Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the α-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, α-galactosidase A (α-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low α-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928del21. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.
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Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008;372:1427–35.
Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34:236–42.
Bennett RL, French KS, Resta RG, Doyle DL. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Couns. 2008;17:424–33.
Momosaki K, Kido J, Matsumoto S, Yoshida S, Takei A, Miyabayashi T, et al. High-risk screening for Gaucher disease in patients with neurological symptoms. J Hum Genet. 2018;63:717–21.
Inoue T, Hattori K, Ihara K, Ishii A, Nakamura K, Hirose S. Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study. J Hum Genet. 2013;58:548–52.
Nagamatsu K, Sekijima Y, Nakamura K, Hattori K, Ota M, Shimizu Y, et al. Prevalence of Fabry disease and GLA c.196G>C variant in Japanese stroke patients. J Hum Genet. 2017;62:665–70.
Sawada J, Katayama T, Kano K, Asanome A, Takahashi K, Saito T, et al. A sporadic case of Fabry disease involving repeated fever, psychiatric symptoms, headache, and ischemic stroke in an adult Japanese woman. Intern Med. 2015;54:3069–74.
Shabbeer J, Yasuda M, Benson SD, Desnick RJ. Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genom. 2006;2:297–309.
Germain DP, Shabbeer J, Cotigny S, Desnick RJ. Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes. Mol Med. 2002;8:306–12.
Shabbeer J, Yasuda M, Luca E, Desnick RJ. Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype. Mol Genet Metab. 2002;76:23–30.
Ashton-Prolla P, Tong B, Shabbeer J, Astrin KH, Eng CM, Desnick RJ. Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. J Investig Med. 2000;48:227–35.
Lukas J, Scalia S, Eichler S, Pockrandt AM, Dehn N, Cozma C, et al. Functional and clinical consequences of novel alpha-galactosidase A mutations in Fabry disease. Hum Mutat. 2016;37:43–51.
Kitani Y, Nakagawa N, Sakamoto N, Takeuchi T, Takahashi F, Momosaki K, et al. Unexpectedly high prevalence of coronary spastic angina in patients with Anderson–Fabry disease. Circ J. 2019;83:481–4.
Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int. 2003;64:801–7.
Kotanko P, Kramar R, Devrnja D, Paschke E, Voigtlander T, Auinger M, et al. Results of a nationwide screening for Anderson–Fabry disease among dialysis patients. J Am Soc Nephrol. 2004;15:1323–9.
Maruyama H, Takata T, Tsubata Y, Tazawa R, Goto K, Tohyama J, et al. Screening of male dialysis patients for fabry disease by plasma globotriaosylsphingosine. Clin J Am Soc Nephrol. 2013;8:629–36.
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;55:261–8.
Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, et al. An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333:288–93.
Linhart A, Elliott PM. The heart in Anderson–Fabry disease and other lysosomal storage disorders. Heart. 2007;93:528–35.
Elliott P, Baker R, Pasquale F, Quarta G, Ebrahim H, Mehta AB, et al. Prevalence of Anderson–Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson–Fabry Disease survey. Heart. 2011;97:1957–60.
Shi Q, Chen J, Pongmoragot J, Lanthier S, Saposnik G. Prevalence of Fabry disease in stroke patients—a systematic review and meta-analysis. J Stroke Cereb Dis. 2014;23:985–92.
Elbin CS, Olivova P, Marashio CA, Cooper SK, Cullen E, Keutzer JM, et al. The effect of preparation, storage and shipping of dried blood spots on the activity of five lysosomal enzymes. Clin Chim Acta. 2011;412:1207–12.
Nakagawa N, Maruyama H, Ishihara T, Seino U, Kawabe J, Takahashi F, et al. Clinical and genetic investigation of a Japanese family with cardiac fabry disease. Identification of a novel alpha-galactosidase A missense mutation (G195V). Int Heart J. 2011;52:308–11.
Kampmann C, Baehner F, Whybra C, Martin C, Wiethoff CM, Ries M, et al. Cardiac manifestations of Anderson–Fabry disease in heterozygous females. J Am Coll Cardiol. 2002;40:1668–74.
Shimokawa H, Nagasawa K, Irie T, Egashira S, Egashira K, Sagara T, et al. Clinical characteristics and long-term prognosis of patients with variant angina. A comparative study between western and Japanese populations. Int J Cardiol. 1988;18:331–49.
