Literature
Clinical Pearls & Morning Reports
Published March 30, 2022
What are some of the clinical features of Fabry’s disease?
The most common cause of left ventricular wall thickening is hypertensive heart disease. Left ventricular wall thickening that is associated with hypertension is reversible. Read the NEJM Case Records of the Massachusetts General Hospital here.
Clinical Pearls
Q: Name some of the inherited systemic disorders that are associated with myocardial hypertrophy.
A: There are various inherited systemic disorders that are associated with myocardial hypertrophy but also cause other, noncardiac dysmorphisms and manifest early in life. These include Noonan’s syndrome and other disorders resulting from genetic mutations in the RAS‒MAPK signaling pathway. Mitochondrial myopathies can be associated with left ventricular hypertrophy. Friedreich’s ataxia, which is an autosomal recessive disease resulting from a defect in FXN (the gene encoding the mitochondrial protein frataxin), can cause left ventricular hypertrophy. Glycogen storage disease type III, which results from a deficiency in glycogen debranching enzyme, can also cause left ventricular hypertrophy.
Q: Name lysosomal storage diseases that are associated with myocardial hypertrophy.
A: Lysosomal storage disorders that are associated with myocardial wall thickening include Danon’s disease, Pompe’s disease, mucopolysaccharidoses, and Fabry’s disease. Danon’s disease is an X-linked dominant disease resulting from genetic defects in LAMP2 (the gene encoding lysosomal-associated membrane protein 2) that causes moderate-to-severe myocardial wall thickening, skeletal myopathy, and intellectual disability. Pompe’s disease is an autosomal recessive disorder that is caused by a deficiency in acid α-glucosidase, which leads to the intralysosomal accumulation of glycogen and an increase in myocardial mass.
Morning Report Questions
Q: What is Fabry’s disease?
A: Fabry’s disease is rare, and there is often a delay between symptom onset and diagnosis, with a mean delay of 14 years in men. Fabry’s disease results from a deficiency in the activity of the glycohydrolase enzyme α-galactosidase A. The primary abnormality involves the accumulation of globotriaosylceramide in a variety of cell types, which starts in utero in the most severe cases. This accumulation of globotriaosylceramide progresses over time and leads to end-organ damage. If untreated, the accumulation of globotriaosylceramide can lead to premature death. In classic cases of Fabry’s disease, symptom onset occurs in childhood and complications arise in adulthood. Therapy for Fabry’s disease includes enzyme-replacement therapy or chaperone therapy.
Q: What are some of the clinical features of Fabry’s disease?
A: The organs that are most often affected include the heart, the kidneys (glomerulosclerosis and proteinuria), and the central and peripheral nervous system (white-matter changes, strokes, and neuropathies). A common clinical manifestation of Fabry’s disease is hypohidrosis. Another common manifestation is systemic hypertension, which is often due to coexisting renal failure. The accumulation of globotriaosylceramide in cardiomyocytes, endothelial cells, and smooth-muscle cells leads to myocardial ischemia, valve abnormalities, and myocardial wall thickening. Diastolic dysfunction and heart failure can develop. Arrhythmias and conduction system disease commonly occur in patients with Fabry’s disease.