Screening for Fabry Disease in Male Patients With Arrhythmia Requiring a Pacemaker or an Implantable Cardioverter–Defibrillator
2021; Lippincott Williams & Wilkins; Volume: 143; Issue: 8 Linguagem: Inglês
10.1161/circulationaha.120.051400
ISSN1524-4539
AutoresDimitri Hemelsoet, Jan De Keyser, Frédéric Van Heuverswyn, Rik Willems, Hans Vandekerckhove, Antoine Bondue, Carlo de Asmundis, Johan Saenen, Stefaan Van de Walle, Pascal Godart, Christoph Kampmann, Hedwig Stepman, Bruce Poppe, Wim Terryn,
Tópico(s)Cellular transport and secretion
ResumoHomeCirculationVol. 143, No. 8Screening for Fabry Disease in Male Patients With Arrhythmia Requiring a Pacemaker or an Implantable Cardioverter–Defibrillator Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBScreening for Fabry Disease in Male Patients With Arrhythmia Requiring a Pacemaker or an Implantable Cardioverter–Defibrillator Dimitri Hemelsoet, MD, Jan De Keyser, MD, Frederic Van Heuverswyn, MD, Rik Willems, MD, PhD, Hans Vandekerckhove, MD, Antoine Bondue, MD, PhD, Carlo de Asmundis, MD, PhD, Johan Saenen, MD, PhD, Stefaan Van de Walle, MD, Pascal Godart, MD, Christoph Kampmann, MD, PhD, Hedwig Stepman, PharmD, PhD, Bruce Poppe, MD, PhD and Wim Terryn, MD, PhD Dimitri HemelsoetDimitri Hemelsoet Dimitri Hemelsoet, MD, Department of Neurology, Ghent University Hospital, C. Heymanslaan 10, B-9000 Ghent, Belgium. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5403-3092 Departments of Neurology (D.H.), Ghent University Hospital, Belgium. UD-PrOZA - Program for Undiagnosed Rare Diseases (D.H., B.P., W.T.), Ghent University Hospital, Belgium. , Jan De KeyserJan De Keyser Departments of Cardiology (J.D.K.), Jan Yperman Hospital, Ypres, Belgium. , Frederic Van HeuverswynFrederic Van Heuverswyn Cardiology (F.V.H.), Ghent University Hospital, Belgium. , Rik WillemsRik Willems Department of Cardiovascular Sciences, University of Leuven, Belgium (R.W.). , Hans VandekerckhoveHans Vandekerckhove Department of Cardiology, AZ Sint-Lucas, Ghent, Belgium (H.V.). , Antoine BondueAntoine Bondue Department of Cardiology, Cliniques Universitaires de Bruxelles Hôpital Erasme and Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium (A.B.). , Carlo de AsmundisCarlo de Asmundis Department of Cardiology, Brussels University Hospital, Belgium (C.d.A.). , Johan SaenenJohan Saenen Department of Cardiology, Antwerp University Hospital, Belgium (J.S.). , Stefaan Van de WalleStefaan Van de Walle Department of Cardiology, AZ Delta, Roeselare, Belgium (S.V.d.W.). , Pascal GodartPascal Godart Department of Cardiology, Centre Hospitalier Universitaire Ambroise Paré, Mons, Belgium (P.G.). , Christoph KampmannChristoph Kampmann https://orcid.org/0000-0002-2929-2970 Department of Cardiology and Inherited Cardiomyopathies, Clinic for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Germany (C.K.). , Hedwig StepmanHedwig Stepman Clinical Biology (H.S.), Ghent University Hospital, Belgium. , Bruce PoppeBruce Poppe UD-PrOZA - Program for Undiagnosed Rare Diseases (D.H., B.P., W.T.), Ghent University Hospital, Belgium. Center for Medical Genetics (B.P.), Ghent University Hospital, Belgium. and Wim TerrynWim Terryn UD-PrOZA - Program for Undiagnosed Rare Diseases (D.H., B.P., W.T.), Ghent University Hospital, Belgium. General Internal Medicine and Nephrology (W.T.), Jan Yperman Hospital, Ypres, Belgium. Originally published22 Feb 2021https://doi.org/10.1161/CIRCULATIONAHA.120.051400Circulation. 2021;143:872–874Fabry disease is an X-linked lysosomal storage disorder attributable to α-galactosidase A enzyme (α-Gal A) deficiency, caused by mutations in the GLA gene which leads to accumulation of glycosphingolipids in various cells and tissues, resulting in a multisystemic disease with variable phenotype and major organ involvement including renal, cardiac, and cerebrovascular disease.1Cardiac manifestations include left ventricular hypertrophy, cardiomyopathy, and conduction abnormalities.2 Severe arrhythmia or sudden cardiac death occurs in a substantial proportion of patients with Fabry disease, with sudden cardiac death being reported as the cause of death in 62%.3We performed a prospective screening study for Fabry disease in a cohort of male patients with arrhythmia requiring a pacemaker or implantable cardioverter–defibrillator that might have been caused by undiagnosed Fabry disease.A total of 531 male patients (mean age, 65.9 years) with a pacemaker (68.0%) or implantable