Genetic analysis of a family with metachromatic leukodystrophy

Abstract

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disease caused by a deficiency of the enzyme arylsulfatase A (ARSA), which is encoded by the ARSA gene. Mutations discovered in the ARSA gene continuously improve our knowledge and understanding of this rare disease. We identified a Chinese family with 15 members. Two of them were diagnosed as MLD. We used Sanger sequencing to analyze eight exons of the ARSA gene and measured the ARSA activity in leukocyte or amniotic cells with p-nitrocatechol sulfate as the substrate. The potential pathological functions of these variants were predicted through SIFT, Polyphen2, and Mutation Taster. Two family members with a diagnosis of MLD were a two-year-old boy and a fetus. Both had a complex heterozygous mutation: c.413C > T (p.Pro138Leu) in exon 2 and c.1344dupC (p.G449fs) in exon 8. This complex heterozygous mutation is the first case of concurrent missense and code shift mutations reported in MLD in China. In these two family members, ARSA activity (20 nmol/17 h/mg protein and 9.8 nmol/17 h/mg protein) is only 10% compared to the normal population.