Homocystinuria

Abstract

inherited defect in methionine metabolism, although a very rare disorder, has been much publicized since its discovery in 1962.1,2 There is now good evidence that the basic defect is a deficiency of the enzyme cystathionine synthetase,3,4 preventing the formation of cystathionine from homocystine. The immediate result of this enzyme block is to increase accumulation of homocystine, a "nonthreshold" amino acid which is rapidly excreted into the urine in the oxidized form as homocystine. The back reaction to methionine, favored by the homocystine accumulation, results in high blood concentrations of the methionine and urinary excretion when tubular reabsorption limit is exceeded.Like other inborn errors of amino acid metabolism, homocystinuria often causes brain damage, the severity varying from minimal intellectual defect to gross cerebral dysfunction. Schimke et al 5 however, judged 16 of 38 patients to be of normal intelligence. Liver biopsies in two of their patients, one retarded and one of normal intelligence, both showed low levels of cystathionine syn-thetase. Those with normal intelligence varied in age from 11 to 45 years with 60% over the age of 23, whereas 90% of the 22 with brain damage were less than 22years old. As in other congenital enzyme-deficiency conditions there are four possible reasons for the pathological features : ( 1 ) the increase in metabolites proximal to the enzymatic block, ie, methionine and homocystine; (2) the lack of metabolites distal to the block, ie, cystathionine and cystine; (3) the increase in other metabolites resulting from little used, alternate pathways; and (4) an unusual demand for coenzymes or vitamins to deal with the unusual biochemical situa¬ tion (cystathionine synthetase is Be de¬ pendent). Much work is still to be done to relate the clinical manifestations to the ap¬ propriate biochemical condition.Cystathionine is known to be present in high concentration in the occipital lobe of the human brain,6 and animal experiments have shown it can be synthetized by the brain.7Controlled postmortem examination of cere¬ brum and brain stem material of homocystinurics has shown an extremely low level of cystathionine.8,9 If normal brain development depends on a certain cystathio¬ nine level, then a low methionine diet is not likely to avert brain damage in the neonate nor modify it in the older patient. The logical step, the feeding of cystathionine, has not been attempted because of its ex-