Novel Splice-Site Mutation in SMN1 Associated with a very Severe SMA-I Phenotype

Spinal muscular atrophy (SMA) is a genetic disorder characterized by degeneration of motor neurons and muscle weakness and atrophy. The majority of patients harbor homozygous SMN1 deletions, resulting in an SMN1-null genotype. A variable number of copies of SMN2, the centromeric copy of SMN1, fails to compensate for the absence of SMN1 but can act as a modifier. Less than 5 % of patients with SMA display intragenic mutations on the second allele, detectable by direct sequencing. The effects of these mutations are not easily predictable, hindering a clear correlation with the clinical phenotype. We describe a novel SMN1 mutation that affected the donor splice site of exon 7 and resulted in an unusually severe SMA phenotype with rapid fatal outcome in an Italian infant.