Filadelfo Irreverre

Homocystinuria: An Enzymatic Defect

A deficiency, or absence, of cystathionine synthetase activity has been demonstrated in liver obtained from a mentally retarded child with homocystinuria.

Sulfite oxidase deficiency in man: demonstration of the enzymatic defect.

An infant who died with neurological abnormalities, mental retardation, and dislocated ocular lenses excreted in his urine abnormally large amounts of S-sulfo-L-cysteine, sulfite, and thiosulfate and virtulally no inorganic sutlfate. The present report establishes the occurrence of an ezymatic defect in this infant. His liver, brain, and kidney specifically lacked sulfite oxidase activity. Deficiency of sulfite oxidase, which has not apparently been described in man, provides a reasonable explanation for the abnormalities in this infant.

Sulfite oxidase deficiency: Studies of a patient with mental retardation, dislocated ocular lenses, and abnormal urinary excretion of S-sulfo-l-cysteine, sulfite, and thiosulfate

Abstract This paper constitutes the first description of a previously unreported disorder of metabolism of sulfur-containing compounds. The patient was born with neurological abnormalities and deteriorated to a virtually decorticate state by nine months. Bilateral ectopia lentis was discovered at 1 year. We studied him at age 30 months and found his urine to contain abnormally increased amounts of S-sulfo- l -cysteine, sulfite, and thiosulfate. His urinary excretion of inorganic sulfate was markedly reduced and, in contrast to normal controls, it did not increase after administration of l -cysteine. These chemical abnormalities are best explained by the presence of a block in the conversion of sulfite to sulfate secondary to a deficiency of sulfite oxidase activity. Studies from tissues obtained from the patient postmortem reveal such a defect (5). The pathology could have been caused by toxic effects of accumulation of sulfite or perhaps other metabolites. Possibly, deficiency of inorganic sulfate could also have caused pathological changes. Although three of the patients seven siblings died in infancy with neurological disease, the remaining siblings and the parents do not bear clinical stigmata suggestive of the patients disease, and as yet we have detected no chemical abnormalities to suggest they are carriers of a trait. Thus, we suspect, but have no definite evidence, that the disease is an hereditary disorder of metabolism. We have named it sulfite oxidase deficiency.

Homocystinuria due to Cystathionine Synthetase Deficiency: The Mode of Inheritance

Deficiency of cystathioninie synthetase activity results in the clinical syndrome of homocystinuria. In both parents of a patient with homocystinuria, the hepatic cystathionine synthetase activity was 40 percent of that in unrelated control patients. These findings demonstrate that the metabolic error is inherited and suggest that the parents, although clinically normal, represent the heterozygous. state. A second case of homocystinuria also is shown to be associated with cystathionine synthetase deficiency.

Sulfite oxidase deficiency: Sulfate esters in tissues and urine

Abstract The possibility of a functionally significant sulfate deficiency in a patient with sulfite oxidase deficiency has been evaluated by study of sulfate esters in tissues and urine of this patient. Sulfatides in brain and kidney were normal qualitatively and normal in concentration. Since the brain weight was decreased, the total brain sulfatide was lower than normal. The daily urinary excretions of tyrosine-O-sulfate and indoxyl-3-sulfate were comparable to excretions found in control patients.

Threonine dehydratase activity in humans lacking cystathionine synthase.

Abstract Evidence has been presented that cystathionine synthase (L-serine hydro-lyase (adding L-homocysteine) E.C.4.2.1.21) of rat liver catalyzes two additional reactions: serine deamination (L-serine hydro-lyase (deaminating) E.C.4.2.1.13) (Selim and Greenberg, 1959) and threonine deamination (L-threonine hydro-lyase (deaminating) E.C.4.2.1.16) (Goldstein, et al. , 1962) . The homogeneous protein possesses all three activities (Greenberg and Nagabhushanam, 1964) . In sheep liver there are clearly two enzymes which convert serine to pyruvate and ammonia: a serine dehydratase which does not deaminate threonine (Sayre and Greenberg, 1956) and a threonine dehydratase which attacks serine at a slower rate (Nishimura and Greenberg, 1961) . A recently discovered human syndrome (Carson and Neill, 1962; Field, et al. , 1962; Gerritsen, et al. , 1962; Carson, et al. , 1963; Gerritsen and Waisman, 1964) is due to a lack of activity of cystathionine synthase (Mudd, et al. , 1964; Finkelstein, et al. , 1964) . The known biochemical features of the disease include homocystinuria and abnormally high concentrations of methionine and homocystine in the plasma. We have investigated threonine metabolism in such patients to determine if they have a block in the deamination of this amino acid, and to obtain additional evidence concerning the relationship of cystathionine synthase to threonine dehydratase. In this paper we report results of assays of threonine dehydratase activity in homogenates of liver specimens from four patients lacking cystathionine synthase.

STUDIES ON HOMOCYSTINURIA

Publisher Summary This chapter presents the studies on homocystinuria. Methionine is converted via S-adenosylmethionine and S-adenosylhomocysteine to homocysteine. Homocysteine may be methylated to form methionine. Human brain is extremely rich in cystathionine. This high concentration is specific for the tissue and for the species. Brains of a variety of other mammals have lower concentrations of cystathionine. Cystathionine synthase is present in brain at concentrations about 20% of the comparable hepatic concentrations. Certainly the brain is one of the relatively few tissues in which major amounts of cystathionine synthesis occurs. The values for cystathionase specific activity in brain are only about 1% of the values for liver. This observation suggests a partial explanation for the high concentration of cystathionine reported in monkey and human brain.