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

2018 ◽  
Vol 19 (12) ◽  
pp. 3726 ◽  
Author(s):  
Giovanni Duro ◽  
Carmela Zizzo ◽  
Giuseppe Cammarata ◽  
Alessandro Burlina ◽  
Alberto Burlina ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Genetic Variants ◽  
Late Onset ◽  
Clinical History ◽  
Classic Phenotype ◽  
Unknown Significance ◽  
Male Patients ◽  
Alpha Gene ◽  
Reliable Marker ◽  
Gla Gene

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.

scholarly journals High Variability of Fabry Disease Manifestations in an Extended Italian Family

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Giuseppe Cammarata ◽  
Pasquale Fatuzzo ◽  
Margherita Stefania Rodolico ◽  
Paolo Colomba ◽  
Luigi Sicurella ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Fabry Disease ◽  
Phenotypic Variability ◽  
Clinical Manifestations ◽  
Clinical History ◽  
History Of ◽  
Extreme Variability ◽  
Mediterranean Fever ◽  
Male Patients ◽  
Gla Gene

Fabry disease (FD) is an inherited metabolic disorder caused by partial or full inactivation of the lysosomal hydrolaseα-galactosidase A (α-GAL). The impairment ofα-GAL results in the accumulation of undegraded glycosphingolipids in lysosomes and subsequent cell and microvascular dysfunctions. This study reports the clinical, biochemical, and molecular characterization of 15 members of the same family. Eight members showed the exonic mutation M51I in the GLA gene, a disease-causing mutation associated with the atypical phenotype. The clinical history of this family highlights a wide phenotypic variability, in terms of involved organs and severity. The phenotypic variability of two male patients is not related to differences inα-GAL enzymatic activity: though both have no enzymatic activity, the youngest shows severe symptoms, while the eldest is asymptomatic. It is noticeable that for two female patients with the M51I mutation the initial clinical diagnosis was different from FD. One of them was diagnosed with Familial Mediterranean Fever, the other with Multiple Sclerosis. Overall, this study confirms that the extreme variability of the clinical manifestations of FD is not entirely attributable to different mutations in the GLA gene and emphasizes the need to consider other factors or mechanisms involved in the pathogenesis of Fabry Disease.

First case of late onset cardiac phenotype Fabry disease due to an AluYb8 insertion in exon 7 of the GLA gene

2019 ◽  
Vol 20 (10) ◽  
pp. 1182-1182
Author(s):  
Constantin Gatterer ◽  
Dietrich Beitzke ◽  
Raute Sunder-Plassmann ◽  
Gere Sunder-Plassmann ◽  
Senta Graf
Keyword(s):  
Fabry Disease ◽  
Late Onset ◽  
Cardiac Phenotype ◽  
First Case ◽  
Gla Gene

scholarly journals Prevalence of Anderson-Fabry Disease in Male Patients With Late Onset Hypertrophic Cardiomyopathy

Circulation ◽  
2002 ◽  
Vol 105 (12) ◽  
pp. 1407-1411 ◽  
Author(s):  
B. Sachdev ◽  
T. Takenaka ◽  
H. Teraguchi ◽  
C. Tei ◽  
P. Lee ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Fabry Disease ◽  
Late Onset ◽  
Male Patients

p.G360R Is a Pathogenic GLA Gene Mutation Responsible for a Classic Phenotype of Fabry Disease

Cardiology ◽  
2019 ◽  
Vol 144 (3-4) ◽  
pp. 125-130 ◽  
Author(s):  
Daniela Marisa Carvalho Silva ◽  
Nuno Marques ◽  
Olga Azevedo ◽  
Gabriel Miltenberger-Miltenyi ◽  
Dina Bento ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Fabry Disease ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Gene Variants ◽  
Fabry Patient ◽  
Enzyme Replacement ◽  
Disease Awareness ◽  
Classic Phenotype ◽  
Gla Gene

The authors report the case of a classic phenotype of Fabry disease in a 60-year-old male patient presenting with left ventricular hypertrophy and stroke. Genetic analysis revealed 2 GLA-gene variants, i.e., p.R356Q and p.G360R. This clinical case highlights that the finding of 2 or more GLA gene variants in a Fabry patient should lead to a careful evaluation in order to determine their exact role in the condition. This case also provides the first clinical evidence that the p.G360R mutation is pathogenic and responsible for a classic phenotype of Fabry disease. The clinical improvement following the initiation of enzyme replacement therapy reinforces the importance of Fabry disease awareness and diagnosis in patients exhibiting red flags, such as left ventricular hypertrophy and stroke.

scholarly journals Migalastat Treatment in a Kidney-Transplanted Patient with Fabry Disease and N215S Mutation: The First Case Report

2021 ◽  
Vol 14 (12) ◽  
pp. 1304
Author(s):  
Valeria Di Stefano ◽  
Marta Mancarella ◽  
Antonia Camporeale ◽  
Anna Regalia ◽  
Marta Ferraresi ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Cardiac Involvement ◽  
Late Onset ◽  
Left Ventricular ◽  
Lysosomal Storage ◽  
Fabry Patient ◽  
First Case ◽  
Gla Gene ◽  
Stage Renal Disease ◽  
End Stage

