Cardiovascular Manifestations of Fabry Disease
Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Renown Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC
Bloch MJ. Cardiovascular manifestations of Fabry disease. Consultant360. Published online August 30, 2021.
Fabry disease is an X-linked glycolipid storage disease that is often diagnosed based on cutaneous, renal, corneal, or neurological manifestations.1 However, it is becoming increasingly clear that many patients with Fabry disease may not present with these classic signs and symptoms.2 Fabry disease needs to be considered in the differential diagnosis of patients presenting with unexplained cardiovascular disease, particularly unexplained left ventricular hypertrophy (LVH) or dysfunction. The widespread availability and efficacy of enzyme-replacement therapy makes early diagnosis of Fabry disease paramount.
The primary metabolic defect in Fabry disease is a deficiency of lysosomal hydrolase α galactosidase A (α-Gal A) leading to toxic accumulation of glycolipids in the lysosomes of various tissues. As an X-linked disorder, most patients with classic Fabry disease are hemizygous young men with very low levels of α-Gal A activity. But increasingly, we are recognizing that there is substantial phenotypic variation, including men with some residual α-Gal A activity and heterozygous women, both of whom may have a variable course and tend to present later in adulthood, often with primarily cardiovascular manifestations. There also appears to be specific cardiac and renal variants that present with disease limited to those organ systems.3
The cardiovascular manifestations of Fabry disease include left ventricular dysfunction, valvular disease, stroke, conduction defects, aortic root dilation, and hypertension. The most common cardiovascular manifestation of Fabry disease is left ventricular dysfunction initially presenting with LVH, and Fabry disease should be considered in the differential diagnosis of any patient with unexplained LVH. Even in the absence of decreased ejection fraction, patients with Fabry disease-mediated LVH often will present with symptoms of dyspnea and chest pain with exertion. Additionally, the toxic metabolites of Fabry disease can accumulate in the small vessels of the coronary arteries, leading to angina in the heart valves, leading to modest stenosis or regurgitation, and in the conduction system, leading to both atrial and ventricular arrythmias. Fabry disease should be in the differential diagnosis for unexplained ascending aortic aneurysm, particularly in young men. Finally, patients with Fabry disease can present with hypertension, usually associated with renal involvement, and stroke risk is increased through a variety of mechanisms.
Patients with known Fabry disease should be monitored with periodic echocardiography to assess left ventricular wall thickness and function and valve morphology, and to monitor for ascending aortic aneurysm. Following cardiac biomarkers like N-terminal pro-brain natriuretic peptide (NT-proBNP) and performing serial cardiac magnetic resonance imaging may be helpful in tracking the severity of disease in patients with known cardiac involvement, but the exact role of these technologies is still evolving.
In addition to managing the individual cardiac manifestations with guideline-directed therapies, Fabry disease-specific therapy should be initiated in all patients with documented cardiovascular manifestations. The most used treatment is intravenous enzyme-replacement therapy given every 2 weeks. There is also an oral chaperone therapy available for patients with amenable mutations. The precise degree of efficacy of these therapies for the cardiac manifestations of Fabry disease remains to be determined, but nonetheless, prompt identification of cases and early administration of enzyme-replacement therapy is likely to be quite beneficial. The diagnosis in young men with classic symptoms is usually made through a widely available enzyme assay test, but in women and in some late-onset men who have residual enzyme activity, genetic testing may be needed to confirm or exclude the diagnosis.
As a rare disease that has mostly been characterized by its noncardiovascular manifestations, Fabry disease may not be top of mind for many providers who treat primarily adults with cardiovascular disease. But recognizing the complex phenotypic expression and potential for late onset of cardiovascular manifestations is paramount to ensure that we do not miss patients who might benefit from treatment. Providers need to keep Fabry disease in the differential diagnosis of adult patients, both men and women, who present with otherwise unexplained cardiovascular disease.
- Balbi A. What you need to know about Fabry disease. Consultant360. Published online August 4, 2021. https://www.consultant360.com/exclusive/consultant360/fabry-disease/what-you-need-know-about-fabry-disease
- Pop quiz: presenting symptoms of Fabry disease. Consultant360. Published online July 26, 2021. https://www.consultant360.com/exclusive/consultant360/fabry-disease/pop-quiz-presenting-symptoms-fabry-disease
- Cassiano Augusto, MD, on renal manifestations of Fabry disease. Consultant360. Published online June 17, 2021. https://www.consultant360.com/exclusive/consultant360/fabry-disease/cassiano-augusto-md-renal-manifestations-fabry-disease