Editor—With a prevalence of 1/6000 live births, spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis.1 2 SMA is characterised by the degeneration of anterior horn cells of the spinal cord, resulting in progressive, symmetrical limb and trunk paralysis associated with muscular atrophy. This condition is clinically heterogeneous and has been subdivided into three types according to age of onset and clinical course3: type I (Werdnig-Hoffmann disease, MIM 253300), type II (intermediate form, MIM 253550), and type III SMA (Kugelberg-Welander disease, MIM 253400). TheSMA locus has been mapped to chromosome 5q11.2-q13.3 within a region characterised by the large inverted duplication of a 500 kb element.4-6 The survival motor neurone (SMN) gene, which lies within this element, is duplicated and both copies are expressed. The telomeric gene (SMN1) has been shown to be deleted or mutated in all three types of SMA.4 SMN1 encodes almost the full length transcript whereas the centromeric copy (SMN2) generates alternatively spliced variants lacking the C-terminal sequence.5 7 TheSMN region contains low copy repeats triggering homologous recombination events. Indeed, approximately 95% of SMA patients lack both SMN1 genes owing to either deletion or gene conversion.4 In SMA patients who lack only one SMN1 gene, allelic intragenic mutations have been identified, confirming the involvement of SMN1 in the pathogenesis of SMA.5 8-10

The heterozygote frequency has been estimated to be 1/40. However, the duplication of the SMA locus makes the detection of SMA carriers in the general population difficult, and this has hampered genetic counselling in affected families. Initial attempts to estimate theSMN copy number were based on the measurement of theSMN1/SMN2ratios,11-13 but the broad variability ofSMN2 copy number hinders reliable …