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Fabry disease update: Cardiac findings and recent screening studies

Prof. Alex Lee
Chinese University of Hong Kong
Hong Kong
Prof. Gavin Oudit
Department of Medicine
University of Alberta
06 Nov 2019

In Fabry disease (FD), an X-linked lysosomal storage disorder, widespread tissue accumulation of globotriaosylceramide (Gb3) causes multisystem damage. Although rare, screening studies in neonates and hypertrophic cardiomyopathy patients suggest that its prevalence is higher than previously estimated. At a Sanofi Genzyme-sponsored symposium in Hong Kong, Professor Gavin Oudit from the Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada, and Professor Alex Lee from the Chinese University of Hong Kong discussed cardiac findings in FD and recent screening studies.

Fabry disease: A multisystem disorder with important cardiac changes

FD is caused by mutations of the X-linked α-galatosidase A (GLA) gene, resulting in deficiencies of the lysosomal enzyme α-galactosidase A (α-GAL A). This disrupts glycosphingolipid metabolism and leads to widespread intracellular accumulation of Gb3, particularly in the heart, kidney, brain, peripheral nerves, gastrointestinal (GI) tract, and the skin. [J Am Coll Cardiol 2016;68:1037-1050]

“There are variable phenotypes and a spectrum of presentations of FD,” explained Oudit. “The type 1, or ‘classic’, phenotype results from mutations encoding little or no α-GAL A activity. The type 2, or ‘variant’, phenotype has mutations encoding residual α-GAL A activity, so there is less Gb3 accumulation.”

Affected type 1 males may suffer acroparesthesia, hypohidrosis, GI symptoms, skin angiokeratomas and corneal dystrophy in childhood, progressing in adulthood to multisystem disorder culminating in renal failure, hypertrophic cardiomyopathy (HCM) and cerebrovascular disease. In the type 2 phenotype, seen in males and females, patients may present with cardiac or renal disease at 20–60 years of age. FD is associated with a median reduction in life expectancy of 20 years in males and 15 years in females. [J Med Genet 2001;38:750-780; J Med Genet 2001;38:700-775] 

There is a median diagnostic delay of 15 years in males and 18 years in females from onset of symptoms. [Mol Genet Metab 2008;93:112-128] “The delay in diagnosis is due to the relative rarity of FD and the involvement of multiple systems,” noted Oudit.

Cardiac manifestations of FD can appear from adolescence onwards due to Gb3 accumulation in cardiac cells, leading to cellular hypertrophy, fibrosis and narrowing of the cardiac vascular bed. This results in electrophysiological, microvascular and structural problems in the heart. Clinical findings include left ventricular hypertrophy (LVH), diastolic dysfunction, arrhythmias, impaired exercise capacity, angina, myocardial infarction, valvular insufficiency, lymphoedema, and thrombosis. FD patients may progress to heart failure (HF), malignant arrhythmia and cardiac death. [Genet Med 2009;11:790-796; Am J Cardiol 2005;96:842-846;  Acta Paediatr Supp 2002;91:15-20; Int J Cardiol 2008;130:367-373; J Am Coll Cardiol 2001;57:1093-1099; Nephrol Dial Transplant 2006;21:345-354]

LVH is a key feature of FD reported in up to 50 percent of male and one-third of female patients. It is progressive and mostly concentric. LV contractility and diastolic function deteriorate in FD patients, with reduced ejection fraction and congestive HF seen in advanced stages. [Int J Cardiol 2008;130:367-373; JIMD Rep 2013;11:53-64;  Acta Paediatr Suppl 2002;91:15-20]

FD prevalence higher than expected

FD is found in all racial groups, with an estimated incidence of 1 in 40,000 men and 1 in 20,000 women. [Inherit Dis 2001;3733-3774; J Genet Couns 2008;17:79-83; Tidsskr Nor Laegeforen 2005;125:1004-1006] The disease is probably underrecognized due to the nonspecific nature of early symptoms, heterogeneous phenotypes, and lack of disease awareness among clinicians. [Orphanet J Rare Dis 2010;5:30]

FD is often misdiagnosed as idiopathic HCM. Studies in HCM patients have reported incidence rates of FD of 4–12 percent. [Circulation 2002;105:1407-1411; Circulation 2004; 110:1047-1053; Circ Cardiovasc Genetics 2017;10: e001639] In a 10-year prospective, multicenter study, expanded screening in patients enrolled from multidisciplinary clinical settings found that of 2,034 probands, 37 (1.8 percent) were carriers of GLA mutations, and cascade family screening identified 60 affected relatives. [J Am Coll Cardiol 2016;68:1037-1050]

Furthermore, four large-scale neonatal epidemiological studies in Japan, Austria, Taiwan and Italy showed that the incidence rates of α-GAL A deficiency and genetically-confirmed FD are much higher than previous estimates. [Heart Fail Rev 2015;20:179-191; Lancet 2012;379:335-341; Circ Cardiovasc Genetics 2009;2:450-456]  

“Overall, FD gene mutations were found in approximately 1 in 3,000 neonates,” said Oudit. Notably, in the Taiwanese study, 82 percent of mutations were the cardiac variant Fabry mutation IVS4+919G>A. Cardiac variant FD has manifestations primarily in the heart and can mimic idiopathic HCM. [Circ Cardiovasc Genetics 2009;2:450-456]

