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.

scholarly journals Characterization and phosphoproteomic analysis of a human immortalized podocyte model of Fabry disease generated using CRISPR/Cas9 technology

2016 ◽  
Vol 311 (5) ◽  
pp. F1015-F1024 ◽  
Author(s):  
Ester M. Pereira ◽  
Anatália Labilloy ◽  
Megan L. Eshbach ◽  
Ankita Roy ◽  
Arohan R. Subramanya ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Human Kidney ◽  
Premature Death ◽  
Antibody Array ◽  
Cell Models ◽  
Lysosomal Storage ◽  
Protein Levels ◽  
Gla Gene ◽  
Fabry Nephropathy ◽  
And Control

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-galactosidase A (α-Gal A), progressively accumulates within cells in a variety of tissues. Establishment of cell models has been useful as a tool for testing hypotheses of disease pathogenesis. 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. Our podocytes lack detectable α-Gal A activity and have increased levels of Gb3. To explore different pathways that could have distinct patterns of activation under conditions of α-gal A deficiency, we used a high-throughput antibody array to perform phosphorylation profiling of CRISPR/Cas9-edited and control podocytes. Changes in both total protein levels and in phosphorylation status per site were observed. Analysis of our candidate proteins suggests that multiple signaling pathways are impaired in FD.

scholarly journals Screening for Fabry Disease in Young Strokes in the Australian Stroke Clinical Registry (AuSCR)

2020 ◽  
Vol 11 ◽  
Author(s):  
Alejandra Malavera ◽  
Dominique A. Cadilhac ◽  
Vincent Thijs ◽  
Joyce Y. Lim ◽  
Brenda Grabsch ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Future Research ◽  
Unknown Etiology ◽  
Lysosomal Storage ◽  
Clinical Registry ◽  
Stroke Registry ◽  
Case Identification ◽  
South Wales ◽  
Alpha Galactosidase ◽  
Gla Gene

Introduction: Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficiency or absence of alpha-galactosidase A (α-GAL A) enzyme, where stroke can be a serious complication. The aim of this study is to determine the feasibility of centralized screening for FD, among young stroke adults registered in the national Australian Stroke Clinical Registry (AuSCR).Methods: The study was conducted in young (age 18 – 55 years) survivors of acute stroke of unknown etiology registered in AuSCR at hospitals in Queensland, Tasmania, New South Wales, and Victoria during 2014 – 2015; and who, at the 3-month outcome assessment, agreed to be re-contacted for future research. Descriptive analyses of case identification from responses and specific enzyme and DNA sequencing analyses were conducted for α-galactosidase A (α-GLA) from dried blood spot (DBS) testing.Results: Of 326 AuSCR-identified patients invited to participate, 58 (18%) provided consent but six were subsequently unable to provide a blood sample and two later withdrew consent to use their data. Among the remaining 50 participants (median age 53 years [48 – 56 years]; 47% female), 67% had experienced an acute ischemic stroke. All males (n = 27) had an initial screen for α-GLA enzyme activity of whom seven with low enzyme levels had normal secondary α-GLA gene analysis. All females (n = 23) had genetic analysis, with one shown to have a pathogenic c.352C>T p.(Arg118Cys) missense mutation of the α-GLA gene for FD.Conclusions: These findings provide logistical data for embedding a process of automated central stroke registry screening for an additional case-finding tool in FD.

A Case of a 49-Year-Old Man with Nonclassical Fabry Disease Diagnosed by Renal Biopsy

Nephron ◽  
2021 ◽  
pp. 1-4
Author(s):  
Lanjun Fu ◽  
Peipei Zhang ◽  
Qingqing Ye ◽  
Manman Wu ◽  
Lingzhi He
Keyword(s):  
Fabry Disease ◽  
Renal Biopsy ◽  
Correct Diagnosis ◽  
Premature Mortality ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
St Segment ◽  
Major Organ ◽  
History Of ◽  
Gla Gene

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficiency of α-GLA activity, leading to major organ failure and premature mortality. According to different disease courses, FD can be divided into classical and nonclassical phenotypes. The nonclassical FD phenotype is always absent of characteristic symptoms, which makes identifying it challenging. This article presents a 49-year-old man with a 10-year history of proteinuria and decreased glomerular filtration rate. An electrocardiogram showed a complete right bundle branch block and abnormal Q waves in high lateral, accompanied by dramatically elevated ST segment. Consequently, a renal biopsy was performed. Vacuolation was found in many podocytes in light microscopic examinations. Similarly, a myelin-like structure was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, genetic analysis, p.R301Q (c.902G>A [p.Arg301Gln]), confirmed the FD diagnosis. Angiotensin receptor blocker and traditional Chinese medicine, but not enzyme replacement therapy, were prescribed due to financial constraints. The patient had stabilization of kidney disease 6 months later. The case showed that renal biopsy should be performed in patients with cardiac and renal symptoms, which could contribute toward the correct diagnosis for nonclassical FD type.

scholarly journals Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-Up

2021 ◽  
Vol 10 (8) ◽  
pp. 1664
Author(s):  
Clara Carnicer-Cáceres ◽  
Jose Antonio Arranz-Amo ◽  
Cristina Cea-Arestin ◽  
Maria Camprodon-Gomez ◽  
David Moreno-Martinez ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Fabry Disease ◽  
Clinical Manifestations ◽  
Organ Injury ◽  
Lysosomal Storage ◽  
Pathogenic Mechanisms ◽  
Enzyme Replacement ◽  
Alpha Galactosidase ◽  
Gla Gene ◽  
Response Biomarkers

Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease.

scholarly journals Utilizing ExAC to Assess the Hidden Contribution of Variants of Unknown Significance to Sanfilippo Type B Incidence

2018 ◽  
Author(s):  
Wyatt T. Clark ◽  
G. Karen Yu ◽  
Mika Aoyagi-Scharber ◽  
Jonathan H. LeBowitz
Keyword(s):  
Disease Incidence ◽  
Potential Contribution ◽  
Type B ◽  
Lysosomal Storage ◽  
Sequencing Data ◽  
Activity Data ◽  
Missense Variants ◽  
Variants Of Unknown Significance ◽  
Monogenic Diseases ◽  
Unknown Significance

AbstractGiven the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested this idea on a rare, monogenic, lysosomal storage disorder, Sanfilippo Type B (Mucopolysaccharidosis type IIIB).Sanfilippo Type B is caused by mutations in the gene encoding α-N-acetylglucosaminidase (NAGLU). There were 189 NAGLU missense variants found in the ExAC dataset that comprises roughly 60,000 individual exomes. Only 24 of the 189 missense variants were known to be pathogenic; the remaining 165 variants were of unknown significance (VUS), and their potential contribution to disease is unknown.To address this problem, we measured enzymatic activities of 164 NAGLU missense VUS in the ExAC dataset and developed a statistical framework for estimating disease incidence with associated confidence intervals. We found that 25% of VUS decreased the activity of NAGLU to levels consistent with Sanfilippo Type B pathogenic alleles. We found that a substantial fraction of Sanfilippo Type B incidence (67%) could be accounted for by novel mutations not previously identified in patients, illustrating the utility of combining functional activity data for VUS with population-wide allele frequency data in estimating disease incidence.

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 Fabry disease screening in high-risk populations in Japan: A nationwide study

2020 ◽  
Author(s):  
Shinichiro Yoshida ◽  
Jun Kido ◽  
Takaaki Sawada ◽  
Ken Momosaki ◽  
Keishin Sugawara ◽  
...  
Keyword(s):  
High Risk ◽  
Fabry Disease ◽  
Dried Blood Spots ◽  
Neurological Manifestations ◽  
Study Results ◽  
Novel Variants ◽  
Screening Study ◽  
Screening Protocol ◽  
High Risk Populations ◽  
Gla Gene

Abstract Background: Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in the deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause multisystemic dysfunction. A recent screening study among neonates reported an increase in the incidence of FD, and numerous FD patients remain undiagnosed or even misdiagnosed . Therefore, this study aimed to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all prefectures in Japan . A total of 601 hospitals participated in this study. Results: Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were identified from among 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment. Conclusions: From among 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.

SCREENING DIAGNOSTICS OF FABRIC DISEASE AMONG PATIENTS WITH CHRONIC KIDNEY DISEASE IN THE NORTH-WESTERN REGION OF RUSSIA

2019 ◽  
Vol 23 (1) ◽  
pp. 51-59
Author(s):  
K. A. Vishnevskii ◽  
E. V. Frolova ◽  
O. M. Domashenko ◽  
T. V. Proshina ◽  
O. V. Makarova ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Russian Federation ◽  
Screening Programs ◽  
Enzyme Replacement ◽  
West Region ◽  
Gla Gene

Fabry disease (FD) is a progressive multi-organ disease leading to the development of cardiovascular and cerebrovascular complications and progression of renal failure. Nonspecificity of clinical signs often leads to late diagnosis of the FD that causes high diagnostic relevance of screening in high risk groups, particularly among patients with chronic kidney disease (CKD). According to the results of screening programs in many countries, the average prevalence of FD among patients with CKD is about 0.26%. THE AIM of this study was to investigate the prevalence of FD in patients with CKD in the northern west region of Russian Federation. PATIENTS AND METHODS. This prospective study assessed α-galactosidase A (α-Gal A) activity in dried blood spots in 1835 stage 1-5 CKD (85% – dialysis, 15% – pre-dialysis) patients, 74% males, mean age 55±12 years. The survey was carried out regardless of gender, age and primary diagnosis leading to CKD. The activity of α-Gal A more than 1.89 umol/l/hr was considered as normal. In the case of identifying the decreased activity of the enzyme the diagnosis was confirmed by GLA gene mutation analysis. RESULTS. The average level of α-Gal A was 5.39±2.69 umol/l/h. The level of α-Gal A was significantly higher in patients with pre-dialysis stages of CKD compared with patients receiving dialysis (7.5±3 vs 4.3±2.3 umol/l/h, p<0.001) as well as in males higher than in females (5.9±3.4 vs 3.4±2.3 umol/l/h, p <0.001). The decrease in α-Gal A activity was detected in 6 patients, of which 3 had the GLA gene mutations (c.427G>A, с.818Т>С, c.895G>C). One patient (p.508G> T) had a confirmed FD and received an enzyme-replacement therapy at the time of screening. All patients with identified FD were males treated by hemodialysis. Thus, the prevalence of FD in patients with CKD C5d was 1:392 (0.26%). A survey of relatives revealed the disease in two additional cases. CONCLUSION. The prevalence of Fabry disease in selected CKD patients of northern west region of Russian Federation is in the mean worldwide range. In all cases, the FD was not timely diagnosed, leading to serious organ damage and delaying the onset of enzyme replacement therapy. Thus, the screening of FD is necessary at the early stages of CKD.

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