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 disease, an X-linked recessive lysosomal storage disease, results from the deficient activity of the exogalactosidase, alpha-galactosidase A (alpha-Gal A). To date, over 270 disease-causing mutations have been identified; however, no coding sequence variants have been reported. In the course of enzyme diagnostic testing, a normal female control had low plasma and leukocyte alpha-Gal A activities. Sequencing her alpha-Gal A gene revealed the D313Y substitution (GAT to TAT at cDNA nucleotide 937). alpha-Gal A mutation and enzyme analyses of family members revealed X-linked transmission and leukocyte alpha-Gal A enzymatic activities in females, consistent with Lyonization. Since D313Y was reported in a classically affected male who had the double mutation, D313Y and G411D, efforts were undertaken to characterize these lesions. Expression of D313Y, G411D, and the doubly mutated construct, D313Y/G411D, resulted in alpha-Gal A levels of 76, 2.9, and 1.7% of mean expressed wild-type activity, respectively. Biosynthetic studies revealed essentially normal processing of the D313Y subunit, but the absence of the mature subunit encoded by the G411D and D313Y/G411D constructs. Thus, G411D is the disease-causing mutation, while D313Y is the first coding sequence variant identified in the human alpha-Gal A gene.
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PMID:Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma. 1468 Sep 77

Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is caused by mutations of the gene encoding the lysosomal hydrolase, alpha-galactosidase A. The enzymatic defect is inherited in an X-linked recessive fashion and leads to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. Although symptoms typically appear in childhood in hemizygous males and some heterozygous females, the diagnosis is often delayed or unrecognized, owing to variable presentations and low incidence. The initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. The later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. Recently published clinical trials have demonstrated the efficacy of enzyme replacement therapy in decreasing neuropathic pain and substrate deposition in target organs. Pediatricians have a key role to play in making the diagnosis, so that therapy can be initiated before irreversible tissue injury develops. Further research is required to determine optimal dosing protocols for treatment and to establish whether therapy can retard the progression of organ dysfunction, or even prevent these complications altogether.
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PMID:Fabry disease in the era of enzyme replacement therapy: a renal perspective. 1506 43

Anderson-Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase A activity. The conception of the disease has changed within the last decade. Studies of the last years have shown that the disease is not limited to the classical full-blown manifestation in affected males, which is well known since more than a century, but may also occur in carrier females. The phenomenology may differ in severity and kind of organ manifestation. Cardiac and renal variants with solely disease manifestation of these organs have also been described in an increasing number. It is likely that a spectrum exists regarding alpha-galactosidase A activity in both genders on the one hand, and an additional one regarding the severity and the number of organs affected on the other. The purpose of this review is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease.
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PMID:The expanding clinical spectrum of Anderson-Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy. 1514 26

Fabry's disease is a rare X-linked recessive disorder resulting from deficient lysosomal enzyme, alpha-galactosidase A (alpha-Gal A) activity. The deficiency leads to progressive glycosphingolipid globotriaosylceramide (Gb3) accumulation in fluids and tissues, including vascular endothelium, connective tissue, kidney, heart, brain and peripheral nerves. Classic Fabry's disease in hemizygous males has high morbidity and mortality due to end-stage renal disease (ESRD) requiring hemodialysis (HD) or kidney transplantation, myocardial involvement and central nervous system (CNS) complications. Most heterozygous females can also suffer from this severe disease deterioration. Until recently, Fabry's disease management consisted of symptomatic and palliative treatment, but this has changed with the availability of the recombinant human alpha-Gal A enzyme, agalsidase. Two different agalsidase formulations have been obtained: one from human fibroblast (agalsidase alpha), and one from Chinese hamster ovary (CHO) cells (agalsidase beta). Both preparations underwent clinical trials that documented the feasibility, efficacy and safety of the treatment. In addition, several clinical observations have proved that agalsidase reduces the storage of the substrate from several organs and tissues and, consequently, improves signs and symptoms of Fabry's disease. Additional clinical experiences have confirmed the initial clinical trial results, but further studies are needed to evaluate the long-term outcome of enzyme replacement therapy (ERT). We reviewed the clinical trial observations, as well as subsequent clinical experiences with ERT in patients with Fabry's disease.
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PMID:Enzyme replacement therapy in Fabry's disease: recent advances and clinical applications. 1536 54

Fabry disease is an X-linked recessive lysosomal storage disorder caused by deficiency of lysosomal alpha-galactosidase A. The disease affects not only kidney, myocardium, central nervous system and the skin but also, in many patients, the gastrointestinal tract. The recent advent of enzyme-replacement therapy has been reported to show beneficial effects on cardiomyopathy, renal function and autonomous nervous function. We report on a 34-year-old patient with Fabry disease in whom gastrointestinal symptoms were major complaints. Enzyme replacements led to remarkable improvement of diarrhoea and constipation. Abdominal pain, the feeling of fullness and meteorism improved, and metoclopramide, which previously had been used regularly, could be discontinued. There were also marked improvements of appetite, body weight, body mass index, physical activity and overall wellbeing. This observation should prompt further investigations into the pathophysiology of gastrointestinal manifestations in Fabry disease and the mechanisms of enzyme-replacement effects on gut function.
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PMID:Effect of enzyme-replacement therapy on gastrointestinal symptoms in Fabry disease. 1537 35

