AIMS: Fabry disease (FD) is a rare X-linked genetic disorder caused by α-galactosidase A (AGALA) deficiency. Whereas 'classic' variant has multisystemic manifestation, the more recently described 'later-onset' variant is characterized by predominant cardiac involvement that often mimics hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Consecutive unrelated patients with HCM were screened for FD in 16 (out of 17) cardiac centres in the Czech Republic covering specialized cardiology care from June 2017 to December 2018. AGALA activity and globotriaosylsphingosine (lyso-Gb3 ) levels were measured in all subjects using the dry blood spot method. FD was suspected in male patients with AGALA activity <1.2 μmol/h/L and in females with either low AGALA activity or lyso-Gb3 > 3.5 ng/mL. Positive screening results were confirmed by genetic testing. We evaluated 589 patients (390 males, 66%) with HCM (mean maximal myocardial thickness 19.1 ± 4.3 mm). The average age was 58.4 ± 14.7 years. In total, 17 patients (11 males, 6 females) had a positive screening result, and subsequently, six of them (four males and two females) had a genetically confirmed pathogenic GLA mutation (total prevalence of 1.02%). Five of these patients were carrying the p.N215S mutation known to cause a typical later-onset cardiac FD. CONCLUSIONS: We confirmed the prevalence of FD repeatedly reported in previous screening programmes (approximately 1% irrespective of gender) in a non-selected HCM population in Central Europe. Our findings advocate a routine screening for FD in all adult patients with HCM phenotype including both genders. The dry blood spot method used led to identification of clearly pathogenic variants.

1st Department of Internal Medicine Cardioangiology St Anne's University Hospital and Masaryk University Brno Czech Republic

1st Department of Medicine Cardioangiology Charles University Faculty of Medicine and University Hospital Hradec Králové Czech Republic

2nd Department of Internal Medicine Cardiology and Angiology General University Hospital and 1st Faculty of Medicine of Charles University Prague Czech Republic

ARCHIMED Life Science GmbH Vienna Austria

Cardiocentre Podlesí Třinec Czech Republic

Department of Cardiology 3rd Faculty of Medicine Charles University and University Hospital Kralovské Vinohrady Prague Czech Republic

Department of Cardiology Hospital České Budějovice České Budějovice Czech Republic

Department of Cardiology Hospital Jihlava Jihlava Czech Republic

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Cardiology Regional Hospital Liberec Liberec Czech Republic

Department of Cardiology Regional Hospital Pardubice and Faculty of Health Studies University of Pardubice Pardubice Czech Republic

Department of Cardiology University Hospital and Faculty of Medicine Pilsen Charles University Prague Czech Republic

Department of Cardiovascular Disease University Hospital in Ostrava Ostrava Czech Republic

Department of Internal Medicine 1 Cardiology Faculty of Medicine and Dentistry Palacký University and University Hospital Olomouc Olomouc Czech Republic

See more in PubMed

Germain DP. Fabry disease. Orphanet J Rare Dis. 2010; 5: 30. PubMed PMC

Machann W, Breunig F, Weidemann F, Sandstede J, Hahn D, Köstler H, Neubauer S, Wanner C, Beer M. Cardiac energy metabolism is disturbed in Fabry disease and improves with enzyme replacement therapy using recombinant human galactosidase A. Eur J Heart Fail. 2011; 13: 278–283. PubMed

Linhart A, Kampmann C, Zamorano JL, Sunder‐Plassmann G, Beck M, Mehta A, Elliott PM, European FOS Investigators . Cardiac manifestations of Anderson‐Fabry disease: Results from the international Fabry outcome survey. Eur Heart J. 2007; 28: 1228–1235. PubMed

Germain DP, Elliott PM, Falissard B, Fomin VV, Hilz MJ, Jovanovic A, Kantola I, Linhart A, Mignani R, Namdar M, Nowak A, Oliveira JP, Pieroni M, Viana‐Baptista M, Wanner C, Spada M. The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts. Mol Genet Metab Rep. 2019; 19: 100454. PubMed PMC

