Treatment of Homocystinuria with Pyridoxine

Homocystinuria is the result of an inborn error in the metabolism of the essential sulphur-containing amino acid, methionine (Carson and Neill, 1962; Gerritsen, Vaughn, and Waisman, 1962). There is now good evidence (Mudd et al., 1964) to show that the basic defect in this disorder is an inactivity of hepatic cystathionine synthetase, which prevents the formation of cystathionine from homocysteine and causes disruption of the normal metabolic pathway (see Fig. 1). This results in an accumulation ofhomocysteine in the blood, and as this is a 'non-threshold' amino acid, it is rapidly excreted in the urine in its oxidized form, homocystine. Homocysteine may be remethylated to methionine with the aid ofmethyl group donors such as N5-methyltetrahydrofolic acid (M5FH4) or betaine; the accumulation of homocysteine favours remethylation, and results in raised serum methionine levels. As cysteine cannot be formed, it now becomes an essential amino acid, and the patient depends on the dietary intake for his cysteine requirements. There also appears in the blood and urine the mixed disulphide of homocysteine and cysteine. Homocysteine and cysteine are converted to their oxidized forms, both enzymatically and non-enzymatically, and unless specific precautions are taken at the time of venepuncture to protect the S-H groups, these amino acids are quickly converted to the S-S form. In this work these compounds have been estimated in their oxidized form and will hereafter be referred to as homocystine, cystine, and their mixed disulphide. Such patients present a distinctive clinical picture. The majority have fair hair, a malar flush, poor peripheral circulation with well-marked livido reticularis. Ectopia lentis is present except in the very young, and mental retardation is common. Cardiovascular disturbances are present in older children; thrombotic episodes occur in about 40 to