Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM ₂ gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM ₂ gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM ₂ gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM ₂ gangliosidosis showed deficiency in hexosaminidase A activity and increased GM ₂ ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly ²⁶⁹ → Ser mutation characteristic for adult GM ₂ gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A- to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.