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

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.

Fabry disease

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.

scholarly journals Nationwide screening for Fabry disease in unselected stroke patients

PLoS ONE ◽  
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.

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.

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

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.

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

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.

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 Frequency of Fabry Disease in a Juvenile Idiopathic Arthritis Cohort

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.

Fabry disease

2015 ◽  
Author(s):  
Stephen Waldek
Keyword(s):  
Fabry Disease ◽  
Clinical Signs ◽  
Left Ventricular ◽  
Lysosomal Storage ◽  
Characteristic P ◽  
Screening Strategies ◽  
Normal Enzyme ◽  
Alpha Galactosidase ◽  
Eye Lesions ◽  
Multiorgan Disease

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, and nervous system. Painful peripheral (‘acral’) neuropathy is characteristic.Key clinical signs are angiokeratoma found by close examination of skin; characteristic eye lesions may be seen; lipid deposits may be seen in urine. Renal biopsy appearances are characteristic and this is commonly where the diagnosis is first made. Increasingly, cardiologists are suspecting the condition in adults with echocardiographic appearances of left ventricular hypertrophy. Diagnosis in men is usually made by measurement of alpha-galactosidase in either white cells or plasma (or using blood spots). Unfortunately, many female patients can have normal enzyme levels so that genetic testing is the only way to confirm a diagnosis. Non-selective screening strategies (e.g. males on renal replacement therapy with uncertain renal diagnoses) have had low yields.

scholarly journals Frequency of Fabry disease in a Juvenile Idiopathic Arthritis Cohort

2021 ◽  
Author(s):  
Luciana Paim-Marques ◽  
Amanda Virginia Cavalcante ◽  
Islane Verçosa ◽  
Paula Carneiro ◽  
Marcia Souto-Maior ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Fabry Disease ◽  
Clinical Laboratory ◽  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Disease Onset ◽  
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). During childhood, classic FD symptomatology is rare. The majority of children may show non-specific symptoms, including in the musculoskeletal system. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients is unknown.Objective: This study aimed 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 a tertiary Children Hospital cohort were selected. Clinical, laboratory and familiar information were recorded. Molecular genetic testing to detect GLA gene mutations was performed in girls and enzymatic analysis in 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). Three additional (3.4%) patients had the enzymatic activity of alpha-galactosidase slightly decreased. We observed the presence of intronic variants in 44.44% of patients in 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 symptoms previously described in the literature. Screening for FD in JIA may be a reasonable strategy for those with an atypical pattern of pain.

Autopsy Findings of Heterozygous Fabry Disease with the Severe Phenotype: A Case Report

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Maki Hiratsuka ◽  
Katsushi Koyama ◽  
Makoto Ito ◽  
Ryo Sato ◽  
Kodai Suzuki ◽  
...  
Keyword(s):  
Renal Failure ◽  
Fabry Disease ◽  
Cerebral Hemorrhage ◽  
Lysosomal Storage ◽  
Severe Phenotype ◽  
Autopsy Findings ◽  
Enzyme Replacement ◽  
Alpha Galactosidase ◽  
End Stage

Fabry disease (FD) is an inherited X-linked lysosomal storage disorder, with hemizygous males being more severely affected than heterozygous females. Herein, we report a rare case of FD in a heterozygous female with a severe phenotype. The patient had obesity and hyperlipidemia and had her first cerebral infarction at the age of 33 years. She underwent renal biopsy and was diagnosed with FD with morphological features of focal segmental glomerulosclerosis nephropathy at the age of 34 years. Her leukocyte alpha-galactosidase A activity was 2.3 Agal/U (normal: &#x3e;20 Agal/U), and genetic analysis revealed the presence of the classical phenotype. Enzyme replacement therapy (ERT) was initiated at the age of 35 years; however, peritoneal dialysis owing to end-stage renal failure occurred at the age of 37 years. The patient died of a cerebral hemorrhage at the age of 44 years. Her Mainz Severity Score Index at the time of death was 48/76, suggestive of the severe phenotype. Autopsy findings revealed remarkable globotriaosylceramide accumulation on electron microscopy, particularly in the major organs and their vascular smooth muscle cells. Regarding the vertebral arteries which sourced the cerebral hemorrhage, the effects of FD-induced vascular thickening and long-term renal failure-induced atherosclerosis were confirmed. Furthermore, the patient’s vascular sclerosis was modified with acquired factors such as lifestyle-related disease associated with obesity. We recommend intensified treatment for metabolic factors simultaneous with ERT to help in delaying the progression of FD.

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