Globoid cell leukodystrophy (Krabbe disease): Normal umbilical cord blood galactocerebrosidase activity and polymorphic mutations

Raghavan, Srinivasa; Zeng, Bai Jin; Torres, Patrícia; Pastores, GM; Kolodny, Edwin H.; Kurtzberg, Joanne; Krivit, William

doi:10.1007/s10545-005-4138-z

Cited by 10 publications

(5 citation statements)

References 8 publications

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“…For example, in children with Krabbe disease (demyelinating LSD) who received UCBCT before symptoms appeared, normal blood galactocerebrosidase levels, central nervous system myelination and continued developmental skill progress were observed. However, it is important to note that children undergoing transplantation after the appearance of the symptoms had minimal neurological improvements [21][22][23][24][25]. Similar results were obtained after UCBCT in patients with metachromatic leukodystrophy (also demyelinating LSD) [26,27].…”

Section: Introductionmentioning

confidence: 57%

Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report

Shaimardanova

Chulpanova

Solovyeva

et al. 2021

Life

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Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder that occurs due to a deficiency of a β hexosaminidase A (HexA) enzyme, resulting in the accumulation of GM2 gangliosides. In this work, we analyzed the effect of umbilical cord blood cell transplantation (UCBCT) and curcumin administration on the course of the disease in a patient with adult TSD. The patient’s serum cytokine profile was determined using multiplex analysis. The level of GM2 gangliosides in plasma was determined using mass spectrometry. The enzymatic activity of HexA in the plasma of the patient was assessed using a fluorescent substrate assay. The HexA α-subunit (HexA) concentration was determined using ELISA. It was shown that both UCBCT and curcumin administration led to a change in the patient’s cytokine profile. The UCBCT resulted in an increase in the concentration of HexA in the patient’s serum and in an improvement in the patient’s neurological status. However, neither UCBCT nor curcumin were able to alter HexA activity and the level of GM2 in patient’s plasma. The data obtained indicate that UCBCT and curcumin administration can alter the immunity of a patient with TSD, reduce the level of inflammatory cytokines and thereby improve the patient’s condition.

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Section: Introductionmentioning

confidence: 57%

Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report

Shaimardanova

Chulpanova

Solovyeva

et al. 2021

Life

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“…However the polymorphism T546 has been reported to be present within the population at allele frequency of 40–45% . Clinical assays for GALC activity in peripheral blood have suggested that the T546 variant has half the activity of the I546 variant, contributing to the highly variable ‘normal’ activity levels within the general population . In order to test the effect of this polymorphism on GALC activity we generated stable expression constructs of each of these polymorphisms and selected high‐yield clones in order to purify milligram quantities of GALC for steady‐state kinetic studies (Figure A and Table S2).…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants

Spratley

Hill

Viuff

et al. 2016

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Krabbe disease is a severe, fatal neurodegenerative disorder caused by defects in the lysosomal enzyme galactocerebrosidase (GALC). The correct targeting of GALC to the lysosome is essential for the degradation of glycosphingolipids including the primary lipid component of myelin. Over 100 different mutations have been identified in GALC that cause Krabbe disease but the mechanisms by which they cause disease remain unclear. We have generated monoclonal antibodies against full‐length human GALC and used these to monitor the trafficking and processing of GALC variants in cell‐based assays and by immunofluorescence microscopy. Striking differences in the secretion, processing and endosomal targeting of GALC variants allows the classification of these into distinct categories. A subset of GALC variants are not secreted by cells, not proteolytically processed, and remain trapped in the ER; these are likely to cause disease due to protein misfolding and should be targeted for pharmacological chaperone therapies. Other GALC variants can be correctly secreted by cells and cause disease due to catalytic defects in the enzyme active site, inappropriate post‐translational modification or a potential inability to bind essential cofactors. The classification of disease pathogenesis presented here provides a molecular framework for appropriate targeting of future Krabbe disease therapies.

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“…The galactosidase can hydrolyze HMU-βGal to produce specific fluorescence products under acidic conditions. The fluorescence value was measured by a F97 series fluorescence spectrophotometer at 365 and 460 nm (12)(13)(14). According to the standard curve and the specific fluorescence value, the activity of GALC enzyme can be calculated.…”

Section: Enzyme Activity Detectionmentioning

confidence: 99%

Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease

et al. 2021

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Background: Krabbe disease, also called globoid cell leukodystrophy, is an autosomal recessive disease caused by a deficiency of lysosomal galactocerebrosidase. Infantile Krabbe occurring before 12 months of age accounts for most cases. Typical clinical features include irritability, seizures, peripheral neuropathy, and progressive neurodegeneration. Methods: We collected and summarized the clinical and genetic data of an 8-month-old boy who demonstrated Krabbe disease onset at around 6 months. Potential pathogenic variants were screened by whole exome sequencing, and effects of candidate variants on alternative transcript and truncated protein were further validated at the RNA and protein level. Results: Galactocerebrosidase activity was nearly absent in his blood, and whole exome sequencing revealed compound heterozygous variants [NM_000153.4: (c.658C>T); (c.328+5G>T)] in galactosylceramidase (GALC). The variant c.328+5G>T was predicted to alter splicing, and the abnormal isoform transcript was validated by observation of abnormal RNA isoforms. The variant c.658C>T was predicted to cause truncation of the protein, which was validated by western blotting. Conclusions: Our findings revealed compound heterozygous variants with solid experimental results for Krabbe disease and provides strong evidence for further Krabbe disease screening and clinical consulting. As a rare inherited systemic disorder, genetic variants in Krabbe disease should be investigated, as experimental validation for clinical diagnosis is needed.

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Globoid cell leukodystrophy (Krabbe disease): Normal umbilical cord blood galactocerebrosidase activity and polymorphic mutations

Cited by 10 publications

References 8 publications

Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report

Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report

Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants

Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease

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