Abstract
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.
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Abbreviations
- AdoCbl:
-
5′-deoxyadenosylcobalamin
- CRF:
-
chronic renal failure
- MCM:
-
methylmalonyl-CoA mutase (EC 5.4.99.2)
- MMA:
-
methylmalonic acid
- OH-Cbl:
-
hydroxycobalamin
References
Willard HF, Rosenberg LE 1980 Inherited methylmalonyl CoA mutase apoenzyme deficiency in human fibroblasts. Evidence for allelic heterogeneity, genetic compounds, and codominant expression. J Clin Invest 65: 690–698
Suormala T, Baumgartner MR, Coelho D, Zavadakova P, Kozich V, Koch HG, Berghauser M, Wreight JE, Burlina A, Sewell A, Herwig J, Fowler B 2004 The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem 279: 42742–42749
Dobson CM, Wai T, Leclerc D, Wilson A, Wu X, Dorè C, Hudson T, Rosenblatt DS, Gravel RA 2002 Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. Proc Natl Acad Sci U S A 99: 15554–15559
Dobson CM, Wai T, Leclerc D, Kadir H, Narang M, Lerner-Ellis JP, Hudson TJ, Rosenblatt DS, Gravel RA 2002 Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Hum Mol Genet 11: 3361–3369
Fenton WA, Gravel RA, Rosenblatt DS 2001 Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York, pp 2165–2193
Hörster F, Hoffmann GF 2004 Pathophysiology, diagnosis, and treatment of methylmalonic aciduria-recent advances and new challenges. Pediatr Nephrol 19: 1071–1074
de Baulny HO, Benoist JF, Rigal O, Touati G, Rabier D, Saudubray JM 2005 Methylmalonic and propionic acidaemias: management and outcome. J Inherit Metab Dis 28: 415–423
Matsui SM, Mahoney MJ, Rosenberg LE 1983 The natural history of the inherited methylmalonic acidemias. N Engl J Med 308: 857–861
Van der Meer SB, Poggi F, Spada M, Bonnefont JP, Ogier H, Hubert P, Depondt E, Rapoport D, Rabier D, Charpentier C 1994 Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 125: 903–908
Nicolaides P, Leonard JV, Surtees R 1998 The neurological outcome of methylmalonic acidaemia. Arch Dis Child 78: 508–512
Baumgarter ER, Viardot C 1995 Long-term follow-up of 77 patients with isolated methylmalonic acidaemia. J Inherit Metab Dis 18: 138–142
Baumgartner ER 1983 Activity of the cobalamin-dependent methylmalonyl-CoA mutase. In: Hall CA (ed) The Cobalamins: Methods in Hematology. Churchill Livingstone, Edinburgh, New York, pp 181–195
Baumgartner R, Giardini O, Cantani A, Sabetta G, Castro M 1982 Methylmalonic acidaemia due to mutase apoenzyme defect: responsive to vitamin B12 in intact fibroblasts but not in vivo. J Inherit Metab Dis 5: 137–141
Willard HF, Ambani LM, Hart AC, Mahoney MJ, Rosenberg LE 1976 Rapid prenatal and postnatal detection of inborn errors of propionate, methylmalonate and cobalamin metabolism- a sensitive assay using cultured cells. Hum Genet 34: 277–283
Fenton WA, Rosenberg LE 1981 The defect in the cblB class of human methylmalonic acidemia: deficiency of cob(I)alamin adenosyltransferase activity in extracts of cultured fibroblasts. Biochem Biophys Res Commun 98: 283–289
Prader A, Largo RH, Molinari L, Issler C 1989 Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development. Helv Paediatr Acta Suppl 52: 1–125
Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A 1976 A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58: 259–263
R: a language and environment for statistical computing. Available at: http://www.R-project.org. Accessed June 01, 2005
Fuoti M, Pinotti M, Villa MC, celano MR, Miceli V, Amoruso C, Rossi G, Parini R, Nebbia G 2005 Hepatic transplantation in methylmalonic acidemia: a case report. Acta Gastroenterol Belg 68: 491
Shevell MI, Matiaszuk N, Ledley FD, Rosenblatt DS 1993 Varying neurological phenotypes among mut0 and mut- patients with methylmalonyl CoA mutase deficiency. Am J Med Genet 45: 619–624
Leonard JV, Vijayaraghavan S, Walter JH 2003 The impact of screening for propionic and methylmalonic acidaemia. Eur J Pediatr 162: S21–S24
Thompson GN, Chalmers RA 1990 Increased urinary metabolite excretion during fasting in disorders of propionate metabolism. Pediatr Res 27: 413–418
Brock M, Buckel W 2004 On the mechanism of action of the antifungal agent propionate. Eur J Biochem 271: 3227–3241
Schwab MA, Sauer SW, Okun JG, Nijtmans LG, Rodenburg RJ, van den Heuvel LP, Drose S, Brandt U, Hoffmann GF, Ter Laak H, Kölker S, Smeitink JA 2006 Secondary mitochondrial dysfunction in propionic aciduria, a pathogenic role for endogenous mitochondrialtoxins. Biochem J 398: 107–112
Kölker S, Okun JG 2005 Methylmalonic acid—an endogenous toxin?. Cell Mol Life Sci 62: 621–624
Schmitt CP, Mehls O, Trefz FK, Hörster F, Weber TL, Kölker S 2004 Reversible end-stage renal disease in an adolescent patient with methylmalonic aciduria. Pediatr Nephrol 19: 1182–1184
Acknowledgements
This study is dedicated to the patients and their families whom the authors thank for their trust and kind cooperation. They thank Mira Günther for her excellent technical assistance with enzymatic studies. They are most thankful for clinical information on patients, which was kindly provided by the following colleagues: C. Boujet, A. Burtscher, I. Braun, F. Carnevale, C. De Laet, C. Dionisi-Vici, F.J.M. Eyskens, B. Francois, F. Freundl, P. Goyens, S. Grünewald, J. Hennermann, B. Hoppe, S. Huber, J. Jaeken, A. Jonnard, H. Korall, I. Kreuder, M. Leichsenring, D. Leupold, M. Lindner, H. Machnik, W. Marg, I. Marquardt, K. Michalski, E. Mönch, D. Möslinger, H. Niederhoff, J.M. Nuoffer, R. Parini, B. Plecko, M.E. Rubio, F. Sarrot-Reynaud, S. Scheibenreiter, D. Scheible, H. Schmidt, D. Schneider, C. Schröder, M. Schütte de Lujan, O. Schwab, E. Simon, K.F. Trefz, S. van der Meer, U. Wendel, and F.A. Wijburg.
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This study was supported by Deutsche Forschungsgemeinschaft (DFG grant HO2501/1-1 to F. Hörster), the Swiss National Science Foundation (grant 3200-066878 to B. Fowler, T. Suormala, and M.R. Baumgartner) and the German Federal Ministry of Education and Science (BMBF grant 01GM0305 to P. Burgard).
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Hörster, F., Baumgartner, M., Viardot, C. et al. Long-Term Outcome in Methylmalonic Acidurias Is Influenced by the Underlying Defect (mut0, mut−, cblA, cblB). Pediatr Res 62, 225–230 (2007). https://doi.org/10.1203/PDR.0b013e3180a0325f
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DOI: https://doi.org/10.1203/PDR.0b013e3180a0325f
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