Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002986 (Fabry)
 5,646 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fabry's disease is a rare, X-linked disorder of the glycosphingolipid metabolism, in which a partial or total deficiency of a lysosomal alpha(alpha)-galactosidase results in the progressive accumulation of neutral glycosphingolipids with terminal alpha galactose moieties (i.e., cerebroside di- and trihexoside) in most body fluids and tissues. Accumulation of neutral glycosphingolipids occurs within the lysosomes of endothelial, perithelial, and smooth muscle cells of the myocardial and renal systems; to a lesser extent in reticuloendothelial and connective cells of the cornea; and in ganglion and perineural cells of the autonomic nervous system. In Korea, 7 cases of Fabry's disease have been reported. A 29-year-old man with fever and headache had typical skin findings and a family history of Fabry's disease, and it was confirmed through renal biopsy and enzyme assay for alpha-galactosidase. We report a case of Fabry's disease with a review of the literatures reported in Korea.
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PMID:Fabry's disease--a case report and review of literatures reported in Korea. 952 88

Fabry disease is an X-linked inborn error of sphingolipid catabolism resulting from deficient enzyme activity of alpha-galactosidase A. The molecular defects of human alpha-galactosidase A gene causing Fabry disease have been characterized, including gene rearrangement and point mutations, which show the genetic heterogeneity in Fabry disease. To characterize the molecular defects of these patients, each exon of alpha-galactosidase A gene including intron-exon junctions were PCR amplified using biotin-labelled primer and sequenced using magnetic beads solid-phase sequencing. A G to C transversion was identified in the last nucleotide of exon 1 in two unrelated Chinese patients. This mutation obliterates an EcoN1 restriction site. Family studies show close linkage with the affected family members. Screening of 100 alleles (22 males, 39 females) of unrelated normal Chinese can not find this mutation. This mutation not only changes the amino acid from serine to threonine, but also likely cause splicing defects. To our knowledge, this is the first report of mutation in Chinese patients with Fabry disease, and a novel mutation causing Fabry disease not reported in literature previously.
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PMID:Identification of a novel point mutation (S65T) in alpha-galactosidase A gene in Chinese patients with Fabry disease. Mutations in brief no. 169. Online. 955 50

Two male relatives with Fabry disease presented striking differences in clinical symptoms and age of onset. The propositus had retarded statural growth and skeletal dysplasia while his nephew suffered mainly from aggravating acroparesthesia and celiac disease. Fabry disease is an X-linked inborn error of glycosphingolipid metabolism resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A) enzyme. The alpha-Gal A gene is located at Xq22.1. Efforts to establish genotype-phenotype correlations have been limited because most patients have private mutations. In previous clinical studies performed in families with Fabry disease, marked differences in phenotype are described between affected relatives. This family also demonstrates the difficulty in predicting the clinical phenotype in patients and relatives with the same alpha-Gal A mutation. Furthermore, in the absence of a family history, the diagnosis may be easily missed.
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PMID:Different phenotypic expression in relatives with fabry disease caused by a W226X mutation. 1006 17

Fabry disease (FD) (angiokeratoma corporis diffusum) is an X-linked inborn error of glycosphingolipid metabolism caused by defects in the lysosomal alpha-galactosidase A gene (GLA). The enzymatic defect leads to the systemic accumulation of neutral glycosphingolipids with terminal alpha-galactosyl moieties. Clinically, affected hemizygous males have angiokeratoma, severe acroparesthesia, renal failure, and vasculopathy of the heart and brain. While demonstration of alpha-galactosidase deficiency in leukocytes is diagnostic in affected males, enzymatic detection of female carriers is often inconclusive, due to random X-chromosomal inactivation, underlining the need of molecular investigations for accurate genetic counseling. By use of chemical cleavage of mismatches adapted to fluorescence-based detection systems, we have characterized the mutations underlying alpha-Gal A deficiency in 16 individuals from six unrelated families with FD. The mutational spectrum included five missense mutations (C202W, C223G, N224D, R301Q, and Q327K) and one splice-site mutation [IVS3 G(-1) --> C]. Studies at the mRNA level showed that the latter led to altered pre-mRNA splicing with consequent alteration of the mRNA translational reading frame and generation of a premature termination codon of translation. By use of this strategy, carrier status was accurately assessed in all seven at-risk females tested, whereas enzymatic dosages failed to diagnose or exclude heterozygosity.
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PMID:Fabry disease: identification of novel alpha-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches. 1020 48

Fabry disease is an X-linked metabolic disorder caused by a deficiency of alpha-galactosidase A (alpha-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with alpha-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated alpha-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of alpha-Gal A -/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of alpha-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.
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PMID:Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice. 1033 3

