LysoGb3 quantification facilitates phenotypic categorization of Fabry disease patients: Insights gained by a novel MS/MS method.

Background: Fabry disease (FD) is an X-linked lysosomal storage disease resulting from pathogenic variants in the GLA gene coding α-galactosidase A (AGAL) and cleaving terminal alpha-linked galactose. Globotriaosylceramide (Gb3) is the predominantly accumulated sphingolipid. Gb3, deacylated-Gb3 (lysoGb3), and methylated-Gb3 (metGb3) have been suggested as FD biomarkers.

The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations.

The aim of this retrospective study was to determine the prevalence of lysosomal storage disorders (LSDs) in the Czech Republic. The data on cases diagnosed between 1975 and 2008 were collected and analyzed. The overall prevalence of LSDs in the Czech population (12.

Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified.

Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations.

Prosaposin deficiency (pSap-d) and saposin B deficiency (SapB-d) are both lipid storage disorders caused by mutations in the PSAP gene that codes for the 65-70 kDa prosaposin protein, which is the precursor for four sphingolipid activator proteins, saposins A-D. We report on two new patients with PSAP gene defects; one, with pSap-d, who had a severe neurovisceral dystrophy and died as a neonate, and the other with SapB-d, who presented with a metachromatic leukodystrophy-like disorder but had normal arylsulfatase activity. Screening for urinary sphingolipids was crucial to the diagnosis of both patients, with electrospray ionization tandem mass spectrometry also providing quantification.

Replacement of alpha-galactosidase A in Fabry disease: effect on fibroblast cultures compared with biopsied tissues of treated patients.

The function and intracellular delivery of enzyme therapeutics for Fabry disease were studied in cultured fibroblasts and in the biopsied tissues of two male patients to show diversity of affected cells in response to treatment. In the mutant fibroblasts cultures, the final cellular level of endocytosed recombinant alpha-galactosidases A (agalsidases, Fabrazyme, and Replagal) exceeded, by several fold, the amount in control fibroblasts and led to efficient direct intra-lysosomal hydrolysis of ((3)H)Gb3Cer. In contrast, in the samples from the heart and some other tissues biopsied after several months of enzyme replacement therapy (ERT) with Fabrazyme, only the endothelial cells were free of storage.

Mutations c.459+1G>A and p.P426L in the ARSA gene: prevalence in metachromatic leukodystrophy patients from European countries.

In this multicentre study, we examined the prevalence of two mutations in the arylsulfatase A (ARSA) gene, i.e., c.

Missense mutations as a cause of metachromatic leukodystrophy. Degradation of arylsulfatase A in the endoplasmic reticulum.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by a deficiency of arylsulfatase A (ASA). Biosynthesis studies of ASA with various structure-sensitive monoclonal antibodies reveal that some epitopes of the enzyme form within the first minutes of biosynthesis whereas other epitopes form later, between 10 and 25 min. When we investigated 12 various ASAs, with amino acid substitutions according to the missense mutations found in metachromatic leukodystrophy patients, immunoprecipitation with monoclonal antibodies revealed folding deficits in all 12 mutant ASA enzymes.

Novel mutations associated with metachromatic leukodystrophy: phenotype and expression studies in nine Czech and Slovak patients.

Metachromatic leukodystrophy (MLD) is an inherited demyelinating disorder caused by the deficiency of arylsulphatase A (ASA). This defect leads to an accumulation of galactosylceramide I(3)-sulphates (sulphatides) in lysosomes of different tissues. We report on mutations found in a group of nine patients from the Czech and Slovak Republics (former Czechoslovakia).