Diagnostic strategies: Echocardiography, cardiac MRI and biomarkers

In suspected FD cases, α-GAL A enzyme assays of plasma, leukocytes or dried blood samples can be used in males, who typically have <1 percent of normal enzyme activity. However, affected females may have normal or low-normal enzyme activity. High levels of plasma lysosome Gb3 may indicate FD in females, and diagnosis can be confirmed with DNA analysis in both males and females. [J Inherit Metab Dis 2011;34:509-514; Nephrol Dial Transplant 2009;24:1736-1743; Mol Genet Metab 2011:104:144-148]

Novel imaging techniques help in diagnosis and monitoring of FD cardiomyopathy. Speckle-tracking echocardiography, which allows strain imaging, may be a more sensitive method to detect subclinical FD cardiomyopathy than conventional echocardiography. [J AmSoc Echocardiogr 2013;26:1407-1414] Cardiac MRI with noncontrast T1 mapping has shown potential as a powerful tool in the assessment of LVH and heart disease in FD patients. (Figure 1) [Circ Cardiovasc Imaging 2013;6:637-645; Circ Cardiovasc Imaging 2013;6:392-398; J Cardiovasc Mag Res 2017;19:75] 

HK-SAN-188md Fabry disease IU1

Blood biomarkers of FD include high-sensitivity troponin, which is an accurate biomarker for staging FD cardiomyopathy. [J Am Heart Assoc 2016;5:e002839] Elevated cardiac troponin 1 (cTn1) levels are common in FD, reflecting cardiac involvement. Therefore, FD patients may benefit from cTn1 monitoring. [PLoS One 2016;11:e0157640] Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations were found to be elevated in patients with FD and early cardiac involvement, suggesting that it too could be a useful biomarker. [Am J Cardiol 2013;111:111-117] 

Early diagnosis and treatment important for Fabry cardiomyopathy

Early diagnosis of FD is important to enable timely intervention before irreversible organ damage develops. [Orphanet J Rare Dis 2010;5:30] “Early recognition of FD also allows early screening of family members, who may be asymptomatic carriers,” said Oudit. “On average, five family members may be identified with FD for every proband.” [J Genet Couns 2008:17:79-83] 

Enzyme replacement therapy (ERT) can delay the progression of FD if treatment is initiated before irreversible organ damage. In a multicenter randomized trial of 58 patients treated with recombinant human α-GAL A ERT every 2 weeks for 20 weeks, reduction in plasma Gb3 and clearance of Gb3 microvascular endothelial deposits were reported. [N Eng J Med 2001;345:9-16] 

Recombinant human α-GAL A ERT also reduces cardiac size, improves cardiac function and increases exercise tolerance. [Circulation 2009;119:524-529; Clin Genet 2004;66:158-165; Am J Cardiol 2006;97:1515-1518; Kidney Int 2006;69:1216-1221; J Inherit Metab Dis 2006;29:112-116; Heart 2009;95:1103-1107; J Inherit Metab Dis 2006;29:572-579] The severity of baseline hypertrophy and fibrosis determines cardiac outcome. [Circulation 2009;119:524-529; Clin Ther 2007:29:S13-S14] 

IVS4+919G>A cardiac variant FD observed in Chinese populations

A pilot neonatal FD screening programme conducted in Taiwan in 2006–2008, using analysis of α-GAL A activity in dried blood samples, found that among 90,288 males screened, 72 had low α-GAL A activity and GLA mutation – an unexpectedly high prevalence of 1 in 1,250 males. [Hum Mutat 2009;30:1397-1405] Of the FD mutations, 86 percent were the cardiac variant IVS4+919G>A – a prevalence of 1 in 1,460 males. 

In adults with IVS4+919G>A mutation, the onset rate of LVH increases sharply at the age of 40 years along with the observation of significant Gb3 accumulation from cardiac biopsies. (Figure 2) [J Am Cardiol 2016;68:2554-2463]

HK-SAN-188md Fabry disease IU2

“Screening studies in individuals at high risk of FD often identify previously unrecognized patients,” said Lee. High-risk patients include those with LVH or HCM, unexplained kidney failure, or young patients with cryptogenic stroke. [J Med Genet 2010;47:217-222; J Med Genet 2014;51:1-9] 

A FD screening study in high-risk LVH patients was conducted at the Prince of Wales Hospital (PWH), Hong Kong. The study included 500 LVH patients (intraventricular septum and/or posterior thickness ≥13 mm) evaluated at the PWH Echocardiography Laboratory. Patients had dried blood spot testing for α-GAL A enzyme activity. Confirmatory analysis, including GLA gene sequencing and endomyocardial biopsy, was done for patients with low levels of enzyme activity. “Among 492 patients who underwent preliminary analysis, seven FD cases (all male) were identified, corresponding to a prevalence of 2.5 percent among all LVH patients [male and female] and 3.8 percent in male LVH patients,” reported Lee. (Figure 3[CL1] ) “All cases had IVS4+919G>A cardiac variant FD mutation and their predominant heritage was the Eastern part of Guangdong Province, China.” 

“Historically, only 30 cases of FD had ever been identified in Hong Kong, but we have identified seven cases in the last 2 years by screening this high-risk group,” he added.

HK-SAN-188md Fabry disease IU3


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Pearl Toh, 04 Jun 2020
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