Analysis of Genetic Abnormality in a Patient with Adult Type Metachromatic Leukodystrophy

To better understand the molecular basis for adult type metachromatic leukodystrophy （MLD）, I have determined a new mutation in the arylsulfatase A （ASA） gene of a patient with adult type MLD. The patient is a 35-year-old female. At the age of 24, slowly progressing dementia appeared and by the age of 30, she became severely demented and required assistance for daily activities. CT scan revealed brain atrophy and white matter low density, and nerve conduction velocities were found to be decreased in both upper and lower extremities. Pronounced reduction in myelinated fibers, thinning of myelin and accumulation of metachromatic materials were observed by sural nerve biopsy ASA activities in cultured skin fibroblasts of the patient were found to be markedly reduced compared with normal subjects. To analyze the genetic abnormality of the patient with adult type MLD, I first elucidated the genomic organizations of the human ASA gene and then compared the nucleotide sequences of exons and splice junctions of the mutant ASA gene with those of a normal control. I have identified a new mutation, G to A transition in exon 2, which results in amino acid substitution of Asp for Gly at codon 99 of the ASA protein. In transient expression study, COS cells transfected with the mutant cDNA carrying G to A transition did not show increase of ASA activity, which confirms the mutation as a cause of adult type MLD