Gal A, Hughes DA, Winchester B. Toward a consensus in the laboratory diagnostics of Fabry disease—recommendations of a European expert group. J Inherit Metab Dis. 2011;34:509–14.
Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123:416–27.
Fujii H, Kono K, Goto S, Onishi T, Kawai H, Hirata K, et al. Prevalence and cardiovascular features of Japanese hemodialysis patients with Fabry disease. Am J Nephrol. 2009;30:527–35.
Saito O, Kusano E, Akimoto T, Asano Y, Kitagawa T, Suzuki K, et al. Prevalence of Fabry disease in dialysis patients: Japan Fabry disease screening study (J-FAST). Clin Exp Nephrol. 2016;20:284–93.
Nakamura K, Sekijima Y, Hattori K, Nagamatsu K, Shimizu Y, Yazaki M, et al. Mutation in the GLA gene is associated with a high risk of cerebral small-vessel occlusion in elderly Japanese males. Eur J Neurol. 2014;21:E66Q.
Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, et al. Treatment of Fabry’s disease with the pharmacologic chaperone migalastat. N Engl J Med. 2016;375:545–55.
We thank Professor Yoshio Makita of Asahikawa Medical University for the genetic counseling and Kaori Kanno of Asahikawa Medical University, Fumiko Nozaki, Naomi Yano, and Matsumi Harada of Kumamoto University for their excellent technical assistance. In addition to the authors, the following investigators and institutions participated in this study: H.N. Medic Sapporo-Higashi (Masataka Tsunoda); H.N. Medic Sapporo (Nobuo Hashimoto); H.N. Medic Kitahiroshima (Ryota Ikee); Kitasaito Hospital (Atsushi Wada, Tomoya Hirayama); Nagayama Kidney and Urology Clinic (Mitsuhiro Mizunaga); Jinyukai Hospital (Kazuyuki Maeno); Tomakomai Nissho Hospital (Kazuya Sakamoto); Hokkaido Kitami Hospital (Kazumi Uekita); Hokkaido Haboro Hospital (Tomoya Koizumi, Wataru Sasao); Abashiri Kosei Hospital (Toshihiro Hirai, Hideki Nakamura); Teine Keijinkai Hospital (Takuto Maeda, Hideki Takizawa); Teine Inazumi Hospital (Susumu Saito); Engaru Kosei Hospital (Kanako Matsuda, Motoi Kijima); Uno Clinic (Motohiro Uno); Kushiro City General Hospital (Ken Morita); Kushiro Red Cross Hospital (Junya Yamamoto); NTT East Sapporo Hospital (Tomochika Maoka); KKR Sapporo Medical Center (Hirofumi Kon); Ebetsu City Hospital (Masahiko Abe); Municipal Ashibetsu Hospital (Yasuhiro Nakamura); Hokkaido Cardiovascular Hospital (Yusuke Kashiwagi); Sawamura Dialysis Clinic (Naruhiko Tanaka); National Hospital Organization Hokkaido Medical Center (Takashi Takenaka); National Hospital Organization Obihiro Hospital (Mayumi Aoki, Hiromi Obata); Hakodate Watanabe Hospital (Hisanobu Ota); Asahikawa Kosei Hospital (Atsushi Yamauchi); National Hospital Organization Asahikawa Medical Center (Yoko Aburakawa); Nayoro City General Hospital (Sarasa Toyoshima); Sapporo Rouaikai Hospital (Hidenori Furui); Nissei Hospital (Hiromitsu Yoshie); Hokusei Hospital (Eriko Yamagishi); Iwamizawa Municipal General Hospital (Yoshiaki Aizawa); Megumino Hospital (Yasutaka Hirayama); Ohkawara Neurosurgical Hospital (Noriaki Shojima); Iburi Urological Clinic (Masashi Bandou, Yutaka Takeuchi); Hakodate Goryoukaku Hospital (Fumio Obara); Hakodate Municipal Hospital (Misuzu Osaka); Kitamihara clinic (Sugako Akihama); Chitose City Hospital (Tomoko Sakai); and Ido Medical Clinic (Akira Ido).
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Nakagawa, N., Sawada, J., Sakamoto, N. et al. High-risk screening for Anderson–Fabry disease in patients with cardiac, renal, or neurological manifestations. J Hum Genet 64, 891–898 (2019). https://doi.org/10.1038/s10038-019-0633-1