Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters
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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 (mut0, 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 mut0 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 mut0 patients.
KeywordsChronic Renal Failure Developmental Delay Newborn Screening Cobalamin Amino Acid Supplement
methylmalonic aciduria cblA type
methylmalonic aciduria cblB type
methylmalonic aciduria and homocystinuria, cblC type
methylmalonic aciduria and homocystinuria, cblD type
methylmalonic aciduria cblF type
chronic renal failure
glomerular filtration rate
likelihood ratio test
complete defect of methylmalonyl-CoA-mutase activity
partial defect of methylmalonyl-CoA-mutase activity
The authors thank Silvia Körner for excellent technical assistance in preparing the questionnaire, METABNET for organizational support, and A Bartuli, B König, D Möslinger, S Picca, U Wendel and M Williams for providing clinical information on their patients. We gratefully acknowledge Milupa Metabolics for sponsoring the 1st International Workshop on Methylmalonic Acidurias (25–27 October 2006 in Heidelberg).
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