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Galactocerebrosidase

About: Galactocerebrosidase is a research topic. Over the lifetime, 130 publications have been published within this topic receiving 4043 citations.


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Journal ArticleDOI
TL;DR: In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared.
Abstract: BACKGROUND: Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS:Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.

279 citations

Journal ArticleDOI
TL;DR: The detection of mutations has greatly improved carrier identification among family members and will permit preimplantation diagnosis for some families, and the molecular characterization of the naturally occurring mouse, dog, and monkey models will permit their use in trials to evaluate different modes of therapy.
Abstract: Galactocerebrosidase (GALC) is a lysosomal β-galactosidase responsible for the hydrolysis of the galactosyl moiety from several galactolipids, including galactosylceramide and psychosine. The deficiency of this enzyme results in the autosomal recessive disorder called Krabbe disease. It is also called globoid cell leukodystrophy (GLD), because of the characteristic storage cells found around cerebral blood vessels in the white matter of affected human patients and animal models. Although most patients present with clinical symptoms before 6 months of age, older patients, including adults, have been diagnosed by their severe deficiency of GALC activity. More than 40 mutations have been identified in patients with all clinical types of GLD. While some mutations clearly result in the infantile type if found homozygous or with another severe mutation, it is difficult to predict the phenotype of novel mutations or when mutations are found in the heterozygous state. A high incidence of polymorphic changes on apparent disease-causing alleles also complicates the interpretation of the effects of mutations. The detection of mutations has greatly improved carrier identification among family members and will permit preimplantation diagnosis for some families. The molecular characterization of the naturally occurring mouse, dog, and monkey models will permit their use in trials to evaluate different modes of therapy. Hum Mutat 10:268–279, 1997. © 1997 Wiley-Liss, Inc.

207 citations

Journal ArticleDOI
TL;DR: It is concluded that the cDNA isolated from a murine testis cDNA library represents a minor species generated by an alternate poly(A) signal and that most of the mRNA has a much longer 3′‐untranslated region.
Abstract: The cDNA for a murine galactocerebrosidase was isolated from a murine testis cDNA library on the basis of its homology with the cDNA for human galactocerebrosidase and a PCR method was used to clone the 5′ end. It has a 2,278-nucleotide sequence including a 2,004-nucleotide open reading frame, which encodes 668 amino acid residues. The identity between the human and murine amino acid sequences was very high, being calculated to be 84%. Sequencing of cDNA from liver of the twitcher mouse revealed a nonsense mutation at codon 339 (TGG TGA). The most abundant mRNA of the murine galactocerebrosidase gave a 3.6-kb band, which was not detected in twitcher mice. This suggests that the cDNA (2,278 bp) we characterized represents a minor species generated by an alternate poly(A) signal and that most of the mRNA has a much longer 3′-untranslated region. Genome analysis revealed that this mutation was homozygous in the twitcher and heterozygous in the carrier but was not present in normal mice. The normal mouse cDNA but not the mutant cDNA of the galactocerebrosidase transfected into COS1 cells gave rise to an increase in enzymatic activity. We concluded that this mutation results in the deficiency of galactocerebrosidase in the twitcher mouse.

186 citations

Journal ArticleDOI
08 Jan 1971-Science
TL;DR: Assays carried out with synthetic, unnatural substrates, such as 4-methylumbelliferyl β-galactoside, do not distinguish patients or heterozygous carriers from normal individuals.
Abstract: The activity of galactocerebroside beta-galactosidase was extremely low in serum, leukocytes, and cultured fibroblasts of patients with Krabbe's disease. Antemortem diagnosis is possible without organ biopsies. The parents of patients showed enzyme activities generally lower than that of normal controls. This finding provides supportive evidence that the deficient activity of galactocerebroside beta-galactosidase is the genetically determined enzymatic defect underlying the disease. Demonstration of this deficiency requires the use of the specific substrate, galactocerebroside. Assays carried out with synthetic, unnatural substrates, such as 4-methylumbelliferyl beta-galactoside, do not distinguish patients or heterozygous carriers from normal individuals.

146 citations

Journal ArticleDOI
TL;DR: Modification of the sequence surrounding the initiation codon to one more favorable for expression, resulted in a 6-fold increase in GALC activity in transfected COS-1 cells.
Abstract: Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. GALC is responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon. We describe the molecular cloning of human GALC cDNA and its expression in COS-1 cells. Degenerate PCR primers, derived from N-terminal amino acid sequence from the 51 kDa band from human brain, were used to amplify cat testes RNA, and the resulting product was used to screen human testes and brain libraries. Two overlapping clones contained the total protein coding region, while additional clones and PCR amplification were needed to obtain the complete 3' end of the cDNA. The 3795 bp obtained include 47 bp 5' to the initiation start site, 2007 bp of open reading frame (coding for 669 amino acids), and 1741 bp of 3' untranslated sequence. Modification of the sequence surrounding the initiation codon to one more favorable for expression, resulted in a 6-fold increase in GALC activity in transfected COS-1 cells. The isolation of this clone will permit investigations into the causes for GALC deficiency in humans and available animal models, development of more accurate tests for patient and carrier identification, and evaluation of methods for effectively treating GALC deficiency, initially using the animal models.

139 citations

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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20214
20207
20192
20182
20171
20169