Fabry Disease – Cardiac Dysfunction

There is considerable clinical heterogeneity with cardiac involvement in Fabry disease. Cardiac manifestations generally develop in patients older than 30 years of age.^[1]

Cardiac-related signs and symptoms of Fabry disease may include:^{[1, 2]}

Left ventricular hypertrophy

Valvular disease (especially mitral valve prolapse and/or regurgitation)

Premature coronary artery disease

Angina

Myocardial infarction

Conduction abnormalities

Arrhythmias

Congestive heart failure

Left ventricular hypertrophy (LVH)

Progressive GL-3 accumulation in myocardial cells may lead to significant enlargement of the heart, particularly the left ventricle.^[1,2] The main determinants of left ventricular mass appear to be age and α-GAL activity.

Left Ventricular Hypertrophy in a 50-year-old patient with Fabry disease

Characteristic electrocardiographic findings include AV conduction abnormalities (short P-R intervals or AV block), signs of left ventricular hypertrophy, and repolarization abnormalities (ST-T wave changes). Supraventricular arrhythmias may also be noted.^[3]

Echocardiographic findings may include aortic root dilatation, enlarged ventricular mass, and valvular disease (especially of the mitral valve). Left ventricular enlargement tends to increase with disease severity and age.^[4]

Atypical variants are subtypes of Fabry disease patients who have residual levels of α-GAL and manifest few or none of the classical Fabry symptoms. Often in these patients, the disease predominantly affects one organ system. Cardiac variants are the most widely recognized and studied of these subtypes. In cardiac variants, disease manifestations typically present later in life and are limited to the heart. The vascular endothelium is generally not affected.

A study in Japan suggests that the cardiac variants of Fabry disease may be under-recognized. Among the 230 unselected males with left ventricular hypertrophy, 3% were found to have low alpha-GAL activity (4-14% of normal).^[5] None of these men exhibited signs and symptoms considered typical of Fabry disease, such as angiokeratomas, acroparesthesias, corneal opacities, or hypohidrosis. An additional study of 79 men with late-onset hypertrophic cardiomyopathy found 6.3% of the hemizygotes to have low alpha-GAL levels.^[6]

References

1. Linhart A, Paleček T, Bultas J, et al. New insights in cardiac structural changes in patients with Fabry's disease. Am Heart J. 2000;39:1101-1108.

2. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001;3733-3774.

3. Linhart A, Lubanda J-C, Palecek T, et al. Cardiac manifestations in Fabry disease. J Inher Metab Dis. 2001;24(Suppl 2):75-83.

4. Goldman ME, Cantor R, Schwartz MF, Baker M, Desnick RJ. Echocardiographic abnormalities and disease severity in Fabry's disease. J Am Col Cardiol. 1986;7:1157-1161.

5. Nakao S, Takenaka T, Maeda M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333:288-293.

6. Sachdev B, Takenaka T, Teraguchi H, et al. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation. 2002;105:1407-1411.