cobamamide and Kidney-Failure--Chronic

Isolated methylmalonic acidurias comprise a heterogeneous group of inborn errors of metabolism caused by defects of methylmalonyl-CoA mutase (MCM) (mut0, mut-) or deficient synthesis of its cofactor 5'-deoxyadenosylcobalamin (AdoCbl) (cblA, cblB). The aim of this study was to compare the long-term outcome in patients from these four enzymatic subgroups. Eighty-three patients with isolated methylmalonic acidurias (age 7-33 y) born between 1971 and 1997 were enzymatically characterized and prospectively followed to evaluate the long-term outcome (median follow-up period, 18 y). Patients with mut0 (n = 42), mut- (n = 10), cblA (n = 20), and cblB (n = 11) defects were included into the study. Thirty patients (37%) died, and 26 patients survived with a severe or moderate neurologic handicap (31%), whereas 27 patients (32%) remained neurologically uncompromised. Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF. Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects. In addition, long-term outcome was dependent on the age cohort and cobalamin responsiveness.

Topics: Adolescent; Adult; Age of Onset; Alkyl and Aryl Transferases; Amino Acid Metabolism, Inborn Errors; Child; Cobamides; Disease Progression; Female; Follow-Up Studies; Gastrointestinal Diseases; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Membrane Transport Proteins; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Mutation; Nervous System Diseases; Prognosis; Prospective Studies; Time Factors; Vitamin B 12; Vitamin B Complex

Renal tubular dysfunction and chronic renal failure are well recognised complications of methylmalonic acidaemia (MMA) and can occur even in the context of optimal medical metabolic management. Organ transplantation, such as renal and combined liver and renal transplants, have been utilised in the past for children whose disease cannot be managed by conservative medical practices and those with end stage renal disease. Our patient was diagnosed with B(12)-responsive MMA (subsequently proven to be cblA-type MMA) in the postoperative period following renal transplantation for idiopathic chronic renal failure. She remains well, with excellent graft function and metabolic control 4 years after transplantation. This patient highlights the importance of testing for the inborn errors of metabolism in patients presenting with recurrent acidosis and progressive renal impairment.

Topics: Adolescent; Cobamides; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Metabolism, Inborn Errors; Methylmalonic Acid; Vitamin B 12