Summary
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 mut0, 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acquaviva C, Benoist JF, Pereira S et al (2005) Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by muto and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene. Hum Mutat 25: 167–176.
Baumgartner ER, Giardini O, Cantani A et al (1982) Methylmalonic acidemia due to apoenzyme defect: responsive to vitamin B12 in intact fibroblasts but not in vivo. J Inherit Metab Dis 5: 137–141.
Baumgartner ER, Viardot C and 47 collegues from 39 hospitals from 7 European countries (1995) Long-term follow-up of 77 patients with isolated methylmalonic aciduria. J Inherit Metab Dis 18: 138–142.
D-A-CH (Deutsche Gesellschaft für Ernährung, Österreichische Gesellschaft für Ernährung, Schweizerische Gesellschaft für Ernährungsforschung) (2000) Referenzwerte für die Nährstoffzufuhr Frankfurt (Main): Umschau Verlag.
Dewey KG, Beaton G, Fjeld C et al (1996) Protein requirements of infants and children. Eur J Clin Nutr 50(Supplement 1): S119–S150.
European Metabolic Group, chairpersons: W. Sperl and G.Gökcay (2006) Protein restriction in MMA and PA. International Workshop on MMA, Istanbul, May 26–28, 2006.
Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2165–2193.
Hörster F, Hoffmann GF (2004) Pathophysiology, diagnosis, and treatment of methylmalonic aciduria-recent advances and new challenges. Pediatr Nephrol 19: 1071–1074.
Hörster F, Baumgartner MR, Viardot C et al (2007) Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut−, cblA, cblB). Pediatr Res 62: 225–230.
Institute of Medicine of the National Academy (2002) Dietary Reference Intakes (DRI) for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Washington DC: The National Academies Press; Food and Nutrition Board.
Leonard JV (1995) The management and outcome of propionic and methylmalonic acidaemia. J Inherit Metab Dis 18: 430–434.
Lempp T, Suormala T, Siegenthaler R et al (2007) Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut− methylmalonic aciduria: identification of seven novel mutations. Mol Genet Metab 90: 284–290.
Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural history of the inherited methylmalonic acidemias. N Engl J Med 308: 857–861.
Nicolaides P, Leonard JV, Surtees R (1998) The neurological outcome of methylmalonic acidaemia. Arch Dis Child 78: 508–512.
Ogier de Baulny H, 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.
Thompson GN, Chalmers RA (1990) Increased urinary metabolite excretion during fasting in disorders of propionate metabolism. Pediatr Res 27: 413–416.
Thompson GN, Chalmers RA, Walter JH (1990) The use of metronidazole in management of methylmalonic and propionic acidemias. Eur J Pediatr 149: 792–796.
Touati G, Valayannopoulos A, Mention K et al (2006) Methylmalonic and propionic acidurias: Mangement without or with a few supplements of specific amino acid mixture. J Inherit Metab Dis 29: 288–298.
van der Meer SB, Poggi F, Spada M et al (1994) Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 125: 903–908.
Walter JH (2003) l-Carnitine in inborn errors of metabolism: what is the evidence? J Inherit Metab Dis 26: 181–188.
Walter JH, Thompson GN, Leonard JV et al (1989) Contribution of amino acid catabolism to propionate production in methylmalonic academia. Lancet 10: 1298–1299.
Worgan LC, Niles K, Tirone JC et al (2006) Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Human Mutat 27: 31–43.
World Health Organisation (1985) Energy and protein requirement. Reports of a Joint FAO/WHO/UNU Expert Consultation. WHO Tech Rep Ser No. 724. Geneva: WHO.
Yannicelli S, Acosta PB, Velazquez A et al (2003) Improved growth and nutrition status in children with methylmalonic and propionic acidemia fed an elemental medical food. Mol Genet Metab 80: 181–188.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Ivo Baric
Competing interests: None declared
References to electronic databases: Methylmalonic aciduria cblA type: OMIM 251100. Methylmalonic aciduria cblB type: OMIM 251110. Methylmalonic aciduria cblC type: OMIM 277400. Methylmalonic aciduria cblD type: OMIM 277410. Methylmalonic aciduria cblF type: OMIM 277380. Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency: OMIM 251000. Propionic aciduria: OMIM 606054 Methylmalonyl-CoA mutase: EC 5.4.99.2.
Rights and permissions
About this article
Cite this article
Zwickler, T., Lindner, M., Aydin, H.I. et al. Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J Inherit Metab Dis 31, 361–367 (2008). https://doi.org/10.1007/s10545-008-0804-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-008-0804-2