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Prof. Aleš Linhart ,
Dr. Lubor Goláň
Dr. Gabriela Dostálová
Fabry disease (FD) is a rare lysosomal storage disorder caused by an alpha-galactosidase A deficiency. A multi-organ involvement requires a multidisciplinary approach and an organ-specific treatment. An enzyme replacement therapy has been available since 2001 and while, at the present time, we have considerable information as to its efficacy, it has become clear that the effect of the therapy depends on the stage of the disease. In this article we describe the management of patients with FD based on the longstanding experience of the national referral center in the Czech Republic.
Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations. The resulting deficient or missing activity of the lysosomal enzyme α-galactosidase A (AGAL) [1,2] leads to progressive accumulation of glycolipids, primarily globotriaosylceramide (Gb3) within many cell types. The storage occurs primarily in vascular endothelium and smooth muscle cells, cardiac myocytes, fibroblasts, and conduction cells, renal podocytes, mesangial and tubular cells, multiple cells within the nervous system and many other cells throughout the body [1,2,3].
“Classic” Fabry disease usually develops in patients with missing or severely reduced AGAL activity with microvascular endothelial Gb3 accumulation . The disease is then characterized by early onset of symptoms and a multisystemic involvement including cutaneous lesions (angiokeratomas), hypohidrosis, peripheral neuropathy, early CNS involvement with white matter lesions and premature stroke development, kidney involvement with proteinuria and renal insufficiency and cardiomyopathy. Subjects with at least partially preserved AGAL activity may present with a “later onset” phenotype with a delayed onset and slower progression manifesting mostly as cardiomyopathy . Heterozygous female patients from both “classic” and “later onset” families may have a wide range of clinical phenotypes depending on mutation type and random X-chromosomal inactivation .
The cardiomyopathy of Fabry disease is characterized by a slowly progressing left ventricular remodeling and hypertrophy with mild-to-moderate filling impairment and preserved ejection fraction. Although the storage and compensatory hypertrophy start to develop from early childhood, significant clinical manifestations are rare before the third decade in males and fourth decade in females . Children may present subtle electrocardiographic changes  and borderline hypertrophy at upper limits of the normal range reported for the general population. Although right ventricular hypertrophy is frequent, it does not result in significant clinical symptoms . Late stages with extensive fibrosis may be associated with systolic dysfunction and restrictive physiology.
Left ventricular outflow tract obstruction (LVOTO) is less frequent than in sarcomeric hypertrophic cardiomyopathy (HCM) but may be provoked by physical exercise .
Many patients develop interstitial and replacement fibrosis, localized typically within the posterolateral basal myocardial segments .
In a subset of patients, FD is associated with short PR interval due to accelerated AV conduction . In contrast, advanced cardiomyopathy may lead to conduction impairment (AV blocks) and/or bradycardia and chronotropic incompetence. Atrial fibrillation is frequent, potentially contributing to the increased stroke risk . In advanced cases, malignant ventricular arrhythmias may occur, increasing the risk of sudden cardiac death .
Valvular involvement in Fabry disease is due to fibroblast storage . The majority of cases develop only mild to moderate structural valvular alterations. However, a small proportion of patients may develop a significant mitral prolapse. Aortic remodeling is frequent, associated with mostly mild aortic dilatation . Coronary artery disease may contribute to the development of angina pain and dyspnea. The arterial involvement is, at least in part, not caused by atherosclerosis: many patients have only depressed coronary flow reserve without involvement of major epicardial arteries .
With the introduction of enzyme replacement therapy (ERT), it is now possible to target the underlying process causing organ changes in Fabry disease. However, the heart remains a difficult target. In spite of ERT, many patients develop cardiac complications over time, especially if the treatment was started late. Advanced stages of cardiac disease are frequently unresponsive. Several adjunctive therapies, including drugs, pacing and implantable cardioverter defibrillator (ICD) implantation, may significantly improve the outcome.
Patients presenting with any cardiovascular symptoms usually already carry a significant organ involvement. None of the symptoms should be underestimated. Some of them may be due to unexpected conditions specific to Fabry disease.
Preventative measures including lifestyle modification, smoking cessation and diet should follow the current guidelines for cardiovascular disease prevention.
