Anderson-Fabry Disease and the Heart
Section snippets
Molecular genetics
Anderson-Fabry disease is caused by mutations of the GLA gene located on the X chromosome (Xq22.1) and is composed of 7 exons. More than 300 mutations, scattered throughout the GLA gene, have been identified, most of which are missense. Many are “private” (ie, confined to single families). The frequency of de novo mutations is uncertain but may be as high as 10% of cases.3, 4
The product of the GLA gene, α-galactosidase A, is composed of 2 identical monomers, each 398 amino acids long. The
Epidemiology
The incidence of AFD is reported to range from 1/117,000 to 1/40,000, but these figures are likely to underestimate the burden of disease because its protean manifestations often lead to misdiagnosis and underreporting.6, 16, 17 The distribution is panethnic, with increased incidence in certain populations in Nova Scotia (Canada) and West Virginia (United States) because of founder effects.2
Screening studies involving patients receiving renal replacement therapy have reported prevalences of
Clinical presentation
Although lysosomal accumulation of globotriaosylceramide starts from the prenatal period,26 symptoms usually develop in early childhood after a latent period of variable duration and slowly progress with advancing age, finally culminating in life-threatening renal, cerebral, and cardiac involvement.2 Untreated males have a median survival of 50 years, 20 years less than males from the general population.27 Despite less severe clinical features, females also experience life-threatening
Cardiac disease
Globotriaosylceramide accumulates in cardiomyocytes, conduction system cells, valvular fibroblasts, endothelial cells, and vascular smooth muscle cells.1 Examination of cardiac myocytes by electron microscopy typically shows a paucity of myofibrillar material, with membrane-lined vacuoles filled with lamellar electron-dense inclusions that contain glycosphingolipids.35 However, the chronic accumulation of globotriaosylceramide in the heart contributes only to 1% to 2% of the total cardiac mass
Cardiomyopathy
Left ventricular hypertrophy is the most common structural cardiac abnormality seen and is associated with the presence of cardiac symptoms.40 The prevalence of LV hypertrophy increases with age and occurs earlier in males than females. Renal function is inversely correlated with increasing LV mass.40 The early stages of AFD-related cardiomyopathy are characterized by concentric LV remodeling that progresses over time to hypertrophy.1, 41 Although concentric LV hypertrophy is the most typical
Electrophysiological abnormalities
A short PR interval is seen in 40% of patients42 and is caused by accelerated atrioventricular (AV) conduction rather than by accessory pathways.61 Accelerated AV conduction is thought to be more common in younger patients without LV hypertrophy, whereas older patients are more likely to develop bundle branch block and progressive AV conduction abnormalities43 with 3% of patients requiring antibradycardia pacing.40 Most male patients have a resting bradycardia and chronotropic incompetence62
Valvular disease
Globotriaosylceramide accumulation in heart valve tissue with secondary fibrosis and calcification can lead to valvular dysfunction.1 Contemporary studies have shown that mild aortic, mitral, and tricuspid regurgitation are the most frequent lesions even in patients with advanced disease.66 In the Fabry outcome survey registry, valve disease was reported in 14.6% of patients, but valve surgery was infrequent suggesting that the lesions are rarely of hemodynamic significance.40
Coronary artery disease
Many patients with AFD, especially those with LV hypertrophy, complain of angina suggestive of myocardial ischemia.40, 43 Despite the high incidence of ischemic symptoms and the diffuse arteriopathy that affects the endothelium, intima, media, and adventitia of blood vessels in AFD, the epicardial coronary arteries are obstructed only in a minority.67 Increased myocardial oxygen demand, endothelial dysfunction and microvascular dysfunction with impaired myocardial blood flow and coronary flow
Vascular disease
Although glycosphingolipid deposition occurs in many cell types, it has a particular affinity to vascular endothelium. Globotriaosylceramide accumulates predominantly in the intima and smooth muscle of the media of arterial walls, leading to thickening of the extracellular matrix and calcification. These changes can result in a morphologically diverse vasculopathy with thinning or thickening of the vessel wall and stenosis.37 Ectasia of basilar and vertebral arteries may compress neurologic
Diagnosis
Biochemical and/or genetic testing is the preferred method for establishing the diagnosis in most patients. In men, the diagnosis can be reached by screening for α-galactosidase A activity in peripheral leukocytes or plasma or by GLA gene sequencing. However, female carriers can have normal enzyme activity, and GLA gene sequencing or testing for a known familial mutation are more reliable.2, 71
Management of cardiac disease
Patients with AFD have multiorgan involvement and a multidisciplinary approach is essential in their management. Cardiac symptom management and the prevention of complications rely on the use of conventional therapies for which there is evidence of benefit in other heart disorders. Many patients complain of exertional angina and coronary angiography may be required in selected patients to rule out concurrent epicardial coronary artery disease. In the absence of coronary disease, patients should
Enzyme replacement therapy
Enzyme replacement therapy (ERT) aims to reduce globotriaosylceramide accumulation in tissues and thus prevent the long-term complications of AFD. Enzyme replacement therapy first became available in 2001 and currently 2 recombinant preparations of α-galactosidase A are available as follows: agalsidase-α, produced in a modified human cell line, and agalsidase-β, produced in Chinese hamster ovary cells. Both preparations are available in Europe, but only agalsidase-β is available in the United
Molecular chaperones
Molecules that increase the residual enzyme activity (chaperones) or reduce globotriaosylceramide formation (substrate inhibitors) may also prove useful in controlling the disease.2 Galactose and other competitive inhibitors of a-galactosidase A can stabilize residual α-galactosidase A activity and have the potential to prevent and/or reverse clinically significant globotriaosylceremide deposition.35 Such molecules are currently under investigation but are not available for routine clinical
Summary
Cardiac involvement is a common feature of AFD and should be considered in the differential diagnosis of patients presenting with unexplained LV hypertrophy. Cardiac involvement carries significant morbidity and mortality, and although conventional cardiac treatment helps control symptoms, it does not affect the underlying disease process. However, there is growing evidence that ERT helps halt progression and possibly reverses cardiac disease in some patients. Screening of asymptomatic
Statement of Conflict of Interest
All authors declare that there are no conflicts of interest.
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Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy
2019, Molecular TherapyCitation Excerpt :Accumulation of these fatty lipids is observed within the lysosomes of multiple tissues, including liver, spleen, kidney, and heart, as well as the vasculature and plasma. Progressive accumulation of such lipids leads to clinical disease, manifesting as angiokeratomas, congestive heart failure, stroke, myocardial infarction, and end-stage renal failure ultimately leading to fatality.2,7–9 Current therapies approved for the treatment of Fabry disease include enzyme replacement therapies (ERTs)10,11 and, more recently, a small molecule chaperone (migalastat).12,13
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Statement of Conflict of Interest: see page 332.