scholarly journals Review of Mechanisms, Pharmacological Management, Psychosocial Implications, and Holistic Treatment of Pain in Fabry Disease

2021 ◽  
Vol 10 (18) ◽  
pp. 4168
Author(s):  
Jonathan Niranjan Rajan ◽  
Katharine Ireland ◽  
Richard Johnson ◽  
Karolina M. Stepien
Keyword(s):  
Fabry Disease ◽  
Lysosomal Storage ◽  
Ischaemic Injury ◽  
Pharmacological Management ◽  
Small Fibre Neuropathy ◽  
Holistic Treatment ◽  
Neuronal Membranes ◽  
Small Fibre ◽  
Gla Gene ◽  
Hands And Feet

Fabry disease is a progressive X-linked lysosomal storage disease caused by a mutation in the GLA gene, encoding the lysosomal hydrolase α-galactosidase A. The consequent reduced enzyme activity results in the toxic accumulation of glycosphingolipids, particularly globortriaosylceramide (Gb3 or GL3), in blood vessels, renal epithelia, myocardium, peripheral nervous system, cornea and skin. Neuropathic pain is the most common manifestation of Fabry disease and can be extremely debilitating. This often develops during childhood and presents with episodes of burning and sharp pain in the hands and feet, especially during exercise and it is worse with increased heat or fever. It is thought to be due to ischaemic injury and metabolic failure, leading to the disruption of neuronal membranes and small fibre neuropathy, caused by a reduced density of myelinated Aδ and unmyelinated C-fibres and alterations in the function of ion channels, mediated by Gb3 and lyso Gb3. It is important to confirm small fibre neuropathy before any Fabry disease treatment modality is considered. There is a clinical need for novel techniques for assessing small fibre function to improve detection of small fibre neuropathy and expand the role of available therapies. The current Fabry disease guidelines are in favour of pharmacological management as the first-line treatment for pain associated with Fabry disease. Refractory cases would benefit from a rehabilitation approach with interdisciplinary input, including medical, physiotherapy and psychological disciplines and including a Pain Management Programme.

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.

Burning hands and feet of acute onset in 4 children with a small-fibre neuropathy with a monophasic course

2017 ◽  
Vol 21 ◽  
pp. e90
Author(s):  
N. Faignart ◽  
C. Soroken ◽  
K. Nguyen ◽  
C. Poloni ◽  
S. Lebon ◽  
...  
Keyword(s):  
Acute Onset ◽  
Small Fibre Neuropathy ◽  
Small Fibre ◽  
Hands And Feet

Small fibre neuropathy in Fabry disease

2012 ◽  
Vol 260 (3) ◽  
pp. 917-919 ◽  
Author(s):  
A. K. Bertelsen ◽  
C. Tøndel ◽  
J. Krohn ◽  
N. Bull ◽  
J. Aarseth ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Small Fibre Neuropathy ◽  
Small Fibre

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.

Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study

2010 ◽  
Vol 18 (4) ◽  
pp. 631-636 ◽  
Author(s):  
C. Tanislav ◽  
M. Kaps ◽  
A. Rolfs ◽  
T. Böttcher ◽  
K. Lackner ◽  
...  
Keyword(s):  
Pilot Study ◽  
Fabry Disease ◽  
Unknown Aetiology ◽  
Small Fibre Neuropathy ◽  
Small Fibre

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 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.

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 Diurnal Variation of Urinary Fabry Disease Biomarkers during Enzyme Replacement Therapy Cycles

2020 ◽  
Vol 21 (17) ◽  
pp. 6114
Author(s):  
Michel Boutin ◽  
Pamela Lavoie ◽  
Iskren Menkovic ◽  
Amanda Toupin ◽  
Mona Abaoui ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Biological Fluids ◽  
Lysosomal Storage ◽  
Sample Collection ◽  
Gene Encoding ◽  
Enzyme Replacement ◽  
Sugar Unit ◽  
Gla Gene

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). Enzyme impairment leads to substrate accumulation in different organs, vascular endothelia, and biological fluids. Enzyme replacement therapy (ERT) is a commonly used treatment. Urinary analysis of Gb3 isoforms (different fatty acid moieties), as well as lyso-Gb3 and its analogues, is a reliable way to monitor treatment. These analogues correspond to lyso-Gb3 with chemical modifications on the sphingosine moiety (−C2H4, −C2H4+O, −H2, −H2+O, +O, +H2O2, and +H2O3). The effects of sample collection time on urinary biomarker levels between ERT cycles were not previously documented. The main objective of this project was to analyze the aforementioned biomarkers in urine samples from seven Fabry disease patients (three treated males, three treated females, and one ERT-naïve male) collected twice a day (morning and evening) for 42 days (three ERT cycles). Except for one participant, our results show that the biomarker levels were generally more elevated in the evening. However, there was less variability in samples collected in the morning. No cyclic variations in biomarker levels were observed between ERT infusions.

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