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity and, consequently, to glycosphingolipid accumulation in a wide variety of cells. Fabry disease due to N215S (c.644A>G, p.Asn215Ser) missense mutation usually results in a late-onset phenotype presenting with isolated cardiac involvement. We herein present the case of a patient with N215S mutation with cardiac involvement, namely left ventricular hypertrophy and ventricular arrhythmias, and end-stage renal disease requiring kidney transplantation. To the best of our knowledge, this is the first report of a kidney-transplanted Fabry patient treated with oral pharmacologic chaperone migalastat.

scholarly journals Endocrine disorders in patients with Fabry disease: insights from a reference centre prospective study

Endocrine ◽  
2021 ◽  
Author(s):  
Christina Bothou ◽  
Felix Beuschlein ◽  
Albina Nowak
Keyword(s):  
Prospective Study ◽  
Fabry Disease ◽  
Late Onset ◽  
Density Lipoprotein ◽  
Endocrine System ◽  
Endocrine Disorders ◽  
Enzyme Replacement ◽  
Reference Centre ◽  
Thyroid Screening ◽  
Classic Phenotype

Abstract Context Fabry Disease (FD) is a rare X-linked storage disease characterised by a-galactosidase A deficiency and diffuse organ accumulation of glycosphingolipids. Enzyme replacement and chaperone therapies are only partially effective. It remains unclear if FD-related endocrine disorders contribute to the observed morbidity. Objective To investigate the function of the endocrine system in patients with FD. Design We conducted an observational prospective study from 2017 to 2020. Setting and patients We included 77 patients with genetically confirmed FD (27 men, 20/27 Classic, 7/26 Late Onset phenotype, 50 women, 41/50 and 9/50 respectively), who are systematically followed by our reference centre. Results 36/77 (46.8%) patients had VitD deficiency (25(0H)VitD <20 μg/L) despite the fact that 19/36 (52.8%) were substituted with cholecalciferol. Only 21/77 (27.3%) patients had normal VitD levels without VitD substitution. 11/77 (14.3%) had significant hypophosphatemia (p < 0.80 mmol/L). Three new cases (3.9%) of subclinical, two (2.6%) of overt and six (7.8%) of known hypothyroidism were identified. Of note, men had significantly higher renin levels than women [61.4 (26.1–219.6) vs.25.4 (10.9–48.0) mU/L, p = 0.003]. There were no major abnormalities in adrenal, growth and sex-hormone axes. Patients of Classic phenotype had significantly higher High-Density Lipoprotein Cholesterol (HDL-C) levels (p = 0.002) and in men those levels were positively correlated with globotriaosylsphingosin (Lyso-Gb3) values. 10/77 (13%) of the patients were underweight. Conclusions VitD supplementation should be considered for all patients with FD. Thyroid screening should be routinely performed. Malnutrition should be prevented or treated, particularly in Classic phenotype patients. Overall, our data suggest that FD specialists should actively seek and diagnose endocrine disorders in their patients.

Genetic Management Algorithm in High-Risk Fabry Disease Cases; especially in Female Indexes with Mutations

2020 ◽  
Vol 20 ◽  
Author(s):  
Ozlem Sezer ◽  
Serdar Ceylaner
Keyword(s):  
High Risk ◽  
Fabry Disease ◽  
Family Members ◽  
Lysosomal Storage ◽  
Genetic Management ◽  
Screening Programs ◽  
Variants Of Unknown Significance ◽  
Management Algorithm ◽  
Unknown Significance ◽  
Gla Gene

Background: Fabry Disease (FD, OMIM#301500) is a progressive, life-threatening, multisystemic, rare lysosomal storage disease. Today, approximately 1000 mutations are recorded in the Human Gene Mutation Database (www.hgmd.org) for GLA. Among the identified mutations, genetic variants of unknown significance (GVUS) and novel mutations cause problems in terms of diagnosis and treatment approach. Methods: In our study, 510 high-risk patients were enrolled. 229 of 510 were Male (45%) (Mean age was 40.8 ±15.0) and 281 of were Female (55%) (Mean age was 39, 7±15.5). The definite diagnosis of FD was confirmed by GLA gene sequence analysis. GLA mutation was found in 15 cases (3.4%). Family members of the relevant indexes were included in the screening programs according to the X-linked inheritance pattern. And then we conducted family screening on 74 family members of 15 index cases. Of those 74 cases 39 had mutations (53%). In males, α-GalA activity and in both gender Lyso-Gb3 levels were measured and multisystem evaluation was performed in all cases with mutation. Results: We found six different familial mutation types; two of them pathogenic; p.D170N (1), p.P205S (13), one of them GVUS; p.Q330R (1), three of them likely benign; p.D313Y (12), p.S126G (25), c.-30G>A (2) mutations were detected. Conclusions: The purpose of this retrospective study is to approach Fabry disease on a genetic basis and to improve its management and to draw attention to the importance of early diagnosis. We also aimed to evaluate the appropriate algorithms to determine whether the mutation is the FD-causing mutation or not.

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