Molecular defects in Krabbe disease.

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous systems due to an enzymatic defect of the galactocerebrosidase. In this study, molecular defects in Krabbe disease were investigated in 11 patients (seven Japanese and four non-Japanese) using cultured 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 missense mutation of Val at codon 550 to Gly. The reduced enzymatic activities expressed from the cDNAs with these missense mutations and from the previously reported nonsense mutation (E369X, Glu at codon 369 to stop codon) were confirmed. Genomic DNA analyses revealed that the P302A and E369X mutations were heterozygous and the V550G mutation was homozygous in these patients. A 12 base deletion with a 3 base insertion was found in three unrelated Japanese infantile patients, but not in 30 controls. The mutation was homozygous in two patients and heterozygous in one patient. We could not find any confirmed mutation in the coding region in the other six patients. These findings suggest that mutations in infantile and late infantile patients are relatively heterogeneous.