LAUSR

It is just over 50 years since classical homocystinuria was first described independently in 1962 by Carson and Neill in Northern Ireland and Gerritsen and colleagues in Madison, Wisconsin [1,2]. In both cases, patients were studied because of mental retardation. Classical homocystinuria is caused by a deficiency of the enzyme cystathionine β-synthase deficiency (CBS) (EC 4.2.1.22) (see Figure 1). It is a rare inborn error of sulfur amino acid metabolism, characterized biochemically by elevation of plasma homocyst(e)ine and methionine and clinically by abnormalities variably affecting the eye (typically dislocated lenses), blood vessels (thromboembolism), central nervous system (intellectual deficits or psychiatric disorder), and the skeleton. Skeletal abnormalities include a Marfanoid habitus, genu valgus or varus, sternal deformity, and what has been described as osteoporosis. There is a wide range of severity. The pathophysiology appears mainly secondary to the elevated homocysteine levels. About half of all patients are biochemically responsive to the cofactor, given as oral pyridoxine (vitamin B6), with significant lowering of plasma homocysteine levels. These patients aremoremildly affected, and sometimes asymptomatic throughout childhood and beyond. Pyridoxine-nonresponsive patients need other homocysteine-lowering treatment including low-methionine diet and betaine [3]. Homocysteinemia andhomocystinuria also occur in several inborn errors affecting homocysteine remethylation as well as in vitamin B12 and folic acid deficiencies and in renal insufficiency, but this commentary relates only to CBS deficiency.