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Fabry disease

Lorenzo Ferri, Giuseppina Covello, Anna Caciotti, Renzo Guerrini, Michela Alessandra Denti, Amelia Morrone
Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of the α-galactosidase A (α-Gal A) enzyme, which is encoded by the GLA gene. GLA transcription in humans produces a major mRNA encoding α-Gal A and a minor mRNA of unknown function, which retains a 57-nucleotide-long cryptic exon between exons 4 and 5, bearing a premature termination codon. NM_000169.2:c.639+861C>T and NM_000169.2:c.639+919G>A GLA deep intronic mutations have been described to cause Fabry disease by inducing overexpression of the alternatively spliced mRNA, along with a dramatic decrease in the major one...
October 25, 2016: Molecular Therapy. Nucleic Acids
Yosep Chong, Minyoung Kim, Eun Sil Koh, Seok Joon Shin, Ho-Shik Kim, Sungjin Chung
BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disorder caused by α-galactosidase A deficiency. With the advancement of molecular diagnostic tools, more disease-causing mutations in α-galactosidase A (GLA) have been identified in Fabry disease. We found a novel mutation in a Korean family with predominant renal manifestations of the disease. CASE PRESENTATION: A 24-year-old man who wanted to donate a kidney to his 28-year-old brother with end-stage renal disease of unknown cause was evaluated...
October 24, 2016: BMC Medical Genetics
Albina Nowak, Thomas P Mechtler, Robert J Desnick, David C Kasper
BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene (GLA) that result in absent or markedly reduce α-galactosidase A (α-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte α-GalA activities...
October 19, 2016: Molecular Genetics and Metabolism
Takashi Kodama, Takahiro Tsukimura, Ikuo Kawashima, Atsuko Sato, Hitoshi Sakuraba, Tadayasu Togawa
In Fabry disease, large amounts of globotriaosylceramide (Gb3) and related glycosphingolipids accumulate in organs due to a deficiency of α-galactosidase A (GLA) activity. Enzyme replacement therapy (ERT) with recombinant GLA is now available, and it has been reported that ERT is beneficial for patients with Fabry disease, especially those who start treatment at an early stage of the disease. However, it seems that the efficacy of ERT differs with each organ, and Gb3 accumulated in the kidneys shows resistance to ERT when it is started at a late stage...
October 12, 2016: Molecular Genetics and Metabolism
Thomas Sené, Olivier Lidove, Joel Sebbah, Jean-Marc Darondel, Hervé Picard, Laurent Aaron, Olivier Fain, Thierry Zenone, Dominique Joly, Philippe Charron, Jean-Marc Ziza
The incidence and predictive factors of arrhythmias and/or conduction abnormalities (ACAs) requiring cardiac device (CD) implantation are poorly characterized in Fabry disease (FD). The aim of our retrospective study was to determine the prevalence, incidence, and factors associated with ACA requiring CD implantation in a monocentric cohort of patients with confirmed FD who were followed up in a department of internal medicine and reference center for FD.Forty-nine patients (20M, 29F) were included. Nine patients (4M, 5F; 18%) had at least one episode of ACA leading to device therapy...
October 2016: Medicine (Baltimore)
Wei-Chieh Cheng, Jen-Hon Wang, Wen-Yi Yun, Huang-Yi Li, Jia-Ming Hu
The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells...
October 5, 2016: European Journal of Medicinal Chemistry
Diana Karpman, Peter Höglund
Orphan drugs designed to treat rare diseases are often overpriced per patient. Novel treatments are sometimes even more expensive for patients with ultra-rare diseases, in part due to the limited number of patients. Pharmaceutical companies that develop a patented life-saving drug are in a position to charge a very high price, which, at best, may enable these companies to further develop drugs for use in rare disease. However, is there a limit to how much a life-saving drug should cost annually per patient? Government interventions and regulations may opt to withhold a life-saving drug solely due to its high price and cost-effectiveness...
