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 is an inborn error of glycosphingolipid catabolism, resulting from deficient activity of lysosomal alpha-galactosidase A (alpha-Gal A). A rare alternative splicing that introduces a 57-nucleotide (nt) intronic sequence to the alpha-Gal A transcript from intron 4 of the gene has been identified. In addition, a novel midintronic base substitution that results in substantially increased alternative splicing has been identified in a patient with Fabry disease who has the cardiac variant phenotype. The sequence of the patient's intron 4 contains a single G-->A transversion at genomic nt 9331 (IVS4+919 G-->A ), located at the minus sign4 position of the 3' end of the intronic insertion (nts 9278--9334 in the genomic sequence). Minigene constructs containing the entire intron 4 sequence with G, A, C, or T at nt 9331 within an alpha-Gal A complementary DNA expression vector were prepared and expressed in COS-1 cells. Whereas transfection of the G or T minigenes transcribed predominantly normal-sized transcripts, the transfection of the A or C minigenes produced a large amount of the alternatively spliced transcript. These results suggest that the G-->A mutation, within an A/C-rich domain, results in increased recognition of the alternative splicing by an A/C-rich enhancer-type exonic splicing enhancer. The intronic mutation was not observed in 100 unrelated unaffected men but was present in 6 unrelated patients with cardiac Fabry disease. Reverse-transcriptase polymerase chain reaction of total RNA of various normal human tissues revealed that the alternatively spliced transcript was present in all of the samples, and especially at a higher ratio in the lung and muscle. The normal transcript was present in the patients' lymphoblasts and resulted in approximately 10% residual enzyme activity, leading to a cardiac phenotype of Fabry disease.
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PMID:Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype. 1182 41

Gene therapy efforts have focused primarily on the use of either the liver or skeletal muscle as depot organs for the production of a variety of therapeutic proteins that act systemically. Here we examined the lung to determine whether it could function as yet another portal for the secretion of proteins into the circulation. Fabry disease is caused by a deficiency of the lysosomal hydrolase alpha-galactosidase A, resulting in the abnormal deposition of the glycosphingolipid globotriaosylceramide (GL-3) in vascular lysosomes. Pulmonary instillation of a recombinant adenoviral vector (Ad2/CMVHI-alpha(gal)) encoding human alpha-galactosidase A into Fabry mice resulted in high-level transduction and expression of the enzyme in the lung. Importantly, enzymatic activity was also detected in the plasma, liver, spleen, heart, and kidneys of the Fabry mice. The detection of enzymatic activity outside of the lung, along with the finding that viral DNA was limited to the lung, indicates that the enzyme crossed the air/blood barrier, entered the systemic circulation, and was internalized by the distal visceral organs. The levels of alpha-galactosidase A attained in these tissues were sufficient to reduce GL-3 to basal levels in the lung, liver, and spleen and to approximately 50% of untreated levels in the heart. Together, these results suggest that the lung may be a viable alternate depot organ for the production and systemic secretion of alpha-galactosidase A for Fabry disease.
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PMID:Adenovirus-transduced lung as a portal for delivering alpha-galactosidase A into systemic circulation for Fabry disease. 1202 59

The nature of the molecular lesions in the alpha-galactosidase A (alpha-Gal A) gene causing Fabry disease was determined in 50 unrelated families with the classic phenotype of this X-linked recessive lysosomal storage disease. Genomic DNA was isolated from affected males or obligate carrier females, and the entire alpha-Gal A coding region as well as the flanking and intronic sequences were analyzed by PCR amplification and automated sequencing. Forty-five new mutations were identified including 38 single base substitutions (32 missense and four nonsense) and nine gene rearrangements: MIR, M42T, G43D, G43V, H46Y, F50C, L68F, G132R, T141I, Y152X, K168R, G183S, V199M, P205R, Y207S, Q221X, C223R, C223Y, D234Y, G271C, A288P, P293A, R301G, I303N, I317T, E341D, P362L, R363C, R363H, G373D, I384N, T385P, Q396X, E398K, S401X, P409A, g7325insC, g7384del13, g8341delG, g8391del4/ins3, g10511delTAGT, g10704delACAG, g11019insG, g11021insG, and g11048delAGG. In the remaining five Fabry families, four previously reported mutations were detected (W81X, R112C, g11011delTC, and g11050delGAG) of which the R112C substitution was found in two families who were unrelated by haplotyping. These studies further define the heterogeneity of mutations in the alpha-Gal A gene causing the classical Fabry disease phenotype, and permit precise carrier detection and prenatal diagnosis in these families.
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PMID:Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype. 1217 77

