RESUMO
OBJECTIVES: To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria. STUDY DESIGN: Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA. RESULTS: Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated homocystinuria, and patient 2 with combined methylmalonic aciduria and homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients. CONCLUSIONS: The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with homocystinuria.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Cobamidas/deficiência , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/genética , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Células Cultivadas , Saúde da Família , Feminino , Fibroblastos/metabolismo , Homocistinúria/genética , Homocistinúria/fisiopatologia , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana Transportadoras/genética , Ácido Metilmalônico/metabolismo , Proteínas de Transporte da Membrana Mitocondrial , Proteínas Mitocondriais/genética , Fenótipo , Deficiência de Vitamina B 12/fisiopatologiaRESUMO
OBJECTIVE: To evaluate prenatal treatment with hydroxycobalamin (OH-Cbl) in a pregnancy at risk for a severe form of the cobalamin C defect and postnatal treatment of the affected child. STUDY DESIGN: Observational study with non-randomized intervention. RESULTS: In contrast to reported pregnancies with affected fetuses in which maternal methylmalonic aciduria was found in the last trimester of pregnancy, there was no maternal methylmalonic aciduria in our case, given prenatal treatment with intramuscular OH-Cbl. We did not find that the concentration of odd long-chain fatty acids in cord blood erythrocytes reflects fetal methylmalonic academia. After birth, the infant was treated with intramuscular OH-Cbl and oral carnitine. Oral folate and betaine were added as adjunct therapy to decrease plasma total homocysteine. Because of inadequate metabolic control, a diet reduced in natural protein was introduced. The child had normal developmental milestones but had nystagmus, hyperpigmented retinopathy, and discrete truncal muscular hypotonia. CONCLUSIONS: Despite prenatal and postnatal treatment, adequate metabolic control, absence of metabolic crises, and normal developmental milestones, this patient with the cobalamin C defect had characteristic symptoms of the disease.