Hughes DA, Nicholls K, Shankar SP, Sunder‐Plassmann G, Koeller D, Nedd K, Vockley G, Hamazaki T, Lachmann R, Ohashi T, Olivotto I, Sakai N, Deegan P, Dimmock D, Eyskens F, Germain DP, Goker‐Alpan O, Hachulla E, Jovanovic A, Lourenco CM, Narita I, Thomas M, Wilcox WR, Bichet DG, Schiffmann R, Ludington E, Viereck C, Kirk J, Yu J, Johnson F, Boudes P, Benjamin ER, Lockhart DJ, Barlow C, Skuban N, Castelli JP, Barth J, Feldt‐Rasmussen U. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18‐month results from the randomised phase III ATTRACT study. J Med Genet. 2017; 54: 288–296. PubMed PMC

Monserrat L, Gimeno‐Blanes JR, Marín F, Hermida‐Prieto M, García‐Honrubia A, Pérez I, Fernández X, de Nicolas R, de la Morena G, Payá E, Yagüe J, Egido J. Prevalence of Fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2007; 50: 2399–2403. PubMed

Paleček T, Honzíková J, Poupětová H, Vlasková H, Kuchynka P, Goláň L, Magage S, Linhart A. Prevalence of Fabry disease in male patients with unexplained left ventricular hypertrophy in primary cardiology practice: Prospective Fabry cardiomyopathy screening study (FACSS). J Inherit Metab Dis. 2014; 37: 455–460. PubMed

Elliott P, Baker R, Pasquale F, Quarta G, Ebrahim H, Mehta AB, Hughes DA, ACES study group . Prevalence of Anderson‐Fabry disease in patients with hypertrophic cardiomyopathy: The European Anderson‐Fabry disease survey. Heart. 2011; 97: 1957–1960. PubMed

Newman DB, Miranda WR, Matern D, Peck DS, Geske JB, Maleszewski JJ, Ommen SR, Ackerman MJ. Cost efficacy of α‐galactosidase a enzyme screening for Fabry disease. Mayo Clin Proc. 2019; 94: 84–88. PubMed

Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM. Prevalence of Anderson‐Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation. 2002; 105: 1407–1411. PubMed

Havndrup O, Christiansen M, Stoevring B, Jensen M, Hoffman‐Bang J, Andersen PS, Hasholt L, Nørremølle A, Feldt‐Rasmussen U, Køber L, Bundgaard H. Fabry disease mimicking hypertrophic cardiomyopathy: Genetic screening needed for establishing the diagnosis in women. Eur J Heart Fail. 2010; 12: 535–540. PubMed

Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018; 123: 416–427. PubMed

Aerts JM, Groener JE, Kuiper S, Donker‐Koopman WE, Strijland A, Ottenhoff R, van Roomen C, Mirzaian M, Wijburg FA, Linthorst GE, Vedder AC, Rombach SM, Cox‐Brinkman J, Somerharju P, Boot RG, Hollak CE, Brady RO, Poorthuis BJ. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A. 2008; 105: 2812–2817. PubMed PMC

Nowak A, Mechtler TP, Hornemann T, Gawinecka J, Theswet E, Hilz MJ, Kasper DC. Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease. Mol Genet Metab. 2018; 123: 148–153. PubMed

Maruyama H, Miyata K, Mikame M, Taguchi A, Guili C, Shimura M, Murayama K, Inoue T, Yamamoto S, Sugimura K, Tamita K, Kawasaki T, Kajihara J, Onishi A, Sugiyama H, Sakai T, Murata I, Oda T, Toyoda S, Hanawa K, Fujimura T, Ura S, Matsumura M, Takano H, Yamashita S, Matsukura G, Tazawa R, Shiga T, Ebato M, Satoh H, Ishii S. Effectiveness of plasma lyso‐Gb3 as a biomarker for selecting high‐risk patients with Fabry disease from multispecialty clinics for genetic analysis. Genet Med. 2019; 21: 44–52. PubMed PMC

Balendran S, Oliva P, Sansen S, Mechtler TP, Streubel B, Cobos PN, Lukacs Z, Kasper DC. Diagnostic strategy for females suspected of Fabry disease. Clin Genet. 2020; 97: 655–660. PubMed