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (if ACE inhibitors are not tolerated) should be used in all patients with hypertension, microalbuminuria/proteinuria and those with systolic dysfunction. In contrast, their use in patients with LVOTO should be avoided.
There is no formal evidence of statin efficacy in FD. Therefore, statins should be used according to current guidelines both in primary and secondary prevention.
Antiaggregation by using low-dose aspirin or P2Y12 inhibitors is mandatory in secondary prevention in patients with proven occlusive vascular events such as acute coronary syndromes, ischemic stroke or peripheral arterial disease according to the respective guidelines. However, in the absence of positive data in primary prevention, the use of aspirin or other antiplatelet drugs in patients without evidence of atherothrombotic disease is not reasonable.
In adult patients, about 5% of males and 3% of females have prevalent arrhythmia. Anticoagulation should be used in all patients with any history of atrial fibrillation regardless of the CHA2DS2VASc score which is not applicable to FD disease. As there is no specific evidence either for novel anticoagulants or for warfarin, the anticoagulation choice should be guided by current guidelines and drug availability.
Amiodarone should be avoided if possible due to its interference with lysosomal function . Little is known about the effects of dronedarone on endosomal/lysosomal trafficking and function. However, dronedarone is contraindicated in NYHA Class III-IV heart failure patients and in those with eGFR <30 ml/min. It should also be kept in mind that sotalol is contraindicated in cases with significant LVH and eGFR <50 ml/min, and flecainide is contraindicated if eGFR <50 ml/min. The use of flecainide and propafenone for pharmacological cardioversion should be limited to patients without major LV hypertrophy. Catheter ablation may be effective for sinus rhythm restoration and maintenance.
Advanced disease is associated with an increased risk of malignant arrhythmic events. Current algorithms used for sudden death risk stratification in hypertrophic cardiomyopathy are not applicable to FD cardiomyopathy. Patients with significant hypertrophy, extensive fibrosis, history of unexplained syncope, and ventricular tachycardias on Holter monitoring may be at higher risk and should be considered for ICD implantation. As in Fabry cardiomyopathy, there is no particular evidence of sudden cardiac death risk increase with exercise. Patients with FD should not be discouraged from playing recreational sports.
In symptomatic patients with LVOTO, the aim is to improve symptoms by using drugs, surgery, alcohol ablation  or pacing according to current guidelines on hypertrophic cardiomyopathy.
Heart failure should be treated according to current recommendations, including device therapy. Beta-blockers and ivabradine should be used with caution and adequacy of heart rate monitored by repeated Holter recordings. The use of ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists (MRAs) is indicated, paying special attention to kalemia and the renal function of FD patients with nephropathy.
These conditions should be treated in accordance with the current ESC guidelines. The benefit of rate-responsive pacing in treating exercise intolerance is uncertain. However, highly symptomatic patients with proven chronotropic incompetence may benefit in terms of symptom improvements.
Exercise-related chest pain often signals the presence of coronary heart disease. However, in many Fabry patients the coronary flow reserve is impaired due to microvascular dysfunction, aggravated by the presence of left ventricular hypertrophy . Several techniques may be used to elucidate the nature of the symptoms, including perfusion imaging, computed tomography (CT) coronary angiography (CTCAG) and conventional coronary angiography (CAG). According to our personal experience, FD patients are prone to respond with spasm to the instrumentation within the coronary arteries. Therefore, less invasive methods should be used first. Coronary artery disease should be managed the same way as in patients without FD. Caution is needed whenever using bradycardia-inducing drugs such as beta-blockers, verapamil or diltiazem, and/or ivabradine due to the increased risk of bradycardia.
Two preparations of recombinant agalsidase ERT are currently available in Europe: agalsidase alfa (Replagal®; Shire Human Genetic Therapies Inc., Lexington, MA, USA), agalsidase beta (Fabrazyme®; Genzyme, a Sanofi company, St Germain en Laye, France). Both drugs are administered bi-weekly in a short intravenous infusion. The major difference between the two available formulations is the prescribed dose - 0.2 mg/kg every two weeks for agalsidase alfa and 1.0 mg/kg every two weeks for agalsidase beta. There are no head-to-head data comparing the long-term effectiveness of high (1.0 mg/kg every two weeks) versus low (0.2 mg/kg every two weeks) dose on cardiovascular events.
