Recently a variant form of Fabry disease was identified with manifestations primarily limited to the heart. These cardiac variants typically, lacked the classic symptoms and typically present in either the fifth or sixth decade of life with left ventricular hypertrophy, cardiomegly and or a form of cardiomyopathy. Hypertrophic cardiomyopathy is usually the misdiagnosis. They may have proteinurea detected as early as the third decade, but renal function is typically within the normal age for their age group and may reflect other age-related complications such as hypertension. Cardiac variants have residual alpha-gal activity due to missense mutations and lack of systemic vascular endothelium as often seen with the classically effected males. These patients typically have alpha GAL levels of between 1 to 30% of normal plasma levels.

In contrast to the classically involved Fabry patients, these cardiac variants have no history of acroparesthesias, angiokeratomas or renal insufficiency, making it difficult for a diagnosis to be made unless a cardiologist considers this rare variant in a differential diagnosis of unexplained left ventricular hyperthrophy or a dilated cardiomyopathy.

Tissue biopsies from autopsy studies of cardiac variants reveal that GL-3 accumulation only occurs in the myocardium where GL-3 is difficult to clear, and not in the vascular endothelium of the heart or other tissues.

Cardiac Variant

Shoichiro Nakao, M.D., Toshihiro Takenaka, M.D., Masato Maeda: An Atypical Variant of Fabry’s Disease in Men with Left Ventricular Hypertrophy: NEJM Vol 333 No 5 288-293

A renal variant form has also been identified. The renal variant will manifest itself later in life. The classic Fabry symptoms were not previously seen and the pathology appears to be isolated to the renal system. The GL-3 accumulation occurs in the vascular endothelium, but there is a higher degree of accumulation in the epithelial cells and podocytes. The renal variants also have a phenotype that is not seen in the classically affected or cardiac variant patients.

The fact that these different variants lack the characteristic manifestations of the classic Fabry patient makes diagnosing these patients that much harder.

Renal Variant

Shoichiro Nakao, Chihaya Kodama, Toshihiro Takenaka: Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype: Kidney International, Vol 64 2003 801-807