We describe four patients with cerebrovascular complications from two unrelated Italian families with Anderson-Fabry disease. Clinical examination, neuroimaging (MRI), biochemical and genetic analyses were carried out in all the patients. Alpha-galactosidase A activity was detected by fluorimetric assay and genetic analysis was performed by DNA sequencing. Family 1. A male patient presented recurrent strokes when he was 34 years old, albuminuria and subsequently progressive renal failure to renal transplantation. Family 2. A male patient, aged 32 years, had diplopia for a few days and then recurrent strokes with left spastic hemiparesis and internuclear ophthalmoplegia. A female patient, aged 48 years, presented L-dopa-responsive parkinsonism, and her sister had stroke when she was 55 years old. MRI was abnormal in all the patients and showed lacunar infarctions in the periventricular white matter, basal ganglia and pons. Lesions were detected by MRI even before stroke in a female patients. In patients with Anderson-Fabry disease, stroke is a frequent complication, and may be the first threatening clinical manifestation. In young people with undefined stroke, even without signs of renal involvement, it is important to consider the diagnosis of Anderson-Fabry disease and so to perform clinical examination and biochemical analyses. The pre-clinical stage of cerebrovascular involvement may be evaluable by MRI.
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PMID:Anderson-Fabry disease with cerebrovascular complications in two Italian families. 1223 91

Fabry's disease is an X-linked inborn error of glycosphingolipid catabolism, resulting from a deficiency in alpha-galactosidase A (alpha-Gal A). A 56-year-old Japanese woman was at first suspected of having hypertrophic cardiomyopathy. The patient and her son had alpha-Gal A activity in leukocytes that was remarkably below the limit of controls. DNA analysis of the alpha-Gal A gene revealed a novel missense mutation at codon 19 in exon 1, resulting in leucine-to-proline substitution. As a result she was confirmed as a classic Fabry heterozygote. Recent advances in enzyme replacement therapy can reverse the storage of glycosphingolipids in Fabry's disease. Thus, in patients with cardiac hypertrophy, it is important to differentiate Fabry's disease from other causes of hypertrophy. Therefore, it is necessary to measure alpha-Gal A activity in all suspected cases and to analyze genetic abnormalities in heterozygotes.
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PMID:Fabry disease female proband with clinical manifestations similar to hypertrophic cardiomyopathy. 1535 80

We present two sisters with a severe form of Fabry disease, who both carry the same mutation in the alpha-galactosidase A (alpha-gal A) gene (Q330X). Each of the sisters developed renal failure in the third decade of life; the older sibling underwent renal transplantation at 40 years of age. The severe phenotype of the siblings correlates with results of the X-inactivation study: examination of methylation status in human androgene receptor (HUMARA) gene suggests preferential inactivation of the wild-type allele in both patients. Patients' parents had no symptoms of Fabry disease and were tested negative for the mutation Q330X in DNA isolated from peripheral leukocytes, mouth wash cells, and urinary sediment cells. Genotype analysis using DXS7424 marker showed paternal origin of the mutation. The father's sperm was then tested for presence of the mutation to examine the possibility of the germline mosaicism. Both mutant and wild-type alleles were found in DNA isolated from father's sperm. The apparent explanation of these findings is germline mosaicism due to mutation event during the embryonic development of sperm producing cells (spermatogonia). This is the first case of germline mosaicism in Fabry disease reported in the literature.
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PMID:Recurrence of Fabry disease as a result of paternal germline mosaicism for alpha-galactosidase a gene mutation. 1571 98