October 13, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Debora Lucia Seguro Danilovic, Bruno Ferraz-de-Souza, Amanda Wictky Fabri, Nathalie Oliveira Santana, Marco Aurelio Kulcsar, Claudio Roberto Cernea, Suemi Marui, Ana Oliveira Hoff
OBJECTIVE: The increasing incidence of thyroid nodules demands identification of risk factors for malignant disease. Several studies suggested the association of higher TSH levels with cancer, but influence of 25-hydroxyvitamin D (25OHD) is controversial. This study aimed to identify the relationship of thyroid cancer with higher TSH levels and hypovitaminosis D and to evaluate their influence on prognostic characteristics of papillary thyroid carcinomas (PTC). METHODS: We retrospectively evaluated 433 patients submitted to thyroidectomy for thyroid nodules...
2016: PloS One
K V Firsov, A S Kotov
Fabry disease (Anderson-Fabry disease) is an X-linked recessive lysosomal storage disorder resulting from deficient activity of lysosomal hydrolase, alpha-galactosidase A (alpha-Gal A), which leads to progressive accumulation of globotriaosylceramide (Gb3) in various cells, predominantly endothelial and vascular smooth muscle cells, with clinical manifestations affecting major organs including the central nervous system. Manifestations of Fabry disease include progressive renal and cardiac insufficiency, neuropathic pain, stroke and cerebral disease, skin and gastrointestinal symptoms...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
H Trimarchi, R Canzonieri, A Schiel, C Costales-Collaguazo, J Politei, A Stern, M Paulero, T Rengel, J Andrews, M Forrester, M Lombi, V Pomeranz, R Iriarte, A Muryan, E Zotta, M D Sanchez-Niño, A Ortiz
BACKGROUND: Certain glomerulopathies are associated with increased levels of CD80 (B7-1). We measured the urinary excretion of CD80, podocyturia and proteinuria in controls and in subjects with Fabry disease either untreated or on enzyme replacement therapy (ERT). METHODS: Cross-sectional study including 65 individuals: controls (n = 20) and Fabry patients (n = 45, 23 of them not on ERT and 22 on ERT). Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), urinary uCD80/creatinine ratio (uCD80) and podocyturia...
October 13, 2016: Journal of Translational Medicine
Sai Kiran C, Rupender Prasad, Sindhu Joshi
No abstract text is available yet for this article.
January 2016: Journal of the Association of Physicians of India
Mona Abaoui, Michel Boutin, Pamela Lavoie, Christiane Auray-Blais
Fabry disease is a multisystemic, X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and resulting in the accumulation of glycosphingolipids in different tissues and biological fluids. Glycosphingolipid biomarkers, such as globotriaosylceramide (Gb3 ) isoforms, globotriaosylsphingosine (lyso-Gb3 ) and related analogs, and galabiosylceramide (Ga2 ) isoforms and analogs, are found to be abnormally increased in urine and in plasma of Fabry patients and have the potential to be used as specific biomarkers of the disease...
October 11, 2016: Current Protocols in Human Genetics
Tomoko Honda, Etsuko Komatsu, Satoshi Furuse, Naobumi Mise
No abstract text is available yet for this article.
2016: Internal Medicine
Ramon Bossardi Ramos, Vitor Fabris, Sheila Bunecker Lecke, Maria Augusta Maturana, Poli Mara Spritzer
BACKGROUND: Genetic studies to date have not provided satisfactory evidence regarding risk polymorphisms for cardiovascular disease (CVD). Conversely, epigenetic mechanisms, including DNA methylation, seem to influence the risk of CVD and related conditions. Because postmenopausal women experience an increase in CVD, we set out to determine whether global DNA methylation was associated with cardiovascular risk in this population. METHODS: In this cross sectional study carried out in a university hospital, 90 postmenopausal women without prior CVD diagnosis (55...
