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)

We describe two female monozygotic (MZ) twins heterozygous for Fabry disease, an X linked disorder resulting from the deficient activity of alpha-galactosidase A. While one of the twins was clinically affected, the other was asymptomatic. Enzymatic assay of alpha-galactosidase in blood leucocytes, skin fibroblasts, Epstein-Barr virus transformed lymphoid cell lines, and hair follicles of the twins and their parents confirmed the heterozygous status of the twins and indicated that Fabry disease had occurred as a result of a de novo mutation. The son of the unaffected twin sister was shown to be hemizygous. Molecular analysis of the alpha-galactosidase A gene permitted the identification of an as yet undescribed point mutation at position 10182 of exon 5 which causes an Asp to Asn substitution at codon 231. Single strand conformation polymorphism (SSCP) analysis again showed the heterozygous status of the twins and a normal pattern in their parents. The basis for the discordant expression of this d novo mutation in the twins was investigated by studying their X inactivation status. Analysis of the inactive X specific methylation at the androgen receptor gene showed unbalanced inactivation in the twins' fibroblasts and in opposite directions. While the maternally derived X chromosome was preferentially active in the asymptomatic twin, the paternal X chromosome was active in the other, affected twin and was found in her hemizygotic nephew. These data suggest that the paternal X chromosome carries the de novo alpha-galactosidase A mutation and that uneven X inactivation is the underlying mechanism for disease expression in this novel female MZ twin pair. This is the first documented case of female twins discordant for Fabry disease.
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PMID:Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene. 886 62

The nature of the molecular lesions in the alpha-galactosidase A gene causing Fabry disease in 12 unrelated families from the United Kingdom and 4 from other European countries was determined in order to provide precise heterozygote detection and prenatal diagnosis for these families. The entire alpha-galactosidase A coding region and flanking intronic sequences were analyzed by amplification of genomic DNA and solid-phase direct sequencing or by SSCP analysis followed by solid-phase direct sequencing. Fourteen new mutations were identified including 10 missense mutations (M42V, R49S, C56Y, D92H, D93G, P205T, W236C, W287G, N298H, and W340R), 2 nonsense mutations (Q107X and Q119X) and 2 small deletions (257del18 and 1087del1). Together with the previously reported mutations, a total of 33 lesions in the alpha-galactosidase A gene have been identified in unrelated British families, further documenting the molecular genetic heterogeneity of this disease.
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PMID:Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries. 887 88

Fabry disease is an X-linked disorder of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A (alpha-Gal A). We identified a novel mutation of alpha-Gal A gene in a family with Fabry disease, which converted a tyrosine at codon 365 to a stop and resulted in a truncation of the carboxy (C) terminus by 65 amino acid (AA) residues. In a heterozygote of this family, although the mutant and normal alleles were equally transcribed in cultured fibroblasts, lymphocyte alpha-Gal A activity was approximately 30% of the normal control and severe clinical symptoms were apparent. COS-1 cells transfected with this mutant cDNA showed a complete loss of its enzymatic activity. Furthermore, those cotransfected with mutant and wildtype cDNAs showed a lower alpha-Gal A activity than those with wild type alone (approximately 30% of wild type alone), which suggested the dominant negative effect of this mutation and implied the importance of the C terminus for its activity. Thus, we generated mutant cDNAs with various deletion of the C terminus, and analyzed. Unexpectedly, alpha-Gal A activity was enhanced by up to sixfold compared with wild-type when from 2 to 10 AA residues were deleted. In contrast, deletion of 12 or more AA acid residues resulted in a complete loss of enzyme activity. Our data suggest that the C-terminal region of alpha-Gal A plays an important role in the regulation of its enzyme activity.
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PMID:A carboxy-terminal truncation of human alpha-galactosidase A in a heterozygous female with Fabry disease and modification of the enzymatic activity by the carboxy-terminal domain. Increased, reduced, or absent enzyme activity depending on number of amino acid residues deleted. 887 32

We used the fluorescence-assisted mismatch analysis (FAMA) method to screen rapidly the alpha-galactosidase A gene in patients with Fabry disease in order to identify unknown mutations and help define genotype-phenotype correlations in this X-linked lysosomal storage disorder. Chemical cleavage at mismatches on heteroduplex DNA end-labeled with strand-specific fluorescent dyes, reliably detects sequence changes in DNA fragments of up to 1.5 kb and locates them precisely. Exhaustive scanning of the alpha-galactosidase gene was accomplished on four polymerase chain reaction-generated amplicons, covering all seven exons, the exon-intron boundaries, and 700 bp of 5'-flanking sequence. Mutations were identified in each of the 15 patients studied from nine unrelated kindreds. Among the seven previously undescribed sequence changes, three are obviously pathogenic because they lead to premature protein termination. The other four, a splicesite mutation and three missense mutations, were the only changes found upon complete scanning of the gene and its promoter. In addition, FAMA also detects female heterozygous carriers more dependably than direct sequencing, and thus provides a valuable diagnostic test. In Fabry disease, this molecular criterion is especially important for genetic counseling since heterozygotes can be asymptomatic and their enzymatic values within the normal range.
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PMID:Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. 893 8

A 28-year-old male patient with both IgA nephropathy and an unusual case of Fabry's disease has been followed for 10 years. Diagnosis of both these diseases was made by histological examination of renal biopsy tissues and the enzyme activities of alpha-galactosidase A. Serial biopsies revealed the hithertofore unrecognized process of glomerular glycolipid accumulation peculiar to Fabry's disease at the initial stages of the disease. Physical examinations and routine laboratory analyses failed to show significant signs of Fabry's disease throughout the 10-year period. While alpha-galactosidase A activity is markedly decreased in the plasma of this patient as in classical Fabry hemizygotes, the activity in leukocytes and culture fibroblasts showed a considerable residual activity. Fabry's disease associated with IgA nephropathy apparently is extremely rare, and the present subclinical case is unique in that the early stages of substrate accumulation are demonstrable.
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PMID:Subclinical Fabry's disease occurring in the context of IgA nephropathy. 904 52

