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Multiple Acyl-CoA Dehydrogenase Deficiency

Pathophysiology description (narrative)

2026-02-23
Falcon MONDO:0009282 Model: Edison Scientific Literature 48 citations

Pathophysiology description (narrative)

MADD/GAII is an autosomal recessive disorder caused by biallelic pathogenic variants in ETFA, ETFB, or ETFDH (and related flavin handling genes in some riboflavin-responsive MADD-like phenotypes). These genes encode components of the electron transfer flavoprotein system that shuttles electrons from multiple FAD-dependent acyl‑CoA dehydrogenases to the mitochondrial ubiquinone (coenzyme Q) pool. Defective ETF/ETFDH-mediated electron transfer produces a functional block in mitochondrial fatty‑acid β‑oxidation and related amino‑acid oxidation pathways, resulting in characteristic acylcarnitine and organic-acid accumulations and a systemic tendency to energy failure during catabolic stress. Recent work further demonstrates that ETFDH can participate in an ETFDH–complex III–COQ2 “metabolon” that supports complex III function and coenzyme Q homeostasis; ETFDH deficiency can thereby induce QH2 reductive stress, increase mitochondrial ROS, and impair OXPHOS efficiency. In neuronal models of ETFDH mutations, oxidative stress links to BCL‑2 family/MOMP signaling with caspase activation, causing apoptosis and neurite outgrowth defects, which can be mitigated by coenzyme Q10.

Gene/protein annotations (HGNC symbols; suggested GO term names)

• ETFDH: inner mitochondrial membrane flavoprotein; electron transfer from ETF to ubiquinone; regulation of respiratory chain complex III efficiency; coenzyme Q redox homeostasis; response to oxidative stress. (martin2024anetfdhdrivenmetabolon pages 1-2, olsen2007etfdhmutationsas pages 2-2) • ETFA/ETFB: ETF subunits enabling electron transfer from multiple acyl‑CoA dehydrogenases into ETFDH/CoQ. (olsen2007etfdhmutationsas pages 2-2, aragao2024revitalisingriboflavinunveiling pages 10-12) • FLAD1: FAD synthesis; riboflavin-responsive MADD-like lipid storage myopathy. (wen2024acomparativestudy pages 4-6) • SLC25A32: mitochondrial flavin transport association evidence (Open Targets). (OpenTargets Search: Multiple acyl-CoA dehydrogenase deficiency,Glutaric acidemia type II,Glutaric aciduria type II)

Phenotype associations (suggested HPO term names)

• Hypoglycemia; metabolic acidosis; hyperammonemia; encephalopathy; muscle weakness; rhabdomyolysis; lipid storage myopathy; cardiomyopathy/arrhythmia risk; hepatomegaly/liver dysfunction; respiratory insufficiency in severe late-onset cohorts. (rao2023lateonsetmultipleacylcoa pages 2-3, rao2023lateonsetmultipleacylcoa pages 3-4, schee2024multipleacylcoadehydrogenase pages 2-3)

Cell types (suggested CL term names)

• Skeletal muscle cell / myofiber; motor neuron–like cells (NSC-34 model). (schee2024multipleacylcoadehydrogenase pages 2-3, lin2024etfdhmutationinvolves pages 1-2)

Anatomy (suggested UBERON term names)

• Skeletal muscle, liver, heart, brain. (rao2023lateonsetmultipleacylcoa pages 3-4, schee2024multipleacylcoadehydrogenase pages 2-3)

Chemical entities (examples; mapable to ChEBI)

• Riboflavin; FAD; coenzyme Q10; L‑carnitine; acylcarnitines; glutaric acid; ethylmalonic acid; 2‑hydroxyglutarate. (martino2024deepintronicetfdh pages 1-2, rao2023lateonsetmultipleacylcoa pages 4-5)

Figure evidence

A pathway schematic of ETF→ETFDH→CoQ electron flow and its connection to OXPHOS is provided in the Nature Metabolism 2024 figures. (martin2024anetfdhdrivenmetabolon media f5fb06a9)

URLs and publication dates (selected)

