Homocysteine, Marfan syndrome and arteriosclerosis.

Homocystinuria is an inherited disease of homocysteine metabolism most commonly caused by deficiency of the pyridoxal phosphate-dependent enzyme, cystathionine synthase. The disease is manifested in many cases by accelerated growth in childhood, dislocated ocular lenses, skeletal abnormalities, retarded mental development, and propensity to thrombosis with increased mortality from vascular disease. Before the discovery of homocystinuria in 1962, many of these subjects were considered to have Marfan Syndrome, because of accelerated growth, dislocated ocular lenses, and vascular disease. Subsequent screening of the urine for homocysteine revealed a number of cases of homocystinuria that were originally attributed to Marfan Syndrome. Review of an archival case of homocystinuria originally reported in 1933 disclosed generalized arteriosclerosis and death from carotid thrombosis and stroke in an eight-year-old boy with mental retardation, dislocated ocular lenses, and skeletal abnormalities. Review of a second case of homocystinuria, caused by deficiency of methionine synthase, a folateand cobalamin-dependent enzyme, disclosed severe and widespread arteriosclerotic plaques in arteries throughout the major organs. Because of the difference in metabolic pattern between these two cases of homocystinuria caused by different enzyme abnormalities, the amino acid homocysteine was concluded to have atherogenic properties because of a direct effect on the cells and tissues of the arteries. A subsequent case of a nineyear-old girl with homocystinuria caused by deficiency of methylenetetrahydrofolate reductase, a folatedependent enzyme, was also found by other investigators to have widespread arteriosclerotic plaques, independently corroborating this conclusion. Early reports of the pathological manifestations of homocystinuria attributed the vascular changes to a lathryogenic effect of homocysteine on the connective tissues of arteries because of a molecular resemblance of homocysteine to penicillamine, a well-known lathryogenic compound. Subsequent study of the role of homocysteine, however, has shown that moderate elevations of blood homocysteine levels are a potent independent risk factor for human arteriosclerotic vascular disease in the general population. In classic cases of Marfan Syndrome the vascular manifestations are principally dilation of aorta and aortic valve with cystic medial necrosis and predisposition to dissecting aneurysm of aortic arch. In homocystinuria the vascular manifestations are principally accelerated arteriosclerosis with predisposition to arterial and venous thrombosis and, occasionally in older subjects, arteriosclerotic aneurysm of abdominal aorta. In the study by Giusti et al. in the current issue of European Heart Journal, the observation of elevated blood homocysteine levels in Marfan Syndrome establishes a new relation of this disease with the pathogenesis of arteriosclerosis. The findings show that Marfan Syndrome patients with the most severe vascular changes, including aortic dissection, have significantly higher homocysteine levels than patients with mild changes or normal controls. In addition, Marfan Syndrome patients with the common homozygous polymorphism of methylenetetrahydrofolate reductase, C677T, have significantly higher homocysteine levels and increased severity of vascular disease. These findings suggest that the pathogenesis of the vascular changes in Marfan Syndrome involves the action of homocysteine at a molecular, cellular and tissue level. Investigation of cultured skin fibroblasts from patients with cystathionine synthase deficiency and homocystinuria revealed an aggregated, granular form of extracellular proteoglycan associated with increased binding of sulphate groups. This change from fibrillar to aggregated molecular conformation has been attributed to a transition from helical to random coil configuration produced by sulphate binding to homocysteine thiolactone that is bound by ionic bonding to protein carboxyl groups. In addition, the cultured cells were found to * Tel.: 617-363-5618; fax: 617-363-5623 E-mail address: [email protected] (K.S. McCully). European Heart Journal (2003) 24, 1995–1996