Cardim N, Galderisi M, Edvardsen T, Plein S, Popescu BA, D'Andrea A, Bruder O, Cosyns B, Davin L, Donal E, Freitas A, Habib G, Kitsiou A, Petersen SE, Schroeder S, Lancellotti P, Camici P, Dulgheru R, Hagendorff A, Lombardi M, Muraru D, Sicari R. Role of multimodality cardiac imaging in the management of patients with hypertrophic cardiomyopathy: An expert consensus of the European Association of Cardiovascular Imaging Endorsed by the Saudi Heart Association. Eur Heart J Cardiovasc Imaging. 2015; 16: 280. PubMed

Doheny D, Srinivasan R, Pagant S, Chen B, Yasuda M, Desnick RJ. Fabry Disease: Prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995‐2017. J Med Genet. 2018; 55: 261–268. PubMed

Linthorst GE, Poorthuis BJ, Hollak CE. Enzyme activity for determination of presence of Fabry disease in women results in 40% false‐negative results. J Am Coll Cardiol. 2008; 51: 2082 author reply 2082‐3. PubMed

Yamashita S, Saotome M, Satoh H, Kajihara J, Mochizuki Y, Mizuno K, Nobuhara M, Miyajima K, Kumazawa A, Tominaga H, Takase H, Tawarahara K, Wakahara N, Matsunaga M, Wakabayashi Y, Matsumoto Y, Terada H, Sano M, Ohtani H, Urushida T, Hayashi H, Ishii S, Maruyama H, Maekawa Y. Plasma globotriaosylsphingosine level as a primary screening target for Fabry disease in patients with left ventricular hypertrophy. Circ J. 2019; 83: 1901–1907. PubMed

Nowak A, Mechtler T, Kasper DC, Desnick RJ. Correlation of lyso‐Gb3 levels in dried blood spots and sera from patients with classic and later‐onset Fabry disease. Mol Genet Metab. 2017; 121: 320–324. PubMed

Smid BE, van der Tol L, Biegstraaten M, Linthorst GE, Hollak CE, Poorthuis BJ. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J Med Genet. 2015; 52: 262–268. PubMed

Germain DP, Levade T, Hachulla E, Knebelmann B, Lacombe D, Seguin VL, Nguyen K, Noël E, Rabès JP. Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease. Clin Genet. 2022; 101: 390–402. PubMed PMC

Germain DP, Brand E, Burlina A, Cecchi F, Garman SC, Kempf J, Laney DA, Linhart A, Maródi L, Nicholls K, Ortiz A, Pieruzzi F, Shankar SP, Waldek S, Wanner C, Jovanovic A. Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry registry study. Mol Genet Genomic Med. 2018; 6: 492–503. PubMed PMC

Lavalle L, Thomas AS, Beaton B, Ebrahim H, Reed M, Ramaswami U, Elliott P, Mehta AB, Hughes DA. Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. PLoS ONE. 2018; 13: e0193550. PubMed PMC

Sugarman M, Choudhury J, Jovanovic A. An atypical p.N215S variant of Fabry disease with end‐stage renal failure. Mol Genet Metab Rep. 2018; 15: 43–45. PubMed PMC

Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Störk S, Voelker W, Ertl G, Wanner C, Strotmann J. Long‐term effects of enzyme replacement therapy on fabry cardiomyopathy: Evidence for a better outcome with early treatment. Circulation. 2009; 119: 524–529. PubMed

Germain DP, Moiseev S, Suárez‐Obando F, Al Ismaili F, Al Khawaja H, Altarescu G, Barreto FC, Haddoum F, Hadipour F, Maksimova I, Kramis M, Nampoothiri S, Nguyen KN, Niu DM, Politei J, Ro LS, Vu Chi D, Chen N, Kutsev S. The benefits and challenges of family genetic testing in rare genetic diseases‐Lessons from Fabry disease. Mol Genet Genomic Med. 2021; 9: e1666. PubMed PMC

Oder D, Liu D, Hu K, Üçeyler N, Salinger T, Müntze J, Lorenz K, Kandolf R, Gröne HJ, Sommer C, Ertl G, Wanner C, Nordbeck P. α‐Galactosidase A genotype N215S induces a specific cardiac variant of Fabry disease. Circ Cardiovasc Genet. 2017; 10: e001691. PubMed