF-ONSET AND SURVIVAL IN SPINAL MUSCULAR-ATROPHY

Childhood-onset autosomal recessive spinal muscular atrophy (SMA) is a ssociated with absence of the telomeric survival motor neuron gene (SM Nt) in most patients, and deletion of the neuronal apoptosis inhibitor y protein (NAIP) gene in the majority of severely affected patients. A nalysis of SMNt has been complicated by the existence of a centromeric copy, SMNc, which is almost identical to SMNt but which can be distin guished from it by restriction enzyme analysis. In this study 143 SMA patients have been genotyped for the presence or absence of the SMNt, SMNc and NAIP genes, and the data correlated with quantifiable clinica l variables. Although a significant correlation was observed between t he presence or absence of the NAIP gene and the severity of the clinic al phenotype in SMA patients generally, there was no difference in age of onset or survival in type I patients with the NAIP+ or NAIP- genot ype. Fluorimetric PCR analysis of SMNc gene dosage in 57 patients homo zygous for the absence of the SMNt gene but in whom the NAIP gene was present showed a highly significant correlation between SMNc copy numb er and SMA subtype, and between SMNc copy number and both age of onset and length of survival. The data provide strong statistical support f or the emerging consensus that the clinical phenotype in SMA is direct ed primarily by the level of functional SMN protein. The lower SMNc co py number in type I patients in whom the NAIP gene is present suggests that the SMNt gene is removed by deletion in the majority of such pat ients, rather than by gene conversion as is the case in SMA types II a nd III.