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Licensed Unlicensed Requires Authentication Published by De Gruyter December 16, 2019

Dietary practices in methylmalonic acidaemia: a European survey

Alex Pinto, Sharon Evans ORCID logo, Anne Daly, Manuela Ferreira Almeida, Murielle Assoun, Amaya Belanger-Quintana, Silvia Maria Bernabei, Sandra Bollhalder, David Cassiman, Helena Champion, Heidi Chan, Karen Corthouts, Jaime Dalmau, Foekje de Boer, Corinne De Laet, An de Meyer, An Desloovere, Alice Dianin, Marjorie Dixon, Katharina Dokoupil, Sandrine Dubois, Francois Eyskens, Ana Faria, Ilaria Fasan, Elisabeth Favre, François Feillet, Anna Fekete, Giorgia Gallo, Cerys Gingell, Joanna Gribben, Kit Kaalund Hansen, Nienke Ter Horst, Camille Jankowski, Renske Janssen-Regelink, Ilana Jones, Catherine Jouault, Gudrun Elise Kahrs, Irene Kok, Agnieszka Kowalik, Catherine Laguerre, Sandrine Le Verge, Alessandra Liguori, Rina Lilje, Cornelia Maddalon, Doris Mayr, Uta Meyer, Avril Micciche, Ulrike Och, Martine Robert, Júlio César Rocha ORCID logo, Hazel Rogozinski, Carmen Rohde, Kathleen Ross, Isabelle Saruggia, Andrea Schlune, Kath Singleton, Elisabeth Sjoqvist, Rachel Skeath, Linn Helene Stolen, Allyson Terry, Corrie Timmer, Lyndsey Tomlinson, Alison Tooke, Kristel Vande Kerckhove, Esther van Dam, Dorine van den Hurk, Liesbeth van der Ploeg, Marleen van Driessche, Margreet van Rijn, Annemiek van Wegberg, Carla Vasconcelos, Helle Vestergaard, Isidro Vitoria, Diana Webster, Fiona White, Lucy White, Heidi Zweers and Anita MacDonald



The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability.


To describe the dietary management of patients with MMA across Europe.


A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0–6 months; 7–12 months; 1–10 years; 11–16 years; >16 years).


Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy.


A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice.


The authors would like to thank the following people for the assistance in data collection: Louise Robertson (University Hospitals Birmingham NHS Foundation Trust, UK); Sharan Lowry (Sheffield Children’s Hospital, UK); Rychelle Winstone, Kate Stonstreet and Karen van Wyk (Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK); Charlotte Ellerton and Rachel Carruthers (Charles Dent Metabolic Unit National Hospital for Neurology and Surgery, London, UK); Isabelle Nedellec (CHU Angers); Skadi Beblo (Hospital of Children’s and Adolescents, University of Leipzig, Germany); Anne-Kathrin Neugebauer (Heinrich-Heine-University, Department of General Paediatrics, Neonatology and Paediatric Cardiology, Dusseldorf); Marianne Diels (Metabolic Center, University Hospitals Leuven and KU Leuven, Belgium); Sophie Defouny (Hôpital Universitaire des Enfants, Reine fabiola, Bruxelles, Belgium); Esmeralda Martins and Anabela Bandeira (Unidade de Doenças Metabólicas, Centro Hospitalar do Porto – CHP, Porto, Portugal); Elisa Leão Teles and Esmeralda Rodrigues (Centro Hospitalar São João – Unidade de Doenças Metabólicas, Porto, Portugal); Mercedes Martinez-Pardo (Unidad de Enfermedades Metabolicas, Servicio de Pediatria, Hospital Ramon y Cajal Madrid, Spain); Jolanta Sykut-Cegielska and Joanna Taybert (Institute of Mother and Child, Poland) and Camilla Caroe and Ann Roskjaer (National University Hospital, Copenhagen, Denmark). We thank the Association “La Vita e’ un Dono” for supporting the fellowship of Giorgia Gallo. We also acknowledge the regional centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and ministerial endorsement for the participation in the European network for inherited metabolic disorders metabERN.

