What is late-onset Fabry disease?
Patients with Fabry disease with residual (≥1‒30%) enzymatic activity levels of alpha-galactosidase A (α-Gal A), due to variants in the GLA gene, typically develop the late-onset phenotype.1,2 Patients with late-onset Fabry disease have a more variable disease course compared with those with classical Fabry disease. In general, patients with late-onset Fabry disease may be less severely affected, and the disease manifestations may be limited to only one organ.3 Moreover, patients with this disease phenotype may have few or none of the hallmark symptoms associated with classical Fabry disease, and typical cardiac and renal symptoms may only become present later in life (fourth to eighth decade), reflecting the delayed onset of the disease and the slower disease progression.1,4-6 Therefore, in some cases patients with late-onset Fabry disease may be identified incidentally.7
Patients with late-onset Fabry disease can be misdiagnosed, or their symptoms may be unrecognised throughout life. One study assessed screening reports in cardiac (left ventricular hypertrophy and/or hypertrophic cardiomyopathy), haemodialysis, renal transplantation and stroke (primarily cryptogenic or ischaemic strokes) clinics to determine the prevalence of pathogenic GLA variants and late-onset Fabry disease among male patients.8
- Cardiac clinics: 38/4054 males (0.94%) had pathogenic GLA variants, of whom 29 patients (76.3%) had late-onset Fabry disease.8
- Haemodialysis clinics: 50/23,954 males (0.21%) had pathogenic GLA variants, of whom 17 patients (34%) had late-onset Fabry disease.8
- Renal transplant clinics: 5/2031 males (0.24%) had pathogenic GLA variants, of whom two patients (40%) had late-onset Fabry disease.8
- Stroke clinics: 5/3904 males (0.13%) had pathogenic GLA variants, of whom two patients (40%) had late-onset Fabry disease.8
Patients with cardiac variants of Fabry disease are essentially asymptomatic during most of their lives, and do not develop the early manifestations associated with classical Fabry disease. Most patients are only diagnosed after the onset of cardiac manifestations.9 This disease phenotype may include development of cardiomegaly (usually involving the left ventricular wall and interventricular septum), electrocardiographic abnormalities consistent with cardiomyopathy, non-obstructive and hypertrophic cardiomyopathy.7,9 Patients may also have mild proteinuria as evidence of coexisting kidney involvement.6,7,9 The missense GLA variant N215S (c.644A>G) has been shown to be consistently observed in patients with Fabry disease with predominantly cardiac disease manifestations.4,5 Moreover, the GLA variant IVS4+919 G>A is associated with severe and progressive cardiomyopathy and fatal arrhythmia.10 In male patients with the cardiac variants of Fabry disease, enzymatic activity levels of α-Gal A in leukocytes are approximately 3‒10% of the normal mean value. Moreover, tissue biopsies or autopsy studies of patients with Fabry disease presenting with the cardiac variant exhibit extensive storage of globotriaosylceramide (Gb3) within cardiomyocytes.6
Some patients with late-onset Fabry disease may develop a renal phenotype. These patients do not experience any of the early-onset signs and symptoms of classical Fabry disease, and instead develop progressive chronic kidney disease in early adulthood, resulting in end-stage renal disease when they are aged 40‒60 years.6 Levels of α-Gal A enzyme activity in leukocytes typically range from approximately 1‒5% of normal mean values in male patients with the renal variant of Fabry disease.6 Accumulation of Gb3 is observed in all glomerular cells in these patients, including within the capillary endothelium.11
Cryptogenic strokes, where no cause can be identified, are more common in young adults (aged <45 years) than in older patients.12,13 A study of 721 young adults (aged 18‒55 years) with acute stroke, revealed that 32 patients (males, n=22; females, n=10) had reduced leukocyte α-Gal A enzyme activity. Identification of pathologically significant variants within the GLA gene indicated a diagnosis of Fabry disease in 28 patients (males, n=21; females, n=7) with acute stroke. Approximately half of these patients with Fabry disease had ≥1 additional cerebrovascular event prior to their diagnosis, and male patients more frequently experienced the clinical signs of ataxia, dysarthria, nausea or dizziness and pathological nystagmus. These clinical symptoms were also more likely to be associated with predominant infarction in the vertebrobasilar artery region in patients with Fabry disease (46.4%) than in those without (21.4%).13 The prevalence of Fabry disease was assessed in a separate study of 5023 patients (males, n=2962; females, n=2061) aged 18‒55 years presenting with acute cerebrovascular event of any cause. Based on significantly reduced α-Gal A enzyme activity and GLA genetic analysis, a diagnosis of Fabry disease was established in 0.5% of patients. Ischaemic stroke was the most common type of cerebrovascular event, followed by transient ischaemic attack in patients with GLA variants associated with Fabry disease.14
C-ANPROM/INT/FAB/0015; Date of preparation: March 2021
- Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416-427.
- Michaud M, Mauhin W, Belmatoug N, et al. When and how to diagnose Fabry disease in clinical pratice. Am J Med Sci 2020; 360: 641-649.
- Arends M, Wanner C, Hughes D, et al. Characterization of classical and nonclassical Fabry disease: a multicenter study. J Am Soc Nephrol 2017; 28: 1631-1641.
- Germain DP, Brand E, Burlina A, et al. 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.
- Patel V, O'Mahony C, Hughes D, et al. Clinical and genetic predictors of major cardiac events in patients with Anderson-Fabry disease. Heart 2015; 101: 961-966.
- Oliveira JP, Ferreira S. Multiple phenotypic domains of Fabry disease and their relevance for establishing genotype– phenotype correlations. Appl Clin Genet 2019; 12: 35-50.
- Wanner C, Oliveira JP, Ortiz A, et al. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry. Clin J Am Soc Nephrol 2010; 5: 2220-2228.
- Doheny D, Srinivasan R, Pagant S, et al. 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.
- Desnick RJ, Ioannou YA, Eng CM. α-galactosidase A deficiency: Fabry disease. In: Scriver C, Beaudet A, Sly W, et al., eds. The Online Metabolic and Molecular Bases of Inherited Disease. 8th Edition. New York, NY: McGraw-Hill, 2001.
- Juang JJ, Shun CT, Chen YS, et al. Fabry disease cardiac variant IVS4+919 G>A is associated with multiple cardiac gene variants in patients with severe cardiomyopathy and fatal arrhythmia. Genet Med 2019; 21: 1890-1891.
- Nakao S, Kodama C, Takenaka T, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int 2003; 64: 801-807.
- Bogousslavsky J, Pierre P. Ischemic stroke in patients under age 45. Neurol Clin 1992; 10: 113-124.
- Rolfs A, Böttcher T, Zschiesche M, et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 2005; 366: 1794-1796.
- Rolfs A, Fazekas F, Grittner U, et al. Acute cerebrovascular disease in the young: the Stroke in Young Fabry Patients study. Stroke 2013; 44: 340-349.