ABSTRACT
Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Biomarkers/analysis , Methylmalonyl-CoA Mutase/deficiency , Adolescent , Adult , Age of Onset , Amino Acid Metabolism, Inborn Errors/epidemiology , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/mortality , Child , Child, Preschool , Cobamides/deficiency , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Methylmalonyl-CoA Mutase/genetics , Outcome Assessment, Health Care , Prognosis , Survival Analysis , Young AdultABSTRACT
The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Methylmalonic Acid/urine , Adolescent , Adult , Amino Acid Metabolism, Inborn Errors/drug therapy , Child , Child, Preschool , Humans , Hydroxocobalamin/therapeutic use , Infant , Infant, Newborn , Vitamin B 12/therapeutic useABSTRACT
We report imaging abnormalities from 5 brain MR examinations in 4 children with methylmalonic acidaemia between the ages of 20 days and 31 months. In addition to bilateral basal ganglia lesions (pallidum) observed in 3 of 4 children, we found signs of delayed brain maturation (myelination delay, immature gyral pattern, incomplete opercularization) in all children and signs of a white matter disorder in the 3 older children. Unexpectedly, brainstem and cerebellar changes were present in all children. Reviewing the brain imaging changes reported for methylmalonic acidaemia, we discuss the findings and patterns observed in our patients. We postulate that delayed myelination and signs of a white matter disorder as well as brainstem and cerebellar involvement are common findings and may be due to a chronic neurotoxic effect on the developing and ageing brain.