Nationwide screening for Fabry disease in unselected stroke patients

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

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

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

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

Frontiers in Neurology ◽

10.3389/fneur.2020.596420 ◽

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.

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

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

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

Family genetic screening in rare hereditary diseases

Clinical pharmacology and therapy ◽

10.32756/0869-5490-2021-4-6-12 ◽

2021 ◽

Vol 31 (4) ◽

pp. 6-12

Author(s):

S.I. Kutsev ◽

S. Moiseev

Keyword(s):

Fabry Disease ◽

Specific Treatment ◽

Left Ventricular ◽

Hereditary Diseases ◽

Lysosomal Storage ◽

Family Screening ◽

At Risk Populations ◽

Ischemic Attack ◽

Stage Renal Disease ◽

End Stage

Family genetic testing of probands with newly diagnosed rare hereditary diseases including Fabry disease improves early diagnosis and allows to initiate specific treatment, if available, at earlier stage in affected family members. Diagnosis of Fabry disease, an X-linked lysosomal storage disorder affecting kidneys, heart, brain and other organs, is usually late due to low awareness of physicians about rare diseases. Moreover, early symptoms can be non-specific (e.g. gastrointestinal disorders and autonomic neuropathy) or misleading (e.g. recurrent unexplained fever) whereas characteristic skin rash and keratopathy (cornea verticillata) are frequently overlooked. Undiagnosed patients with Fabry disease can be detected by screening in at-risk populations, such as patients with end-stage renal disease undergoing dialysis or renal transplantation, patients with unexplained left ventricular hypertrophy, and young adults with a history of stroke or transient ischemic attack who have a higher prevalence of the disease compared to general population. High-risk screening paves the way to family screening to identify affected relatives, including children, who can benefit from earlier treatment and genetic counselling. The major barriers to family screening include costs of testing, cultural and societal issues, stigma associated with a diagnosis of genetic disease, low contacts in the family, weak infrastructure, national regulations.

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

Abstract P654: Predicting Afib in Cryptogenic Ischemic Stroke Patients With Implantable Loop Recorders

Stroke ◽

10.1161/str.52.suppl_1.p654 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Claribel D Wee ◽

Tejeswi Suryadevara ◽

Husitha Vanguru ◽

Rashid Ahmed ◽

Danielle Hawley ◽

...

Keyword(s):

Ischemic Stroke ◽

Median Time ◽

Scoring System ◽

Cryptogenic Stroke ◽

Stroke Patients ◽

Stroke Event ◽

Loop Recorder ◽

Index Stroke ◽

Chart Abstraction ◽

History Of

Paroxysmal atrial fibrillation (Afib) detection in cryptogenic stroke is difficult but essential because it changes management. We describe a scoring system that discriminates between cryptogenic ischemic stroke patients with implantable loop recorder (ILR) that were and were not found to have Afib. Consecutive cryptogenic stroke cases from cardiology’s ILR registry for a 2-year period (7/2017-7/2019) were reviewed. We used standardized case report forms to perform chart abstraction. Cases were excluded if ILR was not placed after the index stroke event, stroke etiology workup was not available, or data was incomplete. Patients found to have Afib on ILR were compared to those without evidence of Afib on ILR. We devised a novel scoring system using variables associated with Afib detection and compared its ability to classify Afib detection against CHA2DS2-VASc and LADS. One hundred fifty-seven patients met inclusion criteria. Afib was detected in 12% of cases (9% at 6 months, 10% at 12 months). The median time from ILR placement to Afib detection was 110 days (IQR 37, 507). Median time from Afib detection to the start of anticoagulation was 3 days (IQR 0, 8). The PAL-CrISP score ranges 0 to 7: age (70=0, ≥70=4), history of antihypertensive medication (no=0, yes=2), PR interval (≤200msec=0, >200msec=1). Of those found to have Afib via ILR, 74% (14/19) had a PAL-CrISP score ≥ 6. PAL-CrISP performed better at predicting Afib detection in cryptogenic ischemic stroke patients with ILR (AUC 0.810, 95% CI 0.706-0.913) than CHA2DS2-VASc (AUC 0.650, 95% CI 0.525-0.774) and LADS (AUC 0.745, 95% CI 0.624-0.866). Using only age, home medication review, and an EKG, the novel PAL-CrISP score performs better at predicting Afib detection than the CHA2DS2-VASc and LADS scores in cryptogenic ischemic stroke patients with an ILR.

Download Full-text

Abstract WP231: Predictors for Early Atrial Fibrillation Detection Among Cryptogenic Stroke Patients with Insertable Cardiac Monitors: A Single-center Experience

Stroke ◽

10.1161/str.48.suppl_1.wp231 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Ganesh Asaithambi ◽

Jane E Monita ◽

Sandra K Hanson

Keyword(s):

Atrial Fibrillation ◽

Cryptogenic Stroke ◽

Single Center ◽

Inclusion Criteria ◽

Stroke Patients ◽

Stroke Event ◽

Single Center Experience ◽

Pr Interval ◽

Index Stroke ◽

Left Atrial Dilatation

Background: The use of insertable cardiac monitors (ICM) has increased the rate of detection of atrial fibrillation (AF) among cryptogenic stroke (CS) patients. We describe a single-center experience for AF detection among CS patients receiving ICMs upon discharge after the index stroke event and attempt to identify predictors for early AF detection. Methods: From April 2014 to April 2016, patients receiving ICMs upon discharge for CS who underwent >90 days of monitoring were reviewed. Time from ICM placement to AF detection, chronic underlying medical illnesses, presence of left atrial dilatation (LAD) on echocardiography, and PR interval on admission EKG were assessed as predictors of early AF detection. Results: A total of 114 patients met inclusion criteria and were followed for a median of 415 [268, 557] days. Among these 32 patients (28.1%) were found to have AF at a median of 53 [5, 132] days from ICM placement. Patients with AF detected <30 days from ICM placement had lower rates of hyperlipidemia (35.7% vs 88.9%, p=0.003) and higher rates of hypertension (100% vs 66.7%, p=0.02), tobaccoism (85.7% vs 33.3%, p=0.005), LAD (64.3% vs 16.7%, p=0.01), and prolonged PR interval (195.3±43.2 ms vs 170.3±23.4 ms, p=0.04) compared to patients with AF detected >30 days from ICM placement. Conclusion: More than one-quarter of CS patients monitored for >90 days with an ICM were found to have previously undiagnosed AF. The majority of patients with AF detected were identified >30 days after their index CS event. Among patients in whom AF was ultimately detected by the ICM, AF may be identified earlier among patients with hypertension and tobaccoism in combination with LAD and prolonged PR interval. Prospective studies are needed to better identify predictors for early AF among the broader population of all CS patients.

Download Full-text