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

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.

Download Full-text

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

Journal of Clinical Medicine ◽

10.3390/jcm10081664 ◽

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.

Download Full-text

Major Organic Involvement in Women with Fabry Disease in Argentina

The Scientific World JOURNAL ◽

10.1155/2018/6515613 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Fernando Perretta ◽

Norberto Antongiovanni ◽

Sebastián Jaurretche

Keyword(s):

Fabry Disease ◽

Significant Proportion ◽

Lysosomal Storage ◽

Protein Loss ◽

Cross Sectional ◽

X Chromosomes ◽

Cornea Verticillata ◽

Lyon Hypothesis ◽

Alpha Galactosidase ◽

Gla Gene

Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the deficiency or absence of the alpha galactosidase A enzyme. Organic involvement in men is well known, but in women it is controversial, partly due to the random X-chromosomes inactivation (Lyon hypothesis). The aim of this study was to describe the organic involvement in women at the time of FD diagnosis. A descriptive, cross-sectional and multicenter study was carried out. Thirty-five women with FD from three reference centers in Argentina were evaluated. The mean age of the whole group (n=35) was 26.6±16.9 years; 22 were adult (over 18) and 13 were paediatric patients. Enzymatic activity was performed in 29/35 patients, which was normal in 24/29 (82.8%). Seven different mutations of the GLA gene were found. The results showed urinary protein loss (45.7%) and decreased glomerular filtration rate (31.4%), mainly in adults. And also, cornea verticillata (56.5%), peripheral neuropathy (51.4%), cardiovascular manifestations (31.4%), hearing loss (20%), angiokeratomas (20%), central nervous system (17.1%), and gastrointestinal involvement (14.3%). Organic compromise in females with FD may be as severe as in men. This analysis has demonstrated a significant proportion of women with signs, symptoms, and major organic involvement at FD diagnosis.

Download Full-text

The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field

International Journal of Molecular Sciences ◽

10.3390/ijms22031331 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1331

Author(s):

Daniela Sorriento ◽

Guido Iaccarino

Keyword(s):

Fabry Disease ◽

Molecular Mechanisms ◽

Cell Damage ◽

Research Field ◽

Cardiac Cell ◽

Lysosomal Storage ◽

Clinical Level ◽

New Findings ◽

Alpha Gene ◽

Alpha Galactosidase

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD’s development and progression that could become useful targets for therapeutics. This review discusses FD’s cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.

Download Full-text

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

AJP Renal Physiology ◽

10.1152/ajprenal.00283.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. F1015-F1024 ◽

Cited By ~ 6

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.

Download Full-text

Fabry disease

10.1093/med/9780199592548.003.0336 ◽

2015 ◽

Author(s):

Stephen Waldek

Keyword(s):

Fabry Disease ◽

Ventricular Hypertrophy ◽

Severe Disease ◽

Sensorineural Deafness ◽

Left Ventricular ◽

Lysosomal Storage ◽

Long Time ◽

Alpha Galactosidase ◽

Multiorgan Disease ◽

Echocardiographic Evidence

Fabry disease is a rare X-linked lysosomal storage disorder in which deficiency of alpha-galactosidase A leads to accumulation of substrate, mostly globotriaosylceramide, which causes a progressive, multiorgan disease affecting predominantly the kidneys, skin, heart, gut, and nervous system. Painful peripheral (‘acral’) neuropathy is characteristic. The disease is commonly diagnosed in children and young men often after some years of usually neuropathic symptoms, with exacerbations (Fabry crises), that commonly elude diagnosis for a long time. These usually occur years in advance of overt involvement of other organs. Diagnosis may also be suspected from renal biopsy, echocardiographic evidence of cardiomyopathy commonly beginning as left ventricular hypertrophy, or characteristic angiokeratomas typically in ‘bathing trunk’ distribution on skin. Renal manifestations are of proteinuria leading to progressive chronic kidney disease associated with deposits in podocytes. Diarrhoea is common. Disordered sweating is typical. Corneal lesions are also typical and there may be tortuosity of retinal vessels. Strokes are increased in frequency, and sensorineural deafness may occur. Women have fewer and later overt manifestations but some develop severe disease.

Download Full-text

Nationwide screening for Fabry disease in unselected stroke patients

PLoS ONE ◽

10.1371/journal.pone.0260601 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0260601

Author(s):

Aleš Tomek ◽

Reková Petra ◽

Jaroslava Paulasová Schwabová ◽

Anna Olšerová ◽

Miroslav Škorňa ◽

...

