globotriaosylceramide and Cardiomegaly

Fabry disease is a rare, progressive, X-linked inherited storage disorder due to absent or deficient of lysosomal alfa galactosidase A activity. Deficient activity of alfa-galactosidase A results in progressive accumulation of globotriaosylceramide in a variety of tissues and organs including myocardium, kidney and nerve system. This disorder predominantly affects males; however, female heterozygotes may also be affected with a less severe clinical picture. Classic Fabry disease is usually diagnosed in early age of childhood because of multiorgan involvement whereas cardiac and renal variants of Fabry are manifested in 30-50 years of age because of late onset of clinical picture in which other organs involvement are uncommon. Although Fabry is known as a very rare disease, its prevalence is reported to be higher in patients with ventricular hypertrophy, chronic kidney disease and cryptogenic stroke. From the cardiology point of view, the most important key finding of the disease is unexplained ventricular hypertrophy. However, in clinical practice, ventricular hypertrophy is usually thought to be due to hypertrophic cardiomyopathy in the absence of hypertension or aortic stenosis and Fabry disease is often undiagnosed or overlooked. Early diagnosis and enzyme replacement therapy have been shown to significantly improve prognosis. The aim of this paper is to provide a comprehensive review including epidemiology, prognosis, clinical presentation, diagnosis and therapeutic approaches of cardiac variant of Fabry based on the available data in the literature.

Topics: Age of Onset; alpha-Galactosidase; Arrhythmias, Cardiac; Cardiomegaly; Early Diagnosis; Echocardiography; Electrocardiography; Electrocardiography, Ambulatory; Enzyme Replacement Therapy; Fabry Disease; Female; Heart Diseases; Heterozygote; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Pedigree; Prognosis; Sex Factors; Symptom Assessment; Trihexosylceramides

Fabry's disease was diagnosed in an adult patient as a lipid storage-induced non-obstructive hypertrophic cardiomyopathy. Stable angina pectoris started 15 years before death, was followed by slowly progressive heart failure and repeated pulmonary thromboembolism with death at 63 years. Autopsy disclosed enormous cardiomegaly (1100 g), cardiac storage of ceramide trihexoside (CTH) of the same intensity as in classical cases of generalized Fabry's disease (11 mg lipid/g wet weight) restricted to cardiocytes. Other tissues (liver, kidney, brain, pancreas, pulmonary artery, coronary arteries) were free of storage. Using proton magnetic resonance analysis on formaldehyde-fixed tissue the stored CTH was identified as globotriaosylceramide. It was enzymatically degradable by control cell cultures but left uncleaved by mutant reference Fabry cells. Alpha-galactosidase activities in peripheral leucocytes of all four of the patient's daughters were in the heterozygous range. The diagnostic difficulties in this monosymptomatic novel variant of Fabry's disease are stressed.

Topics: Cardiomegaly; Fabry Disease; Glycolipids; Humans; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Microscopy, Electron; Middle Aged; Myocardium; Trihexosylceramides