cardioverter–defibrillator (32.0%) for atrioventricular block, sinus dysfunction, or ventricular arrhythmia, implanted between the ages of ≥30 and <76 years (mean, 59.8 years), were eligible to be included in the study. Patients <30 and ≥76 years of age were excluded to avoid non-Fabry disease congenital cardiac disease and age-related cardiac degenerative disease as a cause of arrhythmia. Patients with a previous myocardial infarction (at the discretion of the treating cardiologist in case of pacemaker rhythm or conduction defects or defined within the absence of pacing or conduction defects) or patients who were unable or unwilling to comply with the study procedures were excluded from enrollment.The study was approved by the central ethics committee of Ghent University Hospital. All patients gave written informed consent.Screening for Fabry disease consisted of determination of α-Gal A enzyme activity using a dried blood spot sampled in filter paper. Patients with low or absent enzymatic activity (α-Gal A <0.64 μmol/L/h) were subjected to DNA analysis with direct sequencing of the 7 exons and flanking intronic sequences of the GLA gene.We screened 532 adult male White patients with a pacemaker or implantable cardioverter–defibrillator. We excluded 1 patient A) mutation was identified, confirming a diagnosis of Fabry disease. The patient characteristics and results are summarized in the Table. The data that support the findings of this study are available from the corresponding author on reasonable request.Table. Characteristics of the Identified Patients With Fabry DiseaseCharacteristicPatient 1Patient 2Patient 3Age, y646572α-Galactosidase, µmol/L/h<0.05 Ac.427G>Ac.427G>Ap.Ala143Thrp.Ala143Thrp.Ala143ThrCardiac presentationRecurrent syncopeAtypical angina, dyspnea, palpitationsCardiac arrestArrhythmia with indication pacemaker or implantable cardioverter–defibrillator2nd-degree atrioventricular block (Mobitz type 2), alternating bundle-branch blockSick sinus syndrome with chronotropic incompetenceTotal atrioventricular blockPacemaker or implantable cardioverter–defibrillatorPacemakerPacemakerPacemakerAge at implantation605868Cardiovascular risk profileArterial hypertension, obesity, obstructive sleep apnea, lack of physical activity, history of nicotine abuseArterial hypertension, lack of physical activity, history of nicotine abuse, stressArterial hypertension, obesity, lack of physical activity, history of nicotine abuse, atrial fibrillationECG PR interval, ms190140168ECG QRS duration, ms18696186ECG ST-T wave changesPaced–PacedNonsustained ventricular tachycardia+–+Interventricular wall thickness, mm13.413.415.0Posterior wall thickness, mm12.711.812.0Left ventricular massElevatedElevatedElevatedLeft atrial dilatation–++Heart valve abnormalities–Mitral insufficiency–Angiokeratoma–––Acroparesthesia–––PainArticularArticular–Hypohidrosis–––Hearing loss+++Tinnitus++–White matter lesions (MRI T2/FLAIR)++–Acute ischemic stroke–+–Vascular tortuosity–VertebrobasilarConjunctivalKidney failure/proteinuria––+Gastrointestinal problems–Cramps, diarrhea–Fatigue++–Cornea verticillata–––FLAIR indicates fluid attenuated inversion recovery; and MRI, magnetic resonance imaging.With this prospective screening study, we show that Fabry disease may cause (brady)-arrhythmia requiring device implantation in at least 0.5% of the study cohort. This prevalence is comparable with Fabry disease screening results in other high-risk populations with end-organ manifestations like hypertrophic cardiomyopathy, stroke, and chronic renal failure.4Our study identified 3 previously undiagnosed patients harboring the A143T mutation with absent or very low α-Gal A activity. The pathogenicity of the A143T GLA missense variant has been questioned, although several studies reported a higher prevalence of A143T compared with the general population frequency, and other studies reported this variant to be associated with a broad phenotypic spectrum, including severe classic phenotypes, oligosymptomatic cardiac or neurological presentations, and asymptomatic patients.5 Recently, a Finnish family with cardiomyopathy and a A143T GLA variant was reported with extensive documentation of Fabry disease features using clinical, imaging, biomarker, and histological data. Endomyocardial biopsy showed glycolipid accumulation. It is interesting to note that the female index patient and a son experienced syncopes and were diagnosed