Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder 
caused by the deficiency of galactocerebrosidase, the lysosomal enzyme 
responsible for the degradation of the myelin glycolipid galactocerebroside. 
Although the most common form of the disease is the classical infantile form 
(Krabbe disease), later-onset forms also have been described. We have analyzed 
the galactocerebrosidase gene in 17 patients (nine families) with late-onset GLD 
and in 1 patient with classical Krabbe disease. Half of the patients were 
heterozygous for the large gene deletion associated with the 502C-->T 
polymorphism, the most common mutation in infantile patients. Several novel 
mutations that result in deficient galactocerebrosidase activity were also 
identified in these patients. They include the missense mutations R63H, G95S, 
M101L, G268S, Y298C, and I234T; the nonsense mutation S7X; a one-base deletion 
(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 10 exons of the galactocerebrosidase 
gene and therefore affect the 50-kD subunit of the mature enzyme. Studies on the 
distribution and enzymatic activity of the polymorphic alleles 1637T/C 
(I546/T546) provided support for previous data that had indicated the existence 
of two galactocerebrosidase forms with different catalytic activities in the 
general population. Our data also indicate that the mutations occur 
preferentially in the "low activity" 1637C allele.