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 associated with absence of the telomeric survival motor neuron gene (SMNt) in most patients, and deletion of the neuronal apoptosis inhibitory protein (NAIP) gene in the majority of severely affected patients. Analysis of SMNt has been complicated by the existence of a centromeric copy, SMNc, which is almost identical to SMNt but which can be distinguished 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 clinical variables. Although a significant correlation was observed between the presence or absence of the NAIP gene and the severity of the clinical phenotype in SMA patients generally, there was no difference in age of onset or survival in type I patients with the NAIP+ or NAIP- genotype. Fluorimetric PCR analysis of SMNc gene dosage in 57 patients homozygous for the absence of the SMNt gene but in whom the NAIP gene was present showed a highly significant correlation between SMNc copy number and SMA subtype, and between SMNc copy number and both age of onset and length of survival. The data provide strong statistical support for the emerging consensus that the clinical phenotype in SMA is directed primarily by the level of functional SMN protein. The lower SMNc copy 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 patients, rather than by gene conversion as is the case in SMA types II and III.