Fabry disease is an X-linked inborn error of metabolism resulting from deficient activity of alpha-galactosidase A. Although several case reports have suggested an association between Fabry disease and airway obstruction, this has not been investigated in a large series of patients. We studied 25 unselected, consecutive, enzymatically diagnosed men referred to a General Clinical Research Center for evaluation. Thirty-six percent complained of dyspnea, and 24% had cough and/or wheezing. Symptoms were similar in smokers and nonsmokers. Nine (36%) had airway obstruction on spirometry; this finding was associated with age > or = 26 yr (p < 0.05) and dyspnea or wheezing (p < 0.005), but only weakly with smoking (p = 0.062). Five of eight patients responded to bronchodilators, but all 10 methacholine challenges were negative. Chest radiographs revealed normal lung fields in 24 patients and streaky bibasilar densities in one. No pulmonary uptake occurred on 67Ga citrate scans (18 patients) and 111In-tagged leukocyte scans (16 patients). Specific alpha-galactosidase A mutations were identified in 17 patients; all three patients with frameshift mutations and both subjects with the D264V missense mutation had obstructive impairment. We conclude that airway obstruction commonly occurs in patients with Fabry disease regardless of smoking history, and it increases with age. The presence of obstruction may be associated with certain mutations and most likely results from fixed narrowing of the airways by accumulated glycosphingolipid.
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PMID:Pulmonary involvement in Fabry disease. 911 79

Fabry disease is an X-linked inherited metabolic disorder that is caused by a deficiency of alpha-galactosidase A (alpha-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal a-linked galactosyl moieties in vascular endothelial cells causes renal failure along with premature myocardial infarctions and strokes in patients with this condition. No specific treatment is available for patients with this disorder at this time. An animal model of this condition would be valuable for exploring therapeutic strategies for patients with Fabry disease. We report here the generation of alpha-Gal A deficient mice by gene targeting and an analysis of the resulting phenotype. The knockout mice display a complete lack of alpha-Gal A activity. The mice, however, appeared clinically normal at 10 weeks of age. Ultrastructural analysis revealed concentric lamellar inclusions in the kidneys, and confocal microscopy using a fluorescent-labeled lectin specific for alpha-D-galactosyl residues showed accumulation of substrate in the kidneys as well as in cultured fibroblasts. Lipid analysis revealed a marked accumulation of ceramidetrihexoside in the liver and the kidneys. These findings indicate the similarity of the pathophysiological process in the mutant mice and in patients with Fabry disease. The deficiency of alpha-Gal A activity and the accumulation of material containing terminal alpha-galactosyl residues in cultured embryonic fibroblasts derived from alpha-Gal A(-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses containing human alpha-Gal A cDNA.
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PMID:alpha-Galactosidase A deficient mice: a model of Fabry disease. 912 31

Two-gene vectors with positive or positive-negative drug-selectable markers enable the expansion or elimination of gentetically modified cells in vivo. We have established a bicistronic retroviral vector system which utilizes an internal ribosome entry site (IRES) to co-express two independent genes with high efficiency. As a positive-negative (suicide) marker, Herpes simplex virus thymidine kinase was co-expressed with the human multidrug resistance gene, MDR1. Using this vector, almost all the MDR1-transduced cells showed hypersensitivity to a nucleoside analog, ganciclovir. As a dominant selectable marker, the MDR1 gene was co-expressed with alpha-galactosidase A for the model of gene therapy of Fabry disease. Vincristine selection efficiently enhanced the population of transduced cells expressing the second non-selectable genes. These drug-selectable retroviral vectors could be applicable to the therapy of many diseases.
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PMID:In vivo drug-selectable markers in gene therapy. 920 54

Fabry's disease, a rare X-linked disorder of glycosphingolipid metabolism, can present as an insidious dementia in middle or later life. This genetic disorder produces a deficiency of alpha-galactosidase A which results in the deposition of glycosphingolipids in blood vessel walls in the brain as well as in the kidney, heart, peripheral nerves, and other organs. Among the cerebrovascular manifestations of this disorder is a vascular dementia from involvement of multiple small penetrating blood vessels. Fabry's disease is a consideration in the workup of an otherwise unexplained vascular dementia, particularly in males less than 65 years of age.
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PMID:The vascular dementia of Fabry's disease. 921 72

Fabry disease is an X-linked recessive inborn error of glycosphingolipid catabolism that results from the deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). A rapid, reliable, and universal linkage method was developed for molecular carrier detection and prenatal diagnosis. By determining the informativeness and phase of amplifiable intragenic RFLPs (NcoI and SacI), flanking RFLPs (DXS94 and DXS17), and flanking microsatellite polymorphisms at Xq22.1 (DXS458, DXS454, DXS7424, DXS178, and DXS101), accurate carrier detection, and/or prenatal diagnosis was accomplished in three prototypic, unrelated Fabry families. All linkage diagnoses were confirmed by identification and analysis of the specific alpha-Gal A lesion in each family. Thus, molecular carrier detection and prenatal diagnoses can be performed rapidly and reliably by linkage analysis with intragenic and closely-linked polymorphisms at Xq22.1 in Fabry families whose specific alpha-Gal A lesions have not been determined.
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PMID:Fabry disease: molecular carrier detection and prenatal diagnosis by analysis of closely linked polymorphisms at Xq22.1. 926 4


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