• Martín et al., Nature Metabolism, Jan 2024: https://doi.org/10.1038/s42255-023-00956-y (martin2024anetfdhdrivenmetabolon pages 1-2) • Lin et al., Scientific Reports, Oct 2024: https://doi.org/10.1038/s41598-024-75286-4 (lin2024etfdhmutationinvolves pages 1-2) • Martino et al., Int J Mol Sci, Sep 2024: https://doi.org/10.3390/ijms25179637 (martino2024deepintronicetfdh pages 1-2) • Ma et al., Orphanet J Rare Dis, Feb 2024: https://doi.org/10.1186/s13023-024-03072-6 (ma2024themaletofemaleratio pages 1-2) • Schee et al., J Clin Neurol, May 2024: https://doi.org/10.3988/jcn.2023.0265 (schee2024multipleacylcoadehydrogenase pages 2-3) • Rao et al., BMJ Case Reports, May 2023: https://doi.org/10.1136/bcr-2022-252668 (rao2023lateonsetmultipleacylcoa pages 2-3) • Olsen et al., Brain, Aug 2007: https://doi.org/10.1093/brain/awm135 (olsen2007etfdhmutationsas pages 1-2)

Limitations note

Some requested items (e.g., comprehensive GO/HP/CL/UBERON ID codes and a fully enumerated list of all causal/associated PMIDs beyond those explicitly present in the provided evidence snippets and OpenTargets listing) require a dedicated ontology cross-referencing step and/or additional full-text retrieval beyond the current evidence set; the mechanistic narrative and statistics above are restricted to statements supported directly by the cited sources. (OpenTargets Search: Multiple acyl-CoA dehydrogenase deficiency,Glutaric acidemia type II,Glutaric aciduria type II)

References

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  10. (olsen2007etfdhmutationsas pages 2-2): R. K. J. Olsen, S. E. Olpin, B. S. Andresen, Z. H. Miedzybrodzka, M. Pourfarzam, B. Merinero, F. E. Frerman, M. W. Beresford, J. C. S. Dean, N. Cornelius, O. Andersen, A. Oldfors, E. Holme, N. Gregersen, D. M. Turnbull, and A. A. M. Morris. Etfdh mutations as a major cause of riboflavin-responsive multiple acyl-coa dehydrogenation deficiency. Brain : a journal of neurology, 130 Pt 8:2045-54, Aug 2007. URL: https://doi.org/10.1093/brain/awm135, doi:10.1093/brain/awm135. This article has 374 citations.

  11. (lin2024etfdhmutationinvolves pages 1-2): Chuang-Yu Lin, Wen-Chen Liang, Yi-Chen Yu, Shin-Cheng Chang, Ming-Chi Lai, and Yuh-Jyh Jong. Etfdh mutation involves excessive apoptosis and neurite outgrowth defect via bcl2 pathway. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-75286-4, doi:10.1038/s41598-024-75286-4. This article has 1 citations and is from a peer-reviewed journal.

  12. (lin2024etfdhmutationinvolves pages 7-8): Chuang-Yu Lin, Wen-Chen Liang, Yi-Chen Yu, Shin-Cheng Chang, Ming-Chi Lai, and Yuh-Jyh Jong. Etfdh mutation involves excessive apoptosis and neurite outgrowth defect via bcl2 pathway. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-75286-4, doi:10.1038/s41598-024-75286-4. This article has 1 citations and is from a peer-reviewed journal.

  13. (schee2024multipleacylcoadehydrogenase pages 2-3): Jie Ping Schee, Joo San Tan, Cheng Yin Tan, Nortina Shahrizaila, Kum Thong Wong, and Khean Jin Goh. Multiple acyl-coa dehydrogenase deficiency: phenotypic and genetic features of a malaysian cohort. Journal of Clinical Neurology (Seoul, Korea), 20:422-430, May 2024. URL: https://doi.org/10.3988/jcn.2023.0265, doi:10.3988/jcn.2023.0265. This article has 2 citations.

  14. (wen2024acomparativestudy pages 4-6): Bing Wen, Runqi Tang, Shuyao Tang, Yuan Sun, Jingwen Xu, Dandan Zhao, Tan Wang, and Chuanzhu Yan. A comparative study on riboflavin responsive multiple acyl-coa dehydrogenation deficiency due to variants in flad1 and etfdh gene. Journal of human genetics, 69:125-131, Jan 2024. URL: https://doi.org/10.1038/s10038-023-01216-3, doi:10.1038/s10038-023-01216-3. This article has 10 citations and is from a peer-reviewed journal.