  1. Author contributions: All authors participated in data collection, critical revision of the paper and final approval of the version to be published. Alex Pinto was involved in data quality assessment, data analysis and development of the manuscript. Anita MacDonald was involved in questionnaire development, interpretation of data and writing of the manuscript.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

  6. Conflict of interest: Alex Pinto received an educational grant from Cambrooke Therapeutics and grants from Vitaflo, Nutricia, Merck Serono, Biomarin and Mevalia to attend scientific meetings. Sharon Evans is a research dietitian funded by Nutricia; financial support from Nutricia and Vitaflo to attend study days and conferences. Anne Daly undertook evaluation work for the nutritional companies – Vitaflo Ltd, Nutricia Ltd and Metax. Anita MacDonald received research funding and honoraria from Nutricia, Vitaflo International and Merck Serono. She is a member of the European Nutrition Expert Panel (Biomarin), member of Sapropterin Advisory Board (Biomarin), member of the Advisory Board entitled ELEMENT (Danone-Nutricia) and member of an Advisory Board for Arla and Applied Pharma Research. Allyson Terry received research honoraria and congress travel allowances from Nutricia and Vitaflo International. Liesbeth van der Ploeg received financial support from Nutricia and Vitaflo to attend conferences. Annemiek van Wegberg received several grants from Nutricia and Vitaflo to visit conferences and received honoraria as a speaker from Excemed and Biomarin. Agnieszka Kowalik received financial support from Nutricia and Vitaflo to attend conferences. Gudrun Elise Kahrs received support from Vitaflo and SHS/Nutricia to attend meetings. Corrie Timmer received financial support from Nutricia and Vitaflo to attend conferences. Manuela Ferreira Almeida received grants from Glutamine, Nutricia, Merck Serono, Biomarin, Orphan and Lifediet to attend congress and for education. Júlio César Rocha is member of the European Nutrition Expert Panel (Biomarin), member of an Advisory Board for Applied Pharma Research and Nutricia and received fees from Merck Serono, Vitaflo, Nutricia and Cambrooke. Amaya Bélanger-Quintana, Martine Robert, Esther van Dam, Carina Heidenborg and Margreet van Rijn are members of the European Nutrition Expert Panel (Biomarin). Fiona White received honoraria from Alexion, Nutricia Metabolics and Vitaflo as well as educational and travel grants from Nutricia Metabolics and Vitaflo. Marjorie Dixon received research honoraria and congress travel allowances from Nutricia and Vitaflo International and is a member of the Nutricia Advisory Board. Katharina Dokoupil is a member of the European Nutrition Expert Panel (Biomarin) and member of an Advisory Board (Nestlé). She received honoraria and symposia travel allowances from Nutricia and Vitaflo. Alice Dianin received financial support from Mevalia and DMF to attend conferences. Carmen Rohde received financial support from MetaX, Nutricia and Vitaflo to attend conferences and honoraria from MetaX and Nutricia. Ulrike Och received honoraria from Biomarin, Dr. Schär medical nutrition, Vitaflo and Nutricia as well as support to attend meetings.


1. Oberholzer VG, Levin B, Burgess EA, Young WF. Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child 1967;42:492–504.10.1136/adc.42.225.492Search in Google Scholar PubMed PubMed Central

2. Baumgartner MR, Horster F, Dionisi-Vici C, Haliloglu G, Karall D, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis 2014;9:130.10.1186/s13023-014-0130-8Search in Google Scholar PubMed PubMed Central

3. Leonard JV. Stable isotope studies in propionic and methylmalonic acidaemia. Eur J Pediatr 1997;156 Suppl 1:S67–9.10.1007/PL00014275Search in Google Scholar

4. Castelli MC, Friedman K, Sherry J, Brazzillo K, Genoble L, et al. Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study. Clin Ther 2011;33:358–71.e2.10.1016/j.clinthera.2011.03.003Search in Google Scholar PubMed

5. Zwickler T, Lindner M, Aydin HI, Baumgartner MR, Bodamer OA, et al. Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J Inherit Metab Dis 2008;31:361–7.10.1007/s10545-008-0804-2Search in Google Scholar PubMed

6. Protein and amino acid requirements in human nutrition. World Health Organization technical report series, 2007:1–265, back cover.Search in Google Scholar

7. Adam S, Almeida MF, Assoun M, Baruteau J, Bernabei SM, et al. Dietary management of urea cycle disorders: European practice. Mol Genet Metab 2013;110:439–45.10.1016/j.ymgme.2013.09.003Search in Google Scholar PubMed