Anderson-Fabry disease (AFD) is an X-linked recessive disorder of glycosphingolipid metabolism. Most female carriers are clinically symptomatic; however, psychiatric diagnoses have not been reported in this population. We describe four female carriers of AFD disease who met DSM-IV criteria for major depression. All cases had a score above 26 on the Hamilton Rating Scale for Depression, indicating severe depression. This was independent of the severity or number of symptoms of AFD disease. Excessive guilt, fatigue, occupational difficulty, suicidal ideation and depressed mood were findings in all cases. In conclusion, the common presence of depression in carriers of AFD implies the need for a multidisciplinary approach, including psychiatry, in management of these patients. Further studies are recommended to establish the etiology of psychiatric complications, as well as the incidence and the response to pharmacotherapy and psychotherapy.
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PMID:Psychiatric findings in four female carriers of Fabry disease. 1556 93

Mutations in the alpha-galactosidase A (alpha-Gal A, GLA) gene cause Fabry disease, an X-linked recessive lysosomal storage disease. The majority of mutations are private, and confirmation of carrier status in females requires the definitive identification of a DNA mutation. In addition, knowledge of a family's mutation enables rapid and precise preimplantation and prenatal genetic testing. Here we report the development and use of DHPLC to rapidly and cost-effectively screen for alpha-Gal A mutations. Optimal DHPLC partial denaturing conditions for mutation detection were established for each PCR amplicon corresponding to the seven alpha-Gal A exons and their adjacent intronic/flanking sequences. At least five known mutations in each exon (45 in total) were screened by DHPLC to validate the method. Mutation detection was then performed in 14 affected males diagnosed by enzyme assay and 39 at-risk females, and the amplicons with abnormal DHPLC profiles were sequenced. In all affected males, and in 32 of the 39 at-risk females, four and 16 previously reported and 10 and 15 new mutations were identified, respectively. Sequencing all seven alpha-Gal A gene amplicons in the seven at-risk females who had normal DHPLC profiles excluded them as mutation carriers. Only one mutation (p.P362L) was not initially identified by its DHPLC profile, but in retrospect the profile was abnormal, emphasizing the need for experience in inspecting the profiles. In addition, this technique detected two new intronic polymorphisms, c.640-16A>G and c.1000-22C>T, with frequencies of 0.14 and 0.25 in both normal individuals and Fabry patients, respectively. This DHPLC method should improve the rapidity and cost-effectiveness of alpha-Gal A mutation identification in affected males and carrier females for Fabry disease.
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PMID:Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography. 1571 28

Fabry's disease is an X-linked recessive Lysosomal Storage disease. The underlying metabolic defect is deficiency of lysosomal enzyme ceramidetrihexosidase. The disease has multisystem involvement. Neurological manifestations include small-fiber polyneuropathy manifested as painful distal extremities and anhidrosis. Fabry's disease also presents with both small-vessel and cortical multiple cerebral infarcts. Enzyme-replacement therapy has been found effective but expensive. Gene therapy could evolve as the ultimate therapeutic strategy.
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PMID:Fabry disease with special reference to neurological manifestations. 1574 87

Fabry disease is an under-recognized X-linked recessive lysosomal storage disorder resulting from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A). The first case of Fabry disease in Slovenia was diagnosed in 1991. This 46 year-old male was referred for dermatologic evaluation of a purpura on his abdomen. He was being treated for proteinuria and cardiac symptoms. The diagnosis of angiokeratoma corporis diffusa (Fabry disease) was made clinically and confirmed by demonstration of the deficient leukocyte alpha-Gal A activity. The patient subsequently developed cerebrovascular symptoms, coronary disease, and renal failure, and died from a recurrent myocardial infarction. Family studies identified several other affected males and carrier female relatives with this X-linked recessive disorder. This case illustrates the typical multi-manifestations of this inherited disease which now can be safely and effectively treated by enzyme replacement therapy. Early diagnosis is important for the most effective treatment of this disease.
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PMID:Fabry disease. A case report. 1581 41

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disease in which left ventricular hypertrophy (LVH) is common, and if severe, may mimic hypertrophic obstructive cardiomyopathy. Alcohol-induced percutaneous transluminal septal myocardial ablation (PTSMA) has been used as a safe and effective method to alleviate LVH obstruction in patients with hypertrophic obstructive cardiomyopathy (HCM). We describe a case of a classically affected Fabry 53-year-old male with symptomatic HCM (NYHA class III with exertional angina) who was treated with PTSMA. The procedure safely and effectively alleviated symptomatic left ventricular outflow tract obstruction at long-term follow-up, and the patient's NYHA classification was reduced to NYHA class I to II.
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PMID:Fabry disease: percutaneous transluminal septal myocardial ablation markedly improved symptomatic left ventricular hypertrophy and outflow tract obstruction in a classically affected male. 1583 90


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