  15. (rao2023lateonsetmultipleacylcoa pages 2-3): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.

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  17. (rao2023lateonsetmultipleacylcoa pages 4-5): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.

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  19. (rao2023lateonsetmultipleacylcoa pages 3-4): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.

  20. (rao2023lateonsetmultipleacylcoa pages 1-2): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.

  21. (ma2024themaletofemaleratio pages 1-2): Jing Ma, Huiqiu Zhang, Feng Liang, Guanxi Li, Xiaomin Pang, Rongjuan Zhao, Juan Wang, Xueli Chang, Junhong Guo, and Wei Zhang. The male-to-female ratio in late-onset multiple acyl-coa dehydrogenase deficiency: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases, Feb 2024. URL: https://doi.org/10.1186/s13023-024-03072-6, doi:10.1186/s13023-024-03072-6. This article has 10 citations and is from a peer-reviewed journal.

  22. (ma2024themaletofemaleratio pages 2-5): Jing Ma, Huiqiu Zhang, Feng Liang, Guanxi Li, Xiaomin Pang, Rongjuan Zhao, Juan Wang, Xueli Chang, Junhong Guo, and Wei Zhang. The male-to-female ratio in late-onset multiple acyl-coa dehydrogenase deficiency: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases, Feb 2024. URL: https://doi.org/10.1186/s13023-024-03072-6, doi:10.1186/s13023-024-03072-6. This article has 10 citations and is from a peer-reviewed journal.

  23. (martino2024deepintronicetfdh pages 2-3): Stefania Martino, Pietro D’Addabbo, Antonella Turchiano, Francesca Clementina Radio, Alessandro Bruselles, Viviana Cordeddu, Cecilia Mancini, Alessandro Stella, Nicola Laforgia, Donatella Capodiferro, Simonetta Simonetti, Rosanna Bagnulo, Orazio Palumbo, Flaviana Marzano, Ornella Tabaku, Antonella Garganese, Michele Stasi, Marco Tartaglia, Graziano Pesole, and Nicoletta Resta. Deep intronic etfdh variants represent a recurrent pathogenic event in multiple acyl-coa dehydrogenase deficiency. International Journal of Molecular Sciences, 25:9637, Sep 2024. URL: https://doi.org/10.3390/ijms25179637, doi:10.3390/ijms25179637. This article has 3 citations.

  24. (wang2023clinicalandgene pages 1-2): Xiaoxia Wang and Haining Fang. Clinical and gene analysis of fatty acid oxidation disorders found in neonatal tandem mass spectrometry screening. Pharmacogenomics and Personalized Medicine, 16:577-587, Jun 2023. URL: https://doi.org/10.2147/pgpm.s402760, doi:10.2147/pgpm.s402760. This article has 4 citations and is from a peer-reviewed journal.

  25. (olsen2007etfdhmutationsas pages 6-7): R. K. J. Olsen, S. E. Olpin, B. S. Andresen, Z. H. Miedzybrodzka, M. Pourfarzam, B. Merinero, F. E. Frerman, M. W. Beresford, J. C. S. Dean, N. Cornelius, O. Andersen, A. Oldfors, E. Holme, N. Gregersen, D. M. Turnbull, and A. A. M. Morris. Etfdh mutations as a major cause of riboflavin-responsive multiple acyl-coa dehydrogenation deficiency. Brain : a journal of neurology, 130 Pt 8:2045-54, Aug 2007. URL: https://doi.org/10.1093/brain/awm135, doi:10.1093/brain/awm135. This article has 374 citations.

  26. (olsen2007etfdhmutationsas pages 1-2): R. K. J. Olsen, S. E. Olpin, B. S. Andresen, Z. H. Miedzybrodzka, M. Pourfarzam, B. Merinero, F. E. Frerman, M. W. Beresford, J. C. S. Dean, N. Cornelius, O. Andersen, A. Oldfors, E. Holme, N. Gregersen, D. M. Turnbull, and A. A. M. Morris. Etfdh mutations as a major cause of riboflavin-responsive multiple acyl-coa dehydrogenation deficiency. Brain : a journal of neurology, 130 Pt 8:2045-54, Aug 2007. URL: https://doi.org/10.1093/brain/awm135, doi:10.1093/brain/awm135. This article has 374 citations.