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

Optical fiber extrinsic Fabry-Perot interferometry (EFPI) was investigated as a noncontact temperature sensor and utilized for regulating the temperature of small-volume solutions in microchips. Interference pattern analysis determined the optical path lengths (OPL) associated with reflections from various surfaces on or in the microchip, in particular, from gold sputtered on the bottom of a microchannel. Since OPL is directly proportional to refractive index, which is dependent on solution temperature, the EFPI sensor was capable of noncontact monitoring of solution temperature simply from alterations in the measured path length. Calibration of the sensor against a thermocouple was performed while heating the microchip in a noncontact manner with an IR lamp. The combination of EFPI temperature sensor, IR-mediated heating, and air cooling allowed a fully noncontact system for small-volume temperature control in microchip structures, and its utility was illustrated by optimal digestion of DNA by a temperature-dependent restriction endonuclease in 320 nL. The functionality and simplicity of the microchip EFPI temperature sensor was enhanced by replacing the prebonding sputtered gold with a tunable, chemically plated semireflective silver coating created in situ after chip fabrication. This provided an 8-fold improvement in the lowest detectable temperature change (deltaT = 0.1 degrees C), facilitated primarily by enhanced reflection from both the bottom and top surfaces of the microchannel. This approach for controlling micro- and nanoscale reactions--with heating, cooling, and temperature control being carried out in a completely noncontact fashion--provides an accurate and sensitive method for executing chemical and biochemical reactions in microchips.
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PMID:Extrinsic Fabry-Perot interferometry for noncontact temperature control of nanoliter-volume enzymatic reactions in glass microchips. 1585 83

Hepatocytes are an effective depot for protein production from gene therapy vectors. However, when gene transfer vectors or their delivery induces hepatic inflammation, adaptive immune responses against the transgene product can ensue. In BALB/c mice, hydrodynamic delivery of a CMV-driven plasmid DNA (pDNA) bearing human alpha-galactosidase A (alphagal) to the liver generated antibodies against alphagal. This humoral immune response was more robust in a transgenic knockout for alphagal, the Fabry mouse. The antibody response could be attenuated in both mouse strains by using a promoter more restricted to hepatocytes. In an attempt to reduce further the humoral responses to alphagal, expression from the transgene was attenuated by using siRNA during the period of initial delivery-associated liver inflammation. In both mouse models and with both promoters, codelivering an alphagal siRNA resulted in a 2 log decrease in initial expression that then increased over the next few weeks to levels generated by the pDNA alone. This strategy led to both attenuated antibodies and an immune status approximating "tolerance" to alphagal. Importantly, in the Fabry mouse, an alphagal siRNA together with a hepatocyte-restricted promoter gave minimal anti-alphagal antibodies and profound tolerance, suggesting that such an approach might have clinical utility for genetic diseases.
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PMID:Transient siRNA-mediated attenuation of liver expression from an alpha-galactosidase A plasmid reduces subsequent humoral immune responses to the transgene product in mice. 1594 2

Fabry disease is a rare X-linked lysosomal storage disorder caused by deficient activity of alpha-galactosidase A (alpha-Gal A) resulting in the storage of glycosphingolipids, especially globotriaosylceramide (Gb3), in cells throughout the body, causing life-threatening renal, cardiac, and cerebrovascular complications in hemizygous males and some heterozygous females. Disease manifestations in heterozygotes are being recognized increasingly, but quantitative prospective data on their extent and severity are limited. Prospective clinical and laboratory assessments were performed in a 7-day study of 61 women with signs and symptoms of Fabry disease. Analyses included medical history and physical, neurologic, cardiac, and ophthalmologic assessments; laboratory assessments; renal function tests; magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head; and Fabry-related blood and urine tests, including Gb3 levels in blood and urine, skin biopsies, and DNA genotype analysis of the alpha-Gal A gene to identify causative mutations. Quality of life, pain and concomitant medication were documented using validated questionnaires and diaries. All patients had normal Gb3 levels in plasma; only 1 patient had visible storage material in the superficial dermal vascular endothelial cells. Cardiac, renal, or cerebrovascular abnormalities were documented in 52 of the 57 patients (91%) with confirmed Fabry genotypes. These included electrocardiographic abnormalities in 38 of 52 patients (73%), echocardiographic abnormalities in 8 of 57 (14%), proteinuria (>150 g protein/24-h urine) in 23 of 38 (61%), low estimated glomerular filtration rate (<90 mL/min per 1.73 m) in 24 of 57 (42%), abnormal MRI in 4 of 54 (7%), and abnormal MRA in 10 of 50 patients (20%). Angiokeratomas and corneal epitheliopathy were documented in 63% and 82% of the 57 patients, respectively. Despite the virtual absence of storage material in plasma and skin vascular endothelial cells, this population of women with Fabry disease exhibited a wide spectrum of clinical abnormalities. Useful outcome measures for assessment of specific therapies need to be developed. Studies limited to homogeneously affected subjects may be possible.
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PMID:The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. 1614 26


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