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

  • F. Hörster
  • S. F. Garbade
  • T. Zwickler
  • H. I. Aydin
  • O. A. Bodamer
  • A. B. Burlina
  • A. M. Das
  • J. B. C. De Klerk
  • C. Dionisi-Vici
  • S. Geb
  • G. Gökcay
  • N. Guffon
  • E. M. Maier
  • E. Morava
  • J. H. Walter
  • B. Schwahn
  • F. A. Wijburg
  • M. Lindner
  • S. Grünewald
  • M. R. Baumgartner
  • S. Kölker
Original Article

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.

Keywords

Chronic Renal Failure Developmental Delay Newborn Screening Cobalamin Amino Acid Supplement 

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

Notes

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).

Supplementary material

10545_2009_1189_MOESM1_ESM.doc (40 kb)
Table S1 List of participating metabolic centres (DOC 39.5 KB).

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • F. Hörster
    • 1
  • S. F. Garbade
    • 1
  • T. Zwickler
    • 1
  • H. I. Aydin
    • 2
  • O. A. Bodamer
    • 3
  • A. B. Burlina
    • 4
  • A. M. Das
    • 5
  • J. B. C. De Klerk
    • 6
  • C. Dionisi-Vici
    • 7
  • S. Geb
    • 8
  • G. Gökcay
    • 9
  • N. Guffon
    • 10
  • E. M. Maier
    • 11
  • E. Morava
    • 12
  • J. H. Walter
    • 13
  • B. Schwahn
    • 14
  • F. A. Wijburg
    • 15
  • M. Lindner
    • 1
  • S. Grünewald
    • 16
  • M. R. Baumgartner
    • 17
  • S. Kölker
    • 1
  1. 1.Department of General Pediatrics, Division of Inborn Metabolic DiseasesUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.Department of Metabolism, Children’s HospitalHacettepe University AnkaraAnkaraTurkey
  3. 3.Department of PaediatricsAllgemeines KrankenhausViennaAustria
  4. 4.Department of Paediatrics, Division of Metabolic DisordersUniversity Hospital PadovaPadovaItaly
  5. 5.Department of Paediatrics IIMedizinische Hochschule HannoverHannoverGermany
  6. 6.Sophia Children’s HospitalErasmus Medical CentreRotterdamThe Netherlands
  7. 7.Division of MetabolismBambino Gesù Children’s HospitalRomeItaly
  8. 8.University Children’s Hospital IFrankfurtGermany
  9. 9.Department of Nutrition and MetabolismIstanbul University Medical Faculty Children’s HospitalIstanbulTurkey
  10. 10.Centre de Référence des Maladies Héréditaires du MétabolismeHôpital Femme Mère EnfantLyonFrance
  11. 11.Dr. von Hauner Children’s HospitalMunichGermany
  12. 12.Radboud University Medical Centre NijmegenNijmegenThe Netherlands
  13. 13.Willink UnitRoyal Manchester Children’s HospitalManchesterUK
  14. 14.Department of General PediatricsUniversity Children’s HospitalDüsseldorfGermany
  15. 15.Department of Pediatrics, Academic Medical CentreUniversity HospitalAmsterdamThe Netherlands
  16. 16.Metabolic UnitGreat Ormond Street HospitalLondonUK
  17. 17.Metabolism and Molecular PaediatricsUniversity Children’s HospitalZurichSwitzerland

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