RESUMEN
A patient is described with type I tyrosinemia characterized by urinary excretion of succinylacetone together with increased excretion of tyrosine, p-hydroxyphenyllactic, p-hydroxyphenylpyruvic and p-hydroxyphenylacetic acids. Fumarylacetoacetase was measured in a liver biopsy and found to be very low compared to control liver. Furthermore the mass spectra of succinylacetone and fumarylacetoacetate (methoxime-TMS derivatives) are reported. Control jejunal mucosa, leucocytes and fibroblasts showed no enzyme activity; hence the prenatal diagnosis of this disease by measuring the fumarylacetoacetase activity in cultured amniotic fluid cells is not possible at present.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Hidrolasas/deficiencia , Tirosina/sangre , Acetoacetatos/deficiencia , Fumaratos/deficiencia , Heptanoatos/orina , Humanos , Lactante , Cetoácidos/orina , Hígado/enzimología , MasculinoRESUMEN
Succinylacetone was excreted in the urine from four patients, with hereditary tyrosinemia i.e., two patients with the severe infantile type with fatal outcome and two patients with less severe juvenile form. In the urine from two patients with neonatal transient tyrosinemia and from normal individuals succinylacetone was not detectable. The urinary excretion of delta-aminolevulinic acid was also increased in all patients with hereditary tyrosinemia compared to patients with neonatal transient tyrosinemia and to normal individuals. The results presented support the hypothesis of a deficiency of fumarylacetoacetase in hereditary tyrosinemia. Furthermore an analytical method for the quantitative determination of succinylacetone in urine using GC-MS is described.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/orina , Ácido Aminolevulínico/orina , Heptanoatos/orina , Ácidos Heptanoicos/orina , Ácidos Levulínicos/orina , Tirosina/sangre , Acetoacetatos/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Femenino , Fumaratos/deficiencia , Humanos , Hidrolasas/deficiencia , Lactante , Cetoácidos/orina , Masculino , Modelos BiológicosRESUMEN
The activity of human liver fumarylacetoacetate fumarylhydrolase (EC 3.7.1.2) has been determined with fumarylacetoacetate as substrate. The Km was found to be 1.3 mu mol/l. Subcellular fractionation showed localization of the enzyme in the particle-free supernatant (cytosol). ZnCl2, CuCl2 and p-chloromercuribenzoic acid had a marked inhibitory effect on the enzyme activity, but no inhibition was observed with a number of anions and substrate analogs. Fumarylacetoacetate fumarylhydorlase activity in liver tissue from a patient with hereditary tyrosinemia was found to be less 2% of the controls. The assay is applicable to 3 mg of liver tissue which may be obtained by needle biopsy.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Hidrolasas/análisis , Hígado/enzimología , Tirosina/sangre , Acetoacetatos/análisis , Acetoacetatos/deficiencia , Adulto , Anciano , Fraccionamiento Celular , Citosol/enzimología , Estabilidad de Medicamentos , Fumaratos/análisis , Fumaratos/deficiencia , Humanos , Hidrolasas/deficiencia , Lactante , Cinética , Persona de Mediana EdadRESUMEN
Affected twins with acute hereditary tyrosinaemia type I are described. Attempts at therapy with a phenylalanine-tyrosine-methionine restricted diet supplemented with cysteine, vitamin E and ascorbic acid failed to influence the course of the disorder. The bleeding diathesis was due to a morbid reduction of a number of clotting factors, particularly factor VII, and this was associated with impaired platelet aggregation and release. The liver of one showed a marked reduction in fumarylacetoacetate lyase activity and her urine contained a potent inhibitor of red cell delta-aminolaevulinic acid dehydratase. Biochemical investigations of cultured fibroblasts suggest that these do not express the disorder and are unlikely to prove useful diagnostically.