Molecular basis of late-life globoid cell leukodystrophy

Globoid cell leukodystrophy is an autosomal recessive inherited disease cau sed by deficiency of the lysosomal enzyme galactocerebrosidase (GALC), Alth ough the severe, rapidly progressing infantile form is the most common, lat e-onset forms have been described. We investigated the molecular basis of G ALC deficiency in a patient with a late-life mild form of globoid cell leuk odystrophy who survived into the eighth decade. Since material suitable for mutation analysis was no longer available from the proband, her GALC genot ype was reconstructed by analyzing this gene in her six obligate carrier of fspring. One allele contained the mutation 809G>A (G270D) in the 1637C back ground, while the other allele contained three sequence variants: 1609G>A ( G537R), 1873G>A (A625T), and 1650T>A (V550V) in the 1637T background. These mutations were confirmed in the proband's genomic DNA isolated from a sura l nerve biopsy. Expression studies indicated that the G537R is a disease-ca using mutation, as it resulted in no GALC activity, either alone or togethe r with the A625T. This A625T sequence variant did not affect the enzyme act ivity, at least when expressed in the 1637T background. The mild clinical p henotype was likely to be associated with the 809G>A, since residual GALC a ctivity, about 17% of the control activity, was detected in the expression studies of this mutation. This mutation has been found in several other pat ients with late-onset GLD. Hum Mutat 14:256-262, 1999. (C) 1999 Wiley-Liss, Inc.