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

被引:80
作者
Duro, Giovanni [1 ]
Zizzo, Carmela [1 ]
Cammarata, Giuseppe [1 ]
Burlina, Alessandro [2 ]
Burlina, Alberto [3 ]
Polo, Giulia [3 ]
Scalia, Simone [1 ]
Oliveri, Roberta [1 ]
Sciarrino, Serafina [1 ]
Francofonte, Daniele [1 ]
Alessandro, Riccardo [1 ,4 ]
Pisani, Antonio [5 ]
Palladino, Giuseppe [6 ]
Napoletano, Rosa [7 ]
Tenuta, Maurizio [7 ]
Masarone, Daniele [8 ]
Limongelli, Giuseppe [8 ]
Riccio, Eleonora [5 ]
Frustaci, Andrea [9 ]
Chimenti, Cristina [9 ]
Ferri, Claudio [10 ]
Pieruzzi, Federico [11 ]
Pieroni, Maurizio [12 ]
Spada, Marco [13 ]
Castana, Cinzia [14 ]
Caserta, Marina [14 ]
Monte, Ines [15 ]
Rodolico, Margherita Stefania [16 ]
Feriozzi, Sandro [17 ]
Battaglia, Yuri [18 ]
Amico, Luisa [19 ]
Losi, Maria Angela [20 ]
Autore, Camillo [21 ]
Lombardi, Marco [22 ]
Zoccali, Carmine [23 ]
Testa, Alessandra [23 ]
Postorino, Maurizio [24 ]
Mignani, Renzo [25 ]
Zachara, Elisabetta [26 ,27 ]
Giordano, Antonello [28 ]
Colomba, Paolo [1 ]
机构
[1] CNR, Inst Biomed & Mol Immunol A Monroy, I-90146 Palermo, Italy
[2] St Bassiano Hosp, Neurol Unit, I-36061 Bassano Del Grappa, Italy
[3] Univ Hosp Padova, Dept Women & Childrens Hlth, Reg Ctr Expanded Neonatal Screening, Div Inherited Metab Dis, I-35128 Padua, Italy
[4] Univ Palermo, Sect Biol & Genet, Dept Biopathol & Med Biotechnol, I-90133 Palermo, Italy
[5] Univ Naples Federico II, Nephrol Unit, Dept Publ Hlth, I-80131 Naples, Italy
[6] Univ Hosp San Giovanni Dio & Ruggi dAragona, Nephrol Unit, I-84131 Salerno, Italy
[7] Univ Hosp San Giovanni Dio & Ruggi dAragona, Neurol Unit, I-84131 Salerno, Italy
[8] Univ Naples 2, Div Cardiol, I-80131 Naples, Italy
[9] Sapienza Univ, Dept Cardiovasc Resp Nephrol Anesthesiol & Geriat, I-00161 Rome, Italy
[10] Hosp Laquila, Nephrol Unit, I-67100 Laquila, Italy
[11] Univ Milano Bicocca, Dept Med & Surg, Nephrol Unit, I-20900 Monza, Italy
[12] San Donato Hosp, Cardiovasc Dept, I-52100 Arezzo, Italy
[13] Turin Univ Hosp, Div Metab Dis, Dept Pediat, I-10126 Turin, Italy
[14] Paediat Hosp G Di Cristina, ARNAS Civico, I-90134 Palermo, Italy
[15] Catania Univ, Policlin Vittorio Emanuele, Dept Cardiothorac & Vasc, Echocardiog Lab,Cardiol Dept, I-95124 Catania, Italy
[16] CNR, Inst Neurol Sci ISN, I-95126 Catania, Italy
[17] Belcolle Hosp, Nephrol & Dialysis Unit, I-01100 Viterbo, Italy
[18] St Anna Hosp Univ, Div Nephrol & Dialysis, Dept Specialized Med, I-44124 Ferrara, Italy
[19] Osped Riuniti Villa Sofia Cervello, Unit Nephrol, I-90146 Palermo, Italy
[20] Federico II Univ Naples, Dept Adv Med Sci, I-80131 Naples, Italy
[21] Sapienza Univ Rome, Fac Med & Psychol, Clin & Mol Med Dept, Cardiol Unit, I-00161 Rome, Italy
[22] Mugello Hosp, AS Toscana Ctr, Nephrol & Dialysis Unit, I-50032 Florence, Italy
[23] CNR, Div Nephrol, Inst Clin Physiol, I-89129 Reggio Di Calabria, Italy
[24] Grande Osped Metropolitano Reggio Calabria, Nephrol Unit, I-89124 Reggio Di Calabria, Italy
[25] Infermi Hosp, Dept Nephrol, I-47923 Rimini, Italy
[26] San Camillo Forlanini Hosp, Cardiac Arrhythmia Ctr, I-00152 Rome, Italy
[27] San Camillo Forlanini Hosp, Cardiomyopathies Unit, I-00152 Rome, Italy
[28] Guzzardi Hosp, Dept Neurol, I-97019 Vittoria, Italy
关键词
Fabry disease; GLA gene; LysoGb3; LYSOSOMAL STORAGE DISORDERS; VARIANT; DIAGNOSIS;
D O I
10.3390/ijms19123726
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the alpha-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. alpha-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, alpha-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.
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