title: Molecular basis of late-life globoid cell leukodystrophy.
abstract: Globoid cell leukodystrophy is an autosomal recessive inherited disease caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Although the severe, rapidly progressing infantile form is the most common, late-onset forms have been described. We investigated the molecular basis of GALC deficiency in a patient with a late-life mild form of globoid cell leukodystrophy who survived into the eighth decade. Since material suitable for mutation analysis was no longer available from the proband, her GALC genotype was reconstructed by analyzing this gene in her six obligate carrier offspring. One allele contained the mutation 809G>A (G270D) in the 1637C background, 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 sural nerve biopsy. Expression studies indicated that the G537R is a disease-causing mutation, as it resulted in no GALC activity, either alone or together with the A625T. This A625T sequence variant did not affect the enzyme activity, at least when expressed in the 1637T background. The mild clinical phenotype was likely to be associated with the 809G>A, since residual GALC activity, about 17% of the control activity, was detected in the expression studies of this mutation. This mutation has been found in several other patients with late-onset GLD.
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, New York 10016, USA. desgar01@med.nyu.edu
authors.forename: R
authors.initials: R
authors.lastname: De Gasperi
authors.forename: M A
authors.initials: MA
authors.lastname: Gama Sosa
authors.forename: E
authors.initials: E
authors.lastname: Sartorato
authors.forename: S
authors.initials: S
authors.lastname: Battistini
authors.forename: S
authors.initials: S
authors.lastname: Raghavan
authors.forename: E H
authors.initials: EH
authors.lastname: Kolodny
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000818:Animals; D019556:COS Cells; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005698:Galactosylceramidase / Q000235:genetics*; D015870:Gene Expression; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology* / Q000235:genetics; D008214:Lymphocytes; D010375:Pedigree; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013497:Sural Nerve / Q000378:metabolism; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D005698:Galactosylceramidase