Keyword(s):

Fabry Disease ◽

Dried Blood Spots ◽

Lysosomal Storage ◽

Limited Data ◽

Stroke Patients ◽

Stroke Event ◽

Index Stroke ◽

Alpha Galactosidase ◽

Stroke Type ◽

Ischemic Attack

Background and aims Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. There are limited data on prevalence of FD and stroke risk in unselected stroke patients. Methods A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males—enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3. Results 986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02–0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08–2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables. Conclusions The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.

Download Full-text

Previously Unidentified Gene Variation Associated with Fabry Disease: The Impact on One Family

Case Reports in Nephrology ◽

10.1155/2020/8899703 ◽

2020 ◽

Vol 2020 ◽

pp. 1-3

Author(s):

Amaresh R. Vanga ◽

Samantha A. Schrier Vergano ◽

Jolanta Kowalewska ◽

Thomas R. McCune

Keyword(s):

Fabry Disease ◽

Genetic Disorder ◽

Missense Variant ◽

Lysosomal Storage ◽

Normal Range ◽

Genetic Studies ◽

Gene Variation ◽

Zebra Bodies ◽

Alpha Galactosidase ◽

The Impact

Fabry disease is an X-linked lysosomal storage genetic disorder associated with over 1000 mutations in the alpha-galactosidase-A gene region. We report here a 69-year-old male who underwent a kidney biopsy to evaluate progressive renal failure. He was found to have zebra bodies in visceral epithelial cells on biopsy, with electron microscopy showing inclusions within the cytoplasm of multiple podocytes consistent with Fabry disease. An alpha-galactosidase level was found to be 21 nm/hr/mg (normal range 50–150 nm/hr/mg). Genetic studies revealed a missense variant in the GLA gene with alanine replaced by cysteine at position 682 (c.682 A > C, p.N228H) that had not been previously associated with Fabry disease. The same variant was detected in two additional family members. The pathologic findings, clinical features, and low alpha-galactosidase level suggest that the c.682 A > C variant is associated with Fabry disease.

Download Full-text

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

Nephron ◽

10.1159/000516924 ◽

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.

Download Full-text

Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21165784 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5784

Author(s):

Sanne J. van der Veen ◽

Wytze J. Vlietstra ◽

Laura van Dussen ◽

André B.P. van Kuilenburg ◽

Marcel G. W. Dijkgraaf ◽

...

Keyword(s):

Fabry Disease ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Treatment Prediction ◽

Multiple Variables ◽

Male Patients ◽

Pre Treatment ◽

Alpha Galactosidase ◽

Development Risk ◽

Associated Variables

Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.

Download Full-text

Frequency of Fabry Disease in a Juvenile Idiopathic Arthritis Cohort

10.21203/rs.3.rs-60936/v1 ◽

2020 ◽

Author(s):

Luciana Paim-Marques ◽

Amanda Virginia Cavalcante ◽

Islane Verçosa ◽

Paula Carneiro ◽

Marcia Souto-Maior ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Fabry Disease ◽

Clinical Symptoms ◽

Molecular Genetic ◽

Disease Onset ◽

Pathogenic Mutation ◽

Lysosomal Storage ◽

Variant Of Uncertain Significance ◽

Alpha Galactosidase ◽

Intronic Variants

Abstract Background: Fabry disease (FD) is a rare, X-linked, multisystemic lysosomal storage disorder (LSD) that results from a deficiency in the hydrolase alpha-galactosidase A (⍺-GalA). In childhood, classic FD symptomatology is rare. Majority of children present with mild non-specific symptoms, including the musculoskeletal system. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients is unknown. Objective: The aim was to identify the frequency of FD in a JIA cohort, characterizing early clinical symptoms, enzyme titers and GLA genotyping. Methods: Children with JIA followed in tertiary Children Hospital cohort were selected. Clinical, laboratorial, and familiar information was recorded. Molecular genetic testing to detect GLA gene mutations was performed in the girls and enzymatic analysis in the boys. Results: In 89 patients (56.2% female, age at disease onset: 8.93 ± 4.35 years), one male (1.12%) patient presented pathogenic mutation in GLA gene, c.1244T>C p.L415P, one female patient had a variant of uncertain significance c.38C>T (p.Ala13Val). The enzymatic activity of alpha galactosidase was slightly decreased in 3 additional (3.4%) patients. We observed the presence of intronic variants in 44.44% of our cohort: c.1000-22C> T; c.370-81_-77del; c.640-16A> G; c.10C>T; c.548-125C> G and c.-12G> A. These variants and their combination were associated with clinical symptoms in our cohort. Conclusions: The incidence of FD in our cohort was 1.12%. Intronic variants were associated with symptomatology described in the literature. Screening for FD in JIA may be a reasonable strategy for those with atypical pattern pain.

Download Full-text