with, respectively, sick sinus syndrome and atrioventricular block. It was concluded that the A143T variant is likely to cause a late-onset Fabry disease with cardiomyopathy and has incomplete penetrance.5Our study highlights A143T as a pathogenic variant, associated with an attenuated phenotype, leading to cardiac disease with late-onset severe (brady)-arrhythmia.Because Fabry disease is treatable with enzyme replacement or chaperone therapy (for amenable mutations, including A143T), establishing the diagnosis timely in patients with (brady)-arrhythmia is important to prevent disease progression and additional complications. A correct diagnosis of Fabry disease also enables identification of family members at risk of carrying the pathogenic GLA mutation, allowing early diagnosis, treatment, and genetic counseling.Study limitations are exclusion of female and younger patients, as well as patients with previous myocardial infarction. Molecular confirmation of Fabry disease was not possible in 3 patients with very low or absent α-Gal A activity on dried blood spots. Therefore, additional patients with Fabry disease might have been missed, but all limitations emphasize the even potential higher diagnostic yield of screening in this target population with (brady)-arrhythmia.We conclude that arrhythmia requiring pacemaker/implantable cardioverter–defibrillator in adult male patients can be caused by Fabry disease. Maintaining a high index of suspicion for Fabry disease in these patients is mandatory. The GLA p.Ala143Thr variant is pathogenic and is associated with a late-onset cardiac phenotype with severe (brady)-arrhythmia.AcknowledgmentsThe authors thank all of the patients for participation, local study coordinators and colleagues at participating centers, and Melissa Devos for excellent data management.Sources of FundingThis study was supported by an investigator-initiated grant (IIR-BEL-001041) provided by Shire International GmbH, Switzerland, a member of the Takeda group of companies.Disclosures Drs Hemelsoet, Terryn, and Poppe received research and travel grants from Shire, Genzyme, and Sanofi Genzyme. Dr Willems is supported as postdoctoral clinical researcher by the Fund for Scientific Research Flanders. The other authors report no conflicts.Footnoteshttps://www.ahajournals.org/journal/circDimitri Hemelsoet, MD, Department of Neurology, Ghent University Hospital, C. Heymanslaan 10, B-9000 Ghent, Belgium. Email dimitri.[email protected]beReferences1. Germain DP. Fabry disease.Orphanet J Rare Dis. 2010; 5:30. doi: 10.1186/1750-1172-5-30CrossrefMedlineGoogle Scholar2. Hagège A, Réant P, Habib G, Damy T, Barone-Rochette G, Soulat G, Donal E, Germain D. Fabry disease in cardiology practice: literature review and expert point of Sview.Arch Cardiovasc Dis. 2019; 112:278–287. doi: 10.1016/j.acvd.2019.01.002CrossrefMedlineGoogle Scholar3. Baig S, Edward NC, Kotecha D, Liu B, Nordin S, Kozor R, Moon JC, Geberhiwot T, Steeds RP. Ventricular arrhythmia and sudden cardiac death in Fabry disease: a systematic review of risk factors in clinical practice.Europace. 2018; 20(FI2):f153–f161. doi: 10.1093/europace/eux261CrossrefMedlineGoogle Scholar4. Vardarli I, Rischpler C, Herrmann K, Weidemann F. Diagnosis and screening of patients with Fabry disease.Ther Clin Risk Manag. 2020; 16:551–558. doi: 10.2147/TCRM.S247814CrossrefMedlineGoogle Scholar5. Valtola K, Nino-Quintero J, Hedman M, Lottonen-Raikaslehto L, Laitinen T, Maria M, Kantola I, Naukkarinen A, Laakso M, Kuusisto J. Cardiomyopathy associated with the Ala143Thr variant of the α-galactosidase A gene.Heart. 2020; 106:609–615. doi: 10.1136/heartjnl-2019-315933CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Tassetti L, Fumagalli C, Argirò A, Zampieri M, Gori M, Verrillo F, Zocchi C, Cappelli F and Olivotto I (2022) Prevalence and predictors of bradyarrhythmias requiring permanent pacing in patients with Anderson–Fabry disease, Journal of Cardiovascular Electrophysiology, 10.1111/jce.15409, 33:5, (1072-1078), Online publication date: 1-May-2022. February 23, 2021Vol 143, Issue 8Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.051400PMID: 33617311 Originally publishedFebruary 22, 2021 Keywordsdiagnostic screening programsFabry diseasearrhythmias, cardiacPDF download Advertisement SubjectsAcute Coronary SyndromesBlood PressureDiagnostic TestingElectrocardiology (ECG)PacemakerRemodeling
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