MOLECULAR HETEROGENEITY OF LATE-ONSET FORMS OF GLOBOID-CELL LEUKODYSTROPHY

Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosom al enzyme responsible for the degradation of the myelin glycolipid gal actocerebroside. Although the most common form of the disease is the c lassical infantile form (Krabbe disease), lateronset forms also have b een described, We have analyzed the galactocerebrosidase gene in 17 pa tients (nine families) with late-onset GLD and in 1 patient with class ical Krabbe disease. Half of the patients were heterozygous for the la rge gene deletion associated with the 502C-->T polymorphism, the most common mutation in infantile patients. Several novel mutations that re sult in deficient galactocerebrosidase activity were also identified i n these patients. They include the missense mutations R63H, G95S, M101 L, G268S, Y298C, and I234T; the nonsense mutation S7X; a one-base dele tion (805delG); a mutation that interferes with the splicing of intron 1; and a 34-nt insertion in the RNA, caused by the aberrant splicing of intron 6. All of these genetic defects are clustered in the first 1 0 exons of the galactocerebrosidase gene and therefore affect the 50-k D subunit of the mature enzyme. Studies on the distribution and enzyma tic activity of the polymorphic alleles 1637T/C (I546/T546) provided s upport for previous data that had indicated the existence of two galac tocerebrosidase forms with different catalytic activities in the gener al population. Our data also indicate that the mutations occur prefere ntially in the ''low activity'' 1637C allele.