MOLECULAR DEFECTS IN KRABBE DISEASE

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripher al nervous systems due to an enzymatic defect of the galactocerebrosid ase. In this study, molecular defects in Krabbe disease were investiga ted in 11 patients (seven Japanese and four non-Japanese) using cultur ed skin fibroblasts. A Japanese late infantile patient had a missense mutation of Pro at codon 302 to Ala and a non-Japanese patient had a m issense mutation of Val at codon 550 to Gly. The reduced enzymatic act ivities expressed from the cDNAs with these missense mutations and fro m the previously reported nonsense mutation (E369X, Glu at codon 369 t o stop codon) were confirmed. Genomic DNA analyses revealed that the P 302A and E369X mutations were heterozygous and the V550G mutation was homozygous in these patients. A 12 base deletion with a 3 base inserti on was found in three unrelated Japanese infantile patients, but not i n 30 controls. The mutation was homozygous in two patients and heteroz ygous in one patient. We could not find any confirmed mutation in the coding region in the other six patients. These findings suggest that m utations in infantile and late infantile patients are relatively heter ogeneous.