8. Aguiar A, Ahring K, Almeida MF, Assoun M, Belanger Quintana A, et al. Practices in prescribing protein substitutes for PKU in Europe: no uniformity of approach. Mol Genet Metab 2015;115:17–22.10.1016/j.ymgme.2015.03.006Search in Google Scholar PubMed

9. Daly A, Pinto A, Evans S, Almeida MF, Assoun M, et al. Dietary practices in propionic acidemia: a European survey. Mol Genet Metab Rep 2017;13:83–9.10.1016/j.ymgmr.2017.09.002Search in Google Scholar PubMed PubMed Central

10. Pinto A, Daly A, Evans S, Almeida MF, Assoun M, et al. Dietary practices in isovaleric acidemia: a European survey. Mol Genet Metab Rep 2017;12:16–22.10.1016/j.ymgmr.2017.02.001Search in Google Scholar PubMed PubMed Central

11. Daly A, Evans S, Gerrard A, Santra S, Vijay S, et al. The nutritional intake of patients with organic acidaemias on enteral tube feeding: can we do better? JIMD Rep 2016;28:29–39.10.1007/8904_2015_443Search in Google Scholar PubMed PubMed Central

12. Rafique M. Propionic acidaemia: demographic characteristics and complications. J Pediatr Endocrinol Metab 2013;26: 497–501.10.1515/jpem-2013-0031Search in Google Scholar PubMed

13. Kolker S, Garcia-Cazorla A, Valayannopoulos V, Lund AM, Burlina AB, et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 2015;38:1041–57.10.1007/s10545-015-9839-3Search in Google Scholar PubMed

14. van der Meer SB, Poggi F, Spada M, Bonnefont JP, Ogier H, et al. Clinical outcome and long-term management of 17 patients with propionic acidaemia. Eur J Pediatr 1996;155:205–10.10.1007/BF01953939Search in Google Scholar PubMed

15. Yannicelli S, Acosta PB, Velazquez A, Bock HG, Marriage B, et al. Improved growth and nutrition status in children with methylmalonic or propionic acidemia fed an elemental medical food. Mol Genet Metab 2003;80:181–8.10.1016/j.ymgme.2003.08.012Search in Google Scholar PubMed

16. Touati G, Valayannopoulos V, Mention K, de Lonlay P, Jouvet P, et al. Methylmalonic and propionic acidurias: management without or with a few supplements of specific amino acid mixture. J Inherit Metab Dis 2006;29:288–98.10.1007/s10545-006-0351-7Search in Google Scholar PubMed

17. Burlina A, Cazzorla C, Zanonato E, Viggiano E, Fasan I, et al. Clinical experience with N-carbamylglutamate in a single-centre cohort of patients with propionic and methylmalonic aciduria. Mol Genet Metab Rep 2016;8:34–40.10.1016/j.ymgmr.2016.06.007Search in Google Scholar PubMed PubMed Central

18. Manoli I, Myles JG. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet Med 2016;18:386–95.10.1038/gim.2015.102Search in Google Scholar PubMed PubMed Central

19. Myles JG, Manoli I, Venditti CP. Effects of medical food leucine content in the management of methylmalonic and propionic acidemias. Curr Opin Clin Nutr Metab Care 2018;21:42–8.10.1097/MCO.0000000000000428Search in Google Scholar PubMed PubMed Central

20. Wessels AG, Kluge H, Hirche F, Kiowski A, Schutkowski A, et al. High leucine diets stimulate cerebral branched-chain amino acid degradation and modify serotonin and ketone body concentrations in a pig model. PLoS One 2016;11:e0150376.10.1371/journal.pone.0150376Search in Google Scholar PubMed PubMed Central

21. Yannicelli S. Nutrition therapy of organic acidaemias with amino acid-based formulas: emphasis on methylmalonic and propionic acidaemia. J Inherit Metab Dis 2006;29:281–7.10.1007/s10545-006-0267-2Search in Google Scholar PubMed

22. Evans M, Truby H, Boneh A. The relationship between dietary intake, growth, and body composition in inborn errors of intermediary protein metabolism. J Pediatr 2017;188:163–72.10.1016/j.jpeds.2017.05.048Search in Google Scholar PubMed

Supplementary Material

The online version of this article offers supplementary material (

Received: 2019-06-19
Accepted: 2019-10-23
Published Online: 2019-12-16
Published in Print: 2020-01-28

©2020 Walter de Gruyter GmbH, Berlin/Boston

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