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Practice Guideline
. 2021 May;44(3):566-592.
doi: 10.1002/jimd.12370. Epub 2021 Mar 9.

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Patrick Forny  1 , Friederike Hörster  2 , Diana Ballhausen  3 , Anupam Chakrapani  4 , Kimberly A Chapman  5 , Carlo Dionisi-Vici  6 , Marjorie Dixon  7 , Sarah C Grünert  8 , Stephanie Grunewald  4 , Goknur Haliloglu  9 , Michel Hochuli  10 , Tomas Honzik  11 , Daniela Karall  12 , Diego Martinelli  6 , Femke Molema  13 , Jörn Oliver Sass  14 , Sabine Scholl-Bürgi  12 , Galit Tal  15 , Monique Williams  13 , Martina Huemer  1   16 , Matthias R Baumgartner  1
Affiliations
Practice Guideline

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Patrick Forny et al. J Inherit Metab Dis. 2021 May.

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] J Inherit Metab Dis. 2022 Jul;45(4):862. doi: 10.1002/jimd.12535. J Inherit Metab Dis. 2022. PMID: 35841205 Free PMC article. No abstract available.

Abstract

Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re-evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well-informed decisions in the context of MMA and PA patient care.

Keywords: diagnosis and management; guidelines; inherited metabolic disease; methylmalonic acidaemia; propionic acidaemia.

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Conflict of interest statement

D. B. participated in European Metabolic Group meetings sponsored by Nutricia and received research funds from Nutricia. S. C. G. has received a research fund from Nutricia as well as reimbursement for attending a symposium by MetaX and Vitaflo and fees for speaking on educational events from Nutricia and Vitaflo. J. O. S. received institutional honoraria from Swedish Orphan Biovitrum und Immedica Pharma AB. S. S.‐B. has received reimbursement for symposia fees from Nutricia and Dr Schär and research funds from Nutricia. M. R. B. received a research fund from Nutricia and is a member of the clinical advisory boards of Hemoshear and Moderna. A. C. received financial support from Nutricia, Vitaflo and Recordati/Orphan Europe, including research funds, institutional honoraria and consulting fees. M. D. has received reimbursement to attend symposia and fees for speaking at an organised meeting from Vitaflo and Nutricia and consultancy fees from Nutricia, Vitaflo and Recordati Rare Diseases. The other authors do not declare any conflict of interest related to this work.

Figures

FIGURE 1
FIGURE 1
Propionyl‐CoA is metabolised in the mitochondria by specific enzymes. Defects in the genes MMUT, MMAA, MMAB or MMADHC (more specifically variant 2) lead to isolated MMA, whereas defects in PCCA or PCCB lead to PA. Propionyl‐CoA is derived from various sources and is metabolised to alternative products in the case of accumulation in the above‐described defects. In addition, accumulating methylmalonyl‐CoA in isolated MMA is hydrolysed to methylmalonic acid, the main biomarker of this disease. Gene names are italicised, complementation groups are in parenthesis. MMA, methylmalonic acidaemia; PA, propionic acidaemia
FIGURE 2
FIGURE 2
Scheme depicting the extra‐ and intracellular transport and processing of the cobalamin (Cbl) molecule and the involved proteins. Methylmalonyl‐CoA mutase (MMUT), methylmalonic aciduria type A protein (MMAA), methylmalonic aciduria type B protein (MMAB), methylmalonic aciduria and homocystinuria type D protein variant 2 (MMADHC‐MMA), and propionyl‐CoA carboxylase (PCC) defects and their related diseases are discussed in these guidelines, hence these proteins are depicted in bold print. The other proteins are depicted using official protein nomenclature: amnionless (AMN) and cubulin (CUBN) form the cubam receptor to absorb cobalamin bound to cobalamin binding intrinsic factor (CBLIF); haptocorrin (TCN1; not shown), transcobalamin (TCN2) and transcobalamin receptor (CD320) facilitate cobalamin transport and uptake into the cell; lysosomal cobalamin transporter (ABCD4) and lysosomal cobalamin transport escort protein (LMBD1) export cobalamin from the lysosome; methylmalonic aciduria and homocystinuria type C protein (MMACHC) cleaves the R group of cobalamin (upper‐axial ligand); methylmalonic aciduria and homocystinuria type D protein (MMADHC) targets cobalamin towards further processing in the cytosol or the mitochondrion; methionine synthase (MS), kept in its active form by methionine synthase reductase (MSR), uses cobalamin in its methylated form; methylmalonyl‐CoA epimerase (MCEE) converts (R)‐methylmalonyl‐CoA to (S)‐methylmalonyl‐CoA; succinyl‐CoA synthetase (SCS) also called succinate‐CoA ligase forms succinate from succinyl‐CoA in the citric acid cycle
FIGURE 3
FIGURE 3
Proposed management flowchart for MMA and PA patients during an acute metabolic decompensation, based on expert opinion. All drugs are given intravenously (IV). MMA, methylmalonic acidaemia; PA, propionic acidaemia
FIGURE 4
FIGURE 4
Proposed management flowchart for MMA and PA patients undergoing general anaesthesia, based on expert opinion. MMA, methylmalonic acidaemia; PA, propionic acidaemia
See this image and copyright information in PMC

References

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