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Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease?

Institute of Biomedicine and Molecular Immunology “A. Monroy”, National Research Council, 90146 Palermo, Italy
Neurological Unit, St Bassiano Hospital, 36061 Bassano del Grappa, Italy
Division of Inherited Metabolic Diseases, Regional Center for Expanded Neonatal Screening Department of Women and Children’s Health, University Hospital of Padova, 35128 Padova, Italy
Department of Biopathology and Medical Biotechnologies—Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy
Department of Public Health, Nephrology Unit, University of Naples “Federico II”, 80131 Naples, Italy
Nephrology Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
Neurology Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
Division of Cardiology, Second University of Naples, Presidio Monaldi, 80131 Naples, Italy
Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and GeriatricSciences, Sapienza University, 00161 Rome, Italy
Nephrology Unit, Hospital of L’Aquila, 67100 L’Aquila, Italy
Nephrology Unit, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Cardiovascular Department, San Donato Hospital, 52100 Arezzo, Italy
Department of Pediatrics, Division of Metabolic Diseases, Turin University Hospital, 10126 Turin, Italy
Paediatric Hospital “G. Di Cristina”, ARNAS Civico, 90134 Palermo, Italy
Cardiology Department Echocardiography Laboratory, Department of Cardiothoracic and Vascular, Policlinico Vittorio Emanuele, Catania University, 95124 Catania, Italy
Institute of Neurological Sciences (ISN), National Research Council, 95126 Catania, Italy
Nephrology and Dialysis Unit, Belcolle Hospital, 01100 Viterbo, Italy
Department of Specialized Medicine, Division of Nephrology and Dialysis, St. Anna Hospital-University, 44124 Ferrara, Italy
Unit of Nephrology, Ospedali Riuniti Villa Sofia-Cervello, 90146 Palermo, Italy
Department of Advanced Medical Sciences, Federico II University of Naples, 80131 Naples, Italy
Cardiology Unit, Clinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sapienza University of Rome, 00161 Rome, Italy
Nephrology and Dialysis Unit, Mugello Hospital, A.S. Toscana Centro, Borgo San Lorenzo, 50032 Firenze, Italy
Institute of Clinical Physiology, Division of Nephrology, National Research Council, 89129 Reggio Calabria, Italy
Nephrology Unit, Grande Ospedale Metropolitano Reggio Calabria, 89124 Reggio Calabria, Italy
Department of Nephrology, Infermi Hospital, 47923 Rimini, Italy
Cardiac Arrhythmia Center and Cardiomyopathies Unit, San Camillo-Forlanini Hospital, 00152 Roma, Italy
Department of Neurology, Guzzardi Hospital, 97019 Vittoria, Italy
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 3726;
Received: 29 October 2018 / Revised: 15 November 2018 / Accepted: 18 November 2018 / Published: 23 November 2018
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease. View Full-Text
Keywords: Fabry disease; GLA gene; LysoGb3 Fabry disease; GLA gene; LysoGb3
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Duro, G.; Zizzo, C.; Cammarata, G.; Burlina, A.; Burlina, A.; Polo, G.; Scalia, S.; Oliveri, R.; Sciarrino, S.; Francofonte, D.; Alessandro, R.; Pisani, A.; Palladino, G.; Napoletano, R.; Tenuta, M.; Masarone, D.; Limongelli, G.; Riccio, E.; Frustaci, A.; Chimenti, C.; Ferri, C.; Pieruzzi, F.; Pieroni, M.; Spada, M.; Castana, C.; Caserta, M.; Monte, I.; Rodolico, M.S.; Feriozzi, S.; Battaglia, Y.; Amico, L.; Losi, M.A.; Autore, C.; Lombardi, M.; Zoccali, C.; Testa, A.; Postorino, M.; Mignani, R.; Zachara, E.; Giordano, A.; Colomba, P. Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease? Int. J. Mol. Sci. 2018, 19, 3726.

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