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. Hum Mutat 14:256–262, 1999. © 1999 Wiley‐Liss, Inc.

Deletion of exons 11-17 and novel mutations of the galactocerebrosidase gene in adult- and early-onset patients with Krabbe disease

“…G1873A was present in the heterozygous form in the patients and in one parent but not in controls, suggesting its close association with Krabbe disease. However, expression studies have demonstrated the negative effect of Val550Gly but not Ala625Thr on GALC activity [5,6], suggesting that this latter sequence variant is a polymorphism in tight linkage with Val550Gly (also in the patient described in [6] the two-sequence variants are on the same allele) rather than a causative mutation of GLD.…”

“…In particular, the T1637C-Ile546Thr polymorphism which may decrease GALC activity [1], was present in 41 % of GLD alleles and 45 % of 60 control alleles. This suggests that in our patients, differently than in other cases [7], mutations do not occur preferentially in the 1637C allele.…”

“…Other mutations were investigated by single-strand conformation polymorphism (SSCP) and sequencing of abnormal bands [7]. In 8 of 32 alleles, SSCP did not reveal alterations.…”

Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients

“…The R168C (502C→T) substitution associated with a large deletion (502/del) in the GALC gene has been found at high frequency, together with many mutations in LO-GLD in the allele that carries the 1637C (T546) substitution in Cau- (Rafi et al 1995;Luzi et al 1996;Gasperi et al 1996). However, neither R168C (502C→T), nor a large deletion were found in our patients; the T546 substitution was present in only one allele of patient NG (Fig.…”

Evidence of diffuse brain pathology and unspecific genetic characterization in a patient with an atypical form of adult-onset Krabbe disease

“…The patient was found to be heterozygous for two previously reported mutations: G > A at cDNA position 809 (G270D) and 1026del10. The first mutation, G > A at cDNA position 809 (G270D), has been identified previously in other patients with adult-onset KD [3,6,14]. The second mutation, previously identified in another Italian patient with infantile KD [14], consists of a 10 basepair deletion starting in exon 10 at nucleotide 1026.…”