ERT effectively reduces endothelial myocardial inclusions. On the other hand, clearance of Gb3 from cardiomyocytes is less evident [17,18]. The treatment has been shown to prevent LV hypertrophy development . Mild degrees of LVH may partially regress both in classic and cardiac variant patients . The patients with larger areas of myocardial fibrosis respond less in terms of functional improvement . There is not enough evidence that ERT is able to stop fibrosis development and progression. ERT is currently indicated in all classically affected patients with symptoms and at the earliest signs of organ involvement, including neuropathy, nephropathy and cardiomyopathy. Enzymatic replacement has been shown to improve prognosis mainly by reducing kidney disease progression [21,22]. At the present time, there is no formal evidence of reduction of cardiovascular events, such as heart failure, arrhythmias and cardiac death.
Currently, there is limited evidence on ERT efficacy in cardiac/late-onset variants  showing reduction of LV mass and some evidence of Gb3 clearance from myocardial cells. The natural evolution of late disease forms is characterized by a relatively long latent asymptomatic period and incomplete penetrance. Considering the burden of intravenous infusion therapy and the need for a long-lasting ERT with uncertain ability to prevent cardiomyopathy development and progression and in the absence of proof of hard endpoint reduction, the recommendation on the treatment of late-onset cardiac variant patients cannot be formally issued.
Pharmacological chaperones – small molecules stabilizing wild-type and some mutant forms of AGAL - have been proposed as a potential therapy for Fabry disease. The iminosugar, 1-deoxygalactonojirimycin (AT1001, migalastat hydrochloride) is an analog of the terminal galactose of Gb3. It binds reversibly to the enzyme allowing its better trafficking through the endoplasmic reticulum to the lysosome. Migalastat monotherapy has been shown to reduce the storage of Gb3 in vitro and in vivo. The drug is administered orally, every second day. To achieve its effects when given alone, the drug requires at least some endogenous enzyme production. Therefore, only a limited subset of patients carrying “amenable” missense mutations would respond. The combination with ERT may increase the stability of infused enzyme and allow its better tissue availability. Migalastat is currently in clinical development and not commercially available as yet .
In general, FD patients require lifelong follow-up to detect changes in symptoms, arrhythmia occurrence, and heart failure progression. A clinical evaluation should be performed at baseline and in cases of symptom appearance. According to our experience, follow-up of FD patients in large reference centers allows for a sufficient level of expertise which is a great advantage in treating these patients.
In children, the progression of the cardiac disease is slow and malignant arrhythmias rare . Therefore, re-evaluation may be less frequent (every 2-3 years).
In adult men over the age of 20 and women over the age of 30 a re-evaluation should be performed on a yearly basis. The minimum clinical control should comprise clinical assessment, ECG, echocardiography and Holter monitoring. Cardiac MRI evaluation may be considered every 5 years or every 2-3 years in patients with progressive disease.
Fabry disease cardiomyopathy represents about 0.5% up to 4% of cases of patients with hypertrophic cardiomyopathy. Currently, it is one of the rare examples of inherited myocardial diseases with ERT being the specific therapy. Adequate management of different cardiac complications may improve the outcome of patients progressing to or presenting with an advanced cardiomyopathy. In some respects its management differs from guidelines issued for hypertrophic cardiomyopathy or atrial fibrillation management. Due to the complex nature and multisystemic character of the disease it would seem to be a great advantage to concentrate Fabry patients in large centers with sufficient experience and a multidisciplinary team.
Dr Gabriela Dostálová, MD; Dr Lubor Goláň, MD; Prof. Aleš Linhart, MD, DrSc, FESC
2nd Internal Department – Cardiology and Angiology, General Teaching Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Republic
Author for correspondence:
Dr Gabriela Dostálová,
National Center for Fabry disease,
U Nemocnice 2,
Tel: +420 224966230
Conflict of interest:
Gabriela Dostálová has received speaker's and consultant´s honoraria from Genzyme and Shire. Lubor Goláň has received speaker's and consultant´s honoraria from Genzyme and Shire. Aleš Linhart has received speaker's and consultant´s honoraria from Genzyme and Shire and Amicus.
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