October 10, 2016: BMC Medical Genetics
Ester Miranda Pereira, Anatalia Labilloy, Megan L Eshbach, Ankita Roy, Arohan R Subramanya, Semiramis Monte, Guillaume Labilloy, Ora A Weisz
BACKGROUND: Fabry Nephropathy is a major cause of morbidity and premature death in patients with Fabry disease (FD) a rare X-linked lysosomal storage disorder.Gb3, the main substrate of α-gal A, progressively accumulates within cells in a variety of tissues. Establishment of cell models have been useful as a tool for testing hypotheses of disease pathogenesis. METHODS: We applied CRISPR/Cas9 genome editing technology to the GLA gene to develop human kidney cell models of FD in human immortalized podocytes, which are the main affected renal cell type...
September 28, 2016: American Journal of Physiology. Renal Physiology
Renzo Mignani, Federico Pieruzzi, Francesco Berri, Alessandro Burlina, Benito Chinea, Maurizio Gallieni, Maurizio Pieroni, Alessandro Salviati, Marco Spada
Two disease severity scoring systems, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), have been validated for quantifying the disease burden of Fabry disease. We aimed to develop a dynamic mathematical model [the FASTEX (FAbry STabilization indEX)] to assess the clinical stability. A multidisciplinary panel of experts in Fabry disease first defined a novel score of severity [raw score (RS)] based on three domains with a small number items in each domain (nervous system domain: pain, cerebrovascular events; renal domain: proteinuria, glomerular filtration rate; cardiac domain: echocardiography parameters, electrocardiograph parameters and New York Heart Association class) and evaluated the clinical stability over time...
October 2016: Clinical Kidney Journal
Malte Lenders, Boris Schmitz, Jörg Stypmann, Thomas Duning, Stefan-Martin Brand, Christine Kurschat, Eva Brand
BACKGROUND: Renal and cardiac involvement is responsible for substantial morbidity and mortality in Fabry disease (FD). We analysed the incidence of FD-related renal, cardiac and neurologic end points in patients with FD on long-term enzyme replacement therapy (ERT). METHODS: A retrospective analysis of prospectively collected data from two German FD centres was performed. The impact of renal and cardiac function at ERT-naïve baseline on end point development despite ERT was analysed...
September 27, 2016: Nephrology, Dialysis, Transplantation
B Schmitz, L Thorwesten, M Lenders, T Duning, J Stypmann, E Brand, S-M Brand
The aim of this study was to assess the extent of exercise intolerance in Fabry disease (FD) patients and to report individual effects of physical exercise. Exercise capacity and strength of 14 patients (mean age 46 years, 6 females) were determined using cycle ergometry and isokinetic measurements. Patients performed a strength/circuit exercise training protocol for 12 months. The mean relative maximum performance of the group was low at baseline and increased by 12.1% (baseline: 1.9 [0.9-3.4] W·kg(-1) vs...
September 27, 2016: International Journal of Sports Medicine
Xi Zoë Zhong, Xue Sun, Qi Cao, Gaofeng Dong, Raphael Schiffmann, Xian-Ping Dong
Efficient lysosomal Ca(2+) release plays an essential role in lysosomal trafficking. We have recently shown that lysosomal big conductance Ca(2+)-activated potassium (BK) channel forms a physical and functional coupling with the lysosomal Ca(2+) release channel Transient Receptor Potential Mucolipin-1 (TRPML1). BK and TRPML1 forms a positive feedback loop to facilitate lysosomal Ca(2+) release and subsequent lysosome membrane trafficking. However, it is unclear whether the positive feedback mechanism is common for other lysosomal storage diseases (LSDs) and whether BK channel agonists rescue abnormal lysosomal storage in LSDs...
September 27, 2016: Scientific Reports
Martina Gaggl, Gere Sunder-Plassmann
No abstract text is available yet for this article.
November 2016: Nature Reviews. Nephrology
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