Fabry disease is a recessive, X-linked disorder caused by a deficiency of the lysosomal hydrolase alpha-galactosidase A. Deficiency of this enzyme results in progressive deposition of the glycosphingolipid globotriaosylceramide (GL-3) in the vascular lysosomes, with resultant distension of the organelle. The demonstration of a secretory pathway for lysosomal enzymes and their subsequent recapture by distant cells through the mannose 6-phosphate receptor pathway has provided a rationale for somatic gene therapy of lysosomal storage disorders. Toward this end, recombinant adenoviral vectors encoding human alpha-galactosidase A (Ad2/CEHalpha-Gal, Ad2/CMVHIalpha-Gal) were constructed and injected intravenously into Fabry knockout mice. Administration of Ad2/CEHalpha-Gal to the Fabry mice resulted in an elevation of alpha-galactosidase A activity in all tissues, including the liver, lung, kidney, heart, spleen, and muscle, to levels above those observed in normal animals. However, enzymatic expression declined rapidly such that by 12 weeks, only 10% of the activity observed on day 3 remained. Alpha-galactosidase A detected in the plasma of injected animals was in a form that was internalized by Fabry fibroblasts grown in culture. Such internalization occurred via the mannose 6-phosphate receptors. Importantly, concomitant with the increase in enzyme activity was a significant reduction in GL-3 content in all tissues to near normal levels for up to 6 months posttreatment. However, as expression of alpha-galactosidase A declined, low levels of GL-3 reaccumulated in some of the tissues at 6 months. For protracted treatment, we showed that readministration of recombinant adenovirus vectors could be facilitated by transient immunosuppression using a monoclonal antibody against CD40 ligand (MR1). Together, these data demonstrate that the defects in alpha-galactosidase A activity and lysosomal storage of GL-3 in Fabry mice can be corrected by adenovirus-mediated gene transfer. This suggests that gene replacement therapy represents a viable approach for the treatment of Fabry disease and potentially other lysosomal storage disorders.
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PMID:Correction of enzymatic and lysosomal storage defects in Fabry mice by adenovirus-mediated gene transfer. 1042 12

Fabry disease is an X-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. The mutations responsible for Fabry disease are diverse and include large rearrangements as well as single base substitutions, and they are dispersed throughout the seven exons of the gene. In this study, we found five novel mutations in four different exons. We have detected the mutations by the PCR-SSCP method and then analysed them by direct sequencing. Three of the novel mutations were deletions: 1205delA, 1238del26 and 5236del18. We also found one novel nonsense mutation: W162X. The final novel mutation was an insertion combined with a deletion: 10995ins24del4.
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PMID:Five novel mutations in fourteen patients with Fabry Disease. 1064 4

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from a deficiency of lysosomal alpha-galactosidase activity. Globotriaosylceramide accumulates predominantly in lysosomes of various tissues. Former studies have clarified the nature of this disease, and the accumulated materials in the lysosomes have been analyzed using biochemical techniques. In the present study, transmission electron microscopy was used to reveal the fine structure of these lysosomal deposits, and sugar residues in the lysosomal deposits in Fabry disease were examined by lectin histochemistry combined with enzyme digestion. This is the first report to describe the lysosomal sugar residues in Fabry disease analyzed using lectin histochemistry at the ultrastructural level. With these techniques, we were able to detect alpha-galactosyl, beta-galactosyl and glucosyl sugar residues in the lysosomal deposits. The experimental procedures used in this study have considerable potential for use in investigations of glycolipid and glycoprotein storage diseases without the need for complex methodology and expensive materials.
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PMID:Fabry disease: ultrastructural lectin histochemical analyses of lysosomal deposits. 1066 60

In Fabry disease, an X-linked alpha-galactosidase A deficiency, painful crises and limb paresthesias are possibly linked to thermal exposure. Small nerve fiber function has not yet been tested after cold challenge. In two Fabry patients (15 and 17 years old), their heterozygote mother, their healthy sister, and eight controls, we determined warm and cold perception thresholds at the dorsal foot and the lower medial calf (method of limits, Somedic-Thermotest), before and 1, 5, 10 and 15 min after 30 s immersion of one leg into 5 degrees C water. Discomfort was rated from 0 to 10. At baseline, thermal thresholds of all participants were normal. In contrast to controls, the patients tolerated 30 s cold stimulation only with interruptions. The mother aborted stimulation after 6 s because of pain. The patients and their mother reported intense burning pain and numbness during and after stimulation. After cold exposure, thermal sensation was highly abnormal for 20 min in one and 80 min in the other brother. In controls, thermal thresholds were somewhat elevated after stimulation but normalized within 10.0+/-4.6 min. Discomfort during cold exposure was rated 8-10 by the patients and their mother, but 3-5 by the healthy persons. We assume that glycolipid accumulation in cutaneous and vasa nervorum vessels as well as small nerve axons accounts for skin and small fiber malperfusion during cold induced vasoconstriction. Transitory ischemia initiated burning pain and prolonged small fiber dysfunction.
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PMID:Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients. 1066 42

Fabry disease is an X-linked inherited metabolic disorder caused by a deficiency of alpha-galactosidase (alpha-gal), resulting in the accumulation of ceramide trihexoside (CTH) in body fluids and in many organs and tissues. We constructed a recombinant adenovirus with a human alpha-gal cDNA (AxCAG alpha-gal), and transfected this vector to skin fibroblasts from Fabry patients. Transfected cells expressed high amounts of alpha-gal in their cytoplasm, and a high level of alpha-gal activity was detected in the medium. The accumulated CTH in the fibroblasts disappeared 3 days after infection. The secreted alpha-gal also eliminated the accumulated CTH from uninfected patient's cells. The enzyme may be taken up through mannose-6-phosphate receptors, as the addition of mannose-6-phosphate to the medium completely inhibited the uptake of the enzyme. The infected cells continued to express alpha-gal for more than 10 days. These results suggest that AxCAG alpha-gal could be used as enzyme replacement gene therapy for Fabry disease.
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PMID:Enzymatic corrections for cells derived from Fabry disease patients by a recombinant adenovirus vector. 1069 55


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