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A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene

Journal of Human Genetics volume 69, pages 125–131 (2024)Cite this article

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Abstract

Lipid storage myopathy (LSM) is a heterogeneous group of lipid metabolism disorders predominantly affecting skeletal muscle by triglyceride accumulation in muscle fibers. Riboflavin therapy has been shown to ameliorate symptoms in some LSM patients who are essentially concerned with multiple acyl-CoA dehydrogenation deficiency (MADD). It is proved that riboflavin responsive LSM caused by MADD is mainly due to ETFDH gene variant (ETFDH-RRMADD). We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants (c.1588 C > T p.Arg530Cys and c.1589 G > C p.Arg530Pro, FLAD1-RRMADD). And we compared our patient together with 9 FLAD1-RRMADD cases from literature to 106 ETFDH-RRMADD cases in our neuromuscular center on clinical history, laboratory investigations and pathological features. Furthermore, the transcriptomics study on FLAD1-RRMADD and ETFDH-RRMADD were carried out. On muscle pathology, both FLAD1-RRMADD and ETFDH-RRMADD were proved with lipid storage myopathy in which atypical ragged red fibers were more frequent in ETFDH-RRMADD, while fibers with faint COX staining were more common in FLAD1-RRMADD. Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups. Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features.

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Acknowledgements

The authors are grateful to the patient and his families for their participation. This work was supported by the National Natural Science Foundation of Shandong Province (No.ZR2023MH229), the National Natural Science Foundation of China (No.82071412); the Youth Program of National Natural Science Foundation of China (81701058, 81901278); National Key Research and Development Program of China (2021YFC2700904); Qingdao Technology Program for Health and Welfare (20–3-4–42-nsh); the Taishan Scholars Program of Shandong Province.

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Author notes

  1. These authors contributed equally: Tan Wang, Chuanzhu Yan.

Authors and Affiliations

  1. Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China

    Bing Wen, Shuyao Tang, Jingwen Xu, Dandan Zhao & Chuanzhu Yan

  2. Department of Pathology, Maternal and Child Health Hospital of Liaocheng, Liaocheng, 252000, Shandong, China

    Runqi Tang

  3. Department of Neurology, Qilu Hospital (Qingdao), Shandong University, Qingdao, 266035, Shandong, China

    Yuan Sun

  4. Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China

    Tan Wang

  5. Brain Science Research Institute, Shandong University, Jinan, 250012, Shandong, China

    Chuanzhu Yan

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Correspondence to Tan Wang or Chuanzhu Yan.

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The study was approved by the Ethics Committee of Qilu Hospital, Shandong University (number: KYLL-202208-024). Informed consent was obtained from all patients for being included in the study.

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Wen, B., Tang, R., Tang, S. et al. A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene. J Hum Genet 69, 125–131 (2024). https://doi.org/10.1038/s10038-023-01216-3

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