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Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

An Erratum to this article was published on 31 October 2009

Summary

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.

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Abbreviations

cblA:

methylmalonic aciduria cblA type

cblB:

methylmalonic aciduria cblB type

cblC:

methylmalonic aciduria and homocystinuria, cblC type

cblD:

methylmalonic aciduria and homocystinuria, cblD type

cblF:

methylmalonic aciduria cblF type

CRF:

chronic renal failure

GFR:

glomerular filtration rate

LRT:

likelihood ratio test

MCM:

methylmalonyl-CoA mutase

MMA:

methylmalonic acid

MMAurias:

methylmalonic acidurias

mut0 :

complete defect of methylmalonyl-CoA-mutase activity

mut− :

partial defect of methylmalonyl-CoA-mutase activity

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Acknowledgement

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).

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany

    F. Hörster, S. F. Garbade, T. Zwickler, M. Lindner & S. Kölker

  2. Department of Metabolism, Children’s Hospital, Hacettepe University Ankara, Ankara, Turkey

    H. I. Aydin

  3. Department of Paediatrics, Allgemeines Krankenhaus, Vienna, Austria

    O. A. Bodamer

  4. Department of Paediatrics, Division of Metabolic Disorders, University Hospital Padova, Padova, Italy

    A. B. Burlina

  5. Department of Paediatrics II, Medizinische Hochschule Hannover, Hannover, Germany

    A. M. Das

  6. Sophia Children’s Hospital, Erasmus Medical Centre, Rotterdam, The Netherlands

    J. B. C. De Klerk

  7. Division of Metabolism, Bambino Gesù Children’s Hospital, Rome, Italy

    C. Dionisi-Vici

  8. University Children’s Hospital I, Frankfurt, Germany

    S. Geb

  9. Department of Nutrition and Metabolism, Istanbul University Medical Faculty Children’s Hospital, Istanbul, Turkey

    G. Gökcay

  10. Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant, Lyon, France

    N. Guffon

  11. Dr. von Hauner Children’s Hospital, Munich, Germany

    E. M. Maier

  12. Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands

    E. Morava

  13. Willink Unit, Royal Manchester Children’s Hospital, Manchester, UK

    J. H. Walter

  14. Department of General Pediatrics, University Children’s Hospital, Düsseldorf, Germany

    B. Schwahn

  15. Department of Pediatrics, Academic Medical Centre, University Hospital, Amsterdam, The Netherlands

    F. A. Wijburg

  16. Metabolic Unit, Great Ormond Street Hospital, London, UK

    S. Grünewald

  17. Metabolism and Molecular Paediatrics, University Children’s Hospital, Zurich, Switzerland

    M. R. Baumgartner

Authors
  1. F. Hörster
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  2. S. F. Garbade
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  3. T. Zwickler
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  4. H. I. Aydin
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  6. A. B. Burlina
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  7. A. M. Das
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  8. J. B. C. De Klerk
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  9. C. Dionisi-Vici
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  10. S. Geb
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  11. G. Gökcay
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  13. E. M. Maier
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  14. E. Morava
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  15. J. H. Walter
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  16. B. Schwahn
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  17. F. A. Wijburg
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  18. M. Lindner
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  19. S. Grünewald
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  20. M. R. Baumgartner
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  21. S. Kölker
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Corresponding author

Correspondence to F. Hörster.

Additional information

Communicating editor: Ertan Mayatepek

Competing interests: None declared

References to electronic databases: Methylmalonic aciduria, cblA type: OMIM 251100. Methylmalonic aciduria, cblB type: OMIM 251110. Methylmalonic aciduria and homocystinuria, cblC type: OMIM 277400. Methylmalonic aciduria and homocystinuria, cblD type: OMIM 277410. Methylmalonic aciduria, cblF type, OMIM 277380. Complete defect of methylmalonyl-CoA-mutase activity, mut0: OMIM 251000. Partial defect of methylmalonyl-CoA-mutase activity, mut−: OMIM 251000. Methylmalonyl-CoA mutase: EC 5.4.99.2.

An erratum to this article can be found at http://dx.doi.org/10.1007/s10545-009-9957-x

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Table S1

List of participating metabolic centres (DOC 39.5 KB).

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Hörster, F., Garbade, S.F., Zwickler, T. et al. Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis 32, 630–639 (2009). https://doi.org/10.1007/s10545-009-1189-6

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  • DOI: https://doi.org/10.1007/s10545-009-1189-6

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