OBJECTIVE: We report the cases of 2 patients with late-onset spinal muscular 
atrophy (SMA) type III, who were hemizygous for SMN1 deletion and carriers of 
novel SMN1 intragenic missense mutations, and we investigate the 
genotype-phenotype relationship.
METHODS: Patients were tested for SMN1 deletions with standard methodology. 
Sequencing of all exons, exon-intron junctions, and flanking sequences of SMN1 
by nested PCR was used to detect intragenic point mutations. SMN1 and SMN2 
quantification was undertaken to investigate the genotype-phenotype 
relationship.
RESULTS: Two novel point mutations were identified in exon 3 of SMN1 
(p.Tyr130Cys and p.Tyr130His) in the highly conserved Tudor domain of the Smn 
protein.
CONCLUSIONS: The genetic basis of SMA in the rare cases of compound heterozygous 
carriers of SMN1 deletions is complex. Small intragenic SMN1 mutations often 
lead to severe SMA phenotypes, especially if the point mutations lie in exon 3 
that codes for the highly conserved Tudor domain of the Smn protein. Although 
both our patients were carriers of intragenic SMN1 mutations in the coding 
region of the Tudor domain, they presented with a mild SMA phenotype despite a 
low SMN2 copy number. We discuss the possible determinant role of these novel 
missense mutations in the phenotypic outcome and compensatory mechanisms that 
may account for the genotype-phenotype discrepancy.