Dual molecular genetic diagnosis with combined malonic and methylmalonic aciduria (CMAMMA): implications of coexisting genetic disorders on clinical presentation

Melike Ersoy; Zehra Yavas Abali; Esra Deniz Papatya Cakir; Soner Erdin; Kanay Yararbas; Saygin Abali

doi:10.1515/jpem-2025-0208

Article

Dual molecular genetic diagnosis with combined malonic and methylmalonic aciduria (CMAMMA): implications of coexisting genetic disorders on clinical presentation

Melike Ersoy , Zehra Yavas Abali , Esra Deniz Papatya Cakir , Soner Erdin , Kanay Yararbas and Saygin Abali

Published/Copyright: September 11, 2025

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 12

Abstract

Objectives

Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited metabolic disorder caused by ACSF3 variants leading to malonyl-CoA synthetase (MCS) deficiency. Despite its well-defined genetic basis, the clinical spectrum of CMAMMA remains highly variable.

Case presentation

This study reports six patients from three unrelated families, aged 12 days to 30 years, presenting with heterogeneous clinical manifestations. Exome sequencing (ES) identified a homozygous ACSF3 variant, c.1470G>C [p.(Glu490Asp)], in five patients, and a novel variant, c.1145T>C [p.(Leu382Pro)], in one patient. Notably, in each family’s index case, ES revealed additional pathogenic variants consistent with a dual molecular diagnosis: a homozygous CHRNG variant in one patient; compound heterozygous BTD variants in two siblings, confirming biotinidase deficiency; and a novel CDK10 frameshift variant, c.520_521del [p.(Lys174Glyfs*34)], in another patient. Half of the patients with CMAMMA demonstrated mild to moderate developmental delay. Notably, the sibling with both CMAMMA and biotinidase deficiency exhibited developmental delay, whereas the sibling with isolated CMAMMA had normal development. Symptomatic individuals showed clinical improvement following dietary protein restriction and carnitine supplementation.

Conclusions

These findings highlight that CMAMMA may cause developmental delay, emphasizing the importance of early diagnosis and treatment. Furthermore, in patients with atypical features, high-throughput sequencing technologies offer a comprehensive approach to identifying additional pathogenic variants in genes beyond ACSF3.

Keywords: combined malonic and methylmalonic aciduria; ACSF3 ; biotinidase deficiency; BTD ; CHRNG ; CDK10

Corresponding author: Saygin Abali, MD, Division of Pediatric Endocrinology, Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Halkali Merkez, Turgut Ozal Bulvari No:16, PC 34303, Küçükçekmece, Istanbul, Türkiye, E-mail: saygin.abali@acibadem.edu.tr

Melike Ersoy and Zehra Yavas Abali contributed equally to this work and share first authorship.

Research ethics: The study was approved by the Local Ethics Committee on 22 April 2022 (approval number: ATADEK-2022-07/27) and conducted in accordance with the principles of the Declaration of Helsinki (as revised in 2013).
Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: ChatGPT was used only to improve the language of the manuscript. It was not employed in the design of the manuscript or for the creation or modification of figures.
Conflict of interest: The authors state no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

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Received: 2025-04-13

Accepted: 2025-09-01

Published Online: 2025-09-11

Published in Print: 2025-12-17

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Articles in the same Issue

https://doi.org/10.1515/jpem-2025-0208

Keywords for this article

combined malonic and methylmalonic aciduria; ACSF3; biotinidase deficiency; BTD; CHRNG; CDK10