Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease–specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy.
We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene.
In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy.
These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease–affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy.
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- Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy.Ann Intern Med. 2003; 138: 338-346
- α-Galactosidase A deficiency: Fabry disease.The Online Metabolic and Molecular Bases of Inherited Disease. 2001; https://doi.org/10.1036/ommbid.181
- Fabry disease.Orphanet J Rare Dis. 2010; 5: 30
- Elevated globotriaosylsphingosine is a hallmark of Fabry disease.Proc Natl Acad Sci U S A. 2008; 105: 2812-2817
- Angiokeratoma corporis diffusum–Fabry's disease.Helv Med Acta. 1967; 34: 67-83
- An atypical variant of Fabry's disease with manifestations confined to the myocardium.N Engl J Med. 1991; 324: 395-399
- An atypical variant of Fabry's disease in men with left ventricular hypertrophy.N Engl J Med. 1995; 333: 288-293
- Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.Circulation. 2002; 105: 1407-1411
- Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy.Circulation. 2004; 110: 1047-1053
- Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey.Eur Heart J. 2007; 28: 1228-1235
- Prevalence of Fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy.J Am Coll Cardiol. 2007; 50: 2399-2403
- Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women.Eur J Heart Fail. 2010; 12: 535-540
- Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson-Fabry Disease survey.Heart. 2011; 97: 1957-1960
- Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study.Heart. 2011; 97: 131-136
- 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
- Prevalence and clinical features of Fabry disease in Japanese male patients with diagnosis of hypertrophic cardiomyopathy.J Cardiol. 2017; 69: 302-307
- X-chromosome inactivation in female patients with Fabry disease.Clin Genet. 2016; 89: 44-54
- Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life.Genet Med. 2007; 9: 34-45
- Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.N Engl J Med. 2001; 345: 9-16
- Enzyme replacement therapy in Fabry disease: a randomized controlled trial.JAMA. 2001; 285: 2743-2749
- Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.Ann Intern Med. 2007; 146: 77-86
- Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease.J Med Genet. 2015; 52: 353-358
- The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.Hum Genet. 2017; 136: 665-677
- Identification of a novel GLA gene mutation, p.Ile239Met, in fabry disease with a predominant cardiac phenotype.Int Heart J. 2017; 58: 454-458
- Cardiocyte storage and hypertrophy as a sole manifestation of Fabrys disease. Report on a case simulating hypertrophic non-obstructive cardiomyopathy.Virchows Arch A Pathol Anat Histopathol. 1990; 417: 449-455
- Later onset fabry disease, cardiac damage progress in silence: experience with a highly prevalent mutation.J Am Coll Cardiol. 2016; 68: 2554-2563
- Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives.J Am Coll Cardiol. 2012; 60: 705-715
- Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine.J Am Coll Cardiol. 2014; 64: 83-99
- Cardiovascular manifestations of Fabry disease: relationships between left ventricular hypertrophy, disease severity, and alpha-galactosidase A activity.Eur Heart J. 2010; 31: 1088-1097
- Effect of sample collection on alpha-galactosidase A enzyme activity measurements in dried blood spots on filter paper.Clin Chim Acta. 2009; 403: 159-162
- Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype.Am J Hum Genet. 2002; 70: 994-1002
- Mutation analysis in patients with the typical form of Anderson-Fabry disease.Hum Mol Genet. 1993; 2: 1051-1053
- Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.Mol Med. 1999; 5: 806-811
- The phenotypic characteristics of the p.N215S Fabry disease genotype in male and female patients: a multicenter Fabry registry study.Mol Genet Metab. 2017; 120: S51-S52
- Clinical and genetic predictors of major cardiac events in patients with Anderson-Fabry Disease.Heart. 2015; 101: 961-966
- Significance of appropriate defibrillator shock 3 hours and 20 minutes following implantation in a patient with hypertrophic cardiomyopathy.J Cardiovasc Electrophysiol. 2008; 19: 319-322
- Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium.Eur Heart J. 2003; 24: 2151-2155
- Clinical impact of contemporary cardiovascular magnetic resonance imaging in hypertrophic cardiomyopathy.Circulation. 2015; 132: 292-298
- Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance.J Am Coll Cardiol. 2009; 54: 220-228
- Screening for Fabry disease in patients with left ventricular hypertrophy.Int J Cardiol. 2013; 167 (49): 1059-1061
- Fabry disease in families with hypertrophic cardiomyopathy: clinical manifestations in the classic and later-onset phenotypes.Circ Cardiovasc Genet. 2017; 10 (e001639)
- Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults.Circulation. 1995; 92: 785-789
- New perspectives on the prevalence of hypertrophic cardiomyopathy.J Am Coll Cardiol. 2015; 65: 1249-1254
- High incidence of later-onset fabry disease revealed by newborn screening.Am J Hum Genet. 2006; 79: 31-40
- Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4 + 919G>A).Hum Mutat. 2009; 30: 1397-1405
- Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study.Circulation. 2006; 113: 2697-2705
- Enzyme replacement therapy for Anderson-Fabry disease: a complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies.PLoS One. 2017; 12 (e0173358)
- Long-term enzyme replacement therapy for Fabry disease: efficacy and unmet needs in cardiac and renal outcomes.J Hum Genet. 2016; 61: 923-929
- Long term treatment with enzyme replacement therapy in patients with fabry disease.Nephron. 2016; 134: 30-36
Published online: September 21, 2017
Funding: This study was supported, in part, by a grant from Sanofi Genzyme.
Conflict of Interest: None.
Authorship: All authors had access to the data and a role in writing the manuscript.
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