Hypertrophic cardiomyopathy and lactic acidosis in a child with acyl-CoA dehydrogenase 9 deficiency. Review of the literature and clinical observation

Introduction. Acyl-CoA dehydrogenase 9 deficiency (mitochondrial complex I deficiency) is an autosomal recessive disease from the heterogeneous group of disorders of mitochondrial β-oxidation of fatty acids caused by mutations in the ACAD9 gene. The disease is characterized by a wide range of clinical manifestations, the most common of which are metabolic acidosis, hypertrophic cardiomyopathy, muscle hypotonicity, and impaired motor skills. The article presents the first Russian clinical observation of a rare variant of hypertrophic cardiomyopathy with early debut in a patient with mitochondrial complex I deficiency caused by homozygous mutation c.659C>T (p.A220V) in the ACAD9 gene and emphasizes the importance of early diagnosis of the disease and complex drug therapy to prevent the development of severe complications.

Objective: to describe the clinical course and management of a patient with the pathogenic c.659C>T (p.A220V) variant of the ACAD9 gene.

Detailed analysis of anamnesis data, results of clinical, laboratory, instrumental diagnostic methods, and molecular genetic research performed using high-throughput sequencing and direct Sanger sequencing technology.

The article presents a literature review and detailed data on clinical observation of a child with homozygous c.659C>T (p.A220V) mutation in the ACAD9 gene diagnosed on the basis of the cardiology department of the National Medical Research Center for Children’s Health. Early disease markers and possibilities of complex drug therapy to prevent the development of severe complications are described.

Conclusion. Disruption of mitochondrial beta-oxidation of fatty acids is a heterogeneous group of inherited diseases due to abnormal mitochondrial beta-oxidation and transport of carnitine and fatty acids in mitochondria. A feature of these diseases is the multisystem nature of the lesion and its progressive course. In some cases, the initial clinical manifestations may be various disorders of the cardiovascular system (cardiomyopathy, heart rhythm disturbances), which may cause death in neonatal period and early childhood. Early molecular genetic research provides accurate diagnosis and, accordingly, timely prescription of complex therapy.

Compliance with ethical standards. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee and was approved by the Ethics. The design of the study was approved by the Ethics committee of the National Research Center for Children’s Health of the Russian Ministry of Health.

Contribution:
Gandaeva L.A. — concept and design of the study, collection and processing of material, text editing, approval of the final version of the article;
Basargina E.N. — text editing; approval of the final version of the article;
Davydova Yu.I. — collection and processing of material, text writing; 
Burykina Yu.S. — collection and processing of material, text writing;
Silnova I.V. — collection and processing of material, text writing; 
Pushkov A.A. — collection and processing of material, text writing;
Savostyanov K.V. — concept and design of the study, text editing, approval of the final version of the article.
All co-authors are responsible for the  integrity of all parts of the manuscript and approval of its final version.

Conflict of interest. The authors declare no conflict of interest.

Acknowledgements. The study had no sponsorship. The authors are grateful to the patient’s family for their supporting our research. The authors would like to express their gratitude to Professor A.P. Fisenko, Director of the National Medical Research Center for Children’s Health of the Ministry of Health of the Russian Federation for his support and technical assistance in implementation of this work. The authors would like to thank the entire staff of the National Medical Research Center for Children’s Health for the opportunity of interdisciplinary approach to patient care.

Received: August 14, 2023
Accepted: September 30, 2023
Published: December 28, 2023

1. Disorders of mitochondrial β-oxidation of fatty acids: Clinical guidelines. Ministry of Health of Russia; 2021. (in Russian)

2. Goetzman E.S. Advances in the understanding and treatment of mitochondrial fatty acid oxidation disorders. Curr. Genet. Med. Rep. 2017; 5(3): 132–42. https://doi.org/10.1007/s40142-017-0125-6

3. Nouws J., Wibrand F., van den Brand M., Venselaar H., Duno M., Lund A.M., et al. A patient with complex I deficiency caused by a novel ACAD9 mutation not responding to riboflavin treatment. JIMD Rep. 2014; 12: 37–45. https://doi.org/10.1007/8904_2013_242

4. Zhurkova N.V., Vashakmadze N.D., Surkov A.N., Smirnova O.Ya., Sergienko N.S., Ovsyanik N.G., et al. Mitochondrial fatty acid beta-oxidation disorders in children: literature review. Voprosy sovremennoy pediatrii. 2022; 21(6S): 522–8. https://doi.org/10.15690/vsp.v21i6S.2503 (in Russian)

5. Houten S.M., Violante S., Ventura F.V., Wanders R.J. The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annu. Rev. Physiol. 2016; 78: 23–44. https://doi.org/10.1146/annurev-physiol-021115-105045

6. Vishwanath V.A. Fatty acid beta-oxidation disorders: a brief review. Ann. Neurosci. 2016; 23(1): 51–5. https://doi.org/10.1159/000443556

7. Nikolaeva E.A. Heterogeneity of mitochondrial diseases caused by defects in mitochondrial respiratory chain complex I. Rossiyskiy vestnik perinatologii i pediatrii. 2015; 60(3): 21–5. https://elibrary.ru/txohgz (in Russian)

8. Repp B.M., Mastantuono E., Alston C.L., Schiff M., Haack T.B., Rötig A., et al. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? Orphanet. J. Rare Dis. 2018; 13(1): 120. https://doi.org/10.1186/s13023-018-0784-8

9. Wanders R.J.A., Visser G., Ferdinandusse S., Vaz F.M., Houtkooper R.H. Mitochondrial fatty acid oxidation disorders: laboratory diagnosis, pathogenesis, and the complicated route to treatment. J. Lipid Atheroscler. 2020; 9(3): 313–33. https://doi.org/10.12997/jla.2020.9.3.313

10. Collet M., Assouline Z., Bonnet D., Rio M., Iserin F., Sidi D., et al. High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood. Eur. J. Hum. Genet. 2016; 24(8): 1112–6. https://doi.org/10.1038/ejhg.2015.264

11. Dewulf J.P., Barrea C., Vincent M.F., De Laet C., Van Coster R., Seneca S., et al. Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients. Mol. Genet. Metab. 2016; 118(3): 185–9. https://doi.org/10.1016/j.ymgme.2016.05.005

12. Angerer H., Zwicker K., Wumaier Z., Sokolova L., Heide H., Steger M., et al. A scaffold of accessory subunits links the peripheral arm and the distal proton-pumping module of mitochondrial complex I. Biochem. J. 2011; 437(2): 279–88. https://doi.org/10.1042/BJ20110359

13. Aintablian H.K., Narayanan V., Belnap N., Ramsey K., Grebe T.A. An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach. Mol. Genet. Metab. Rep. 2016; 10: 38–44. https://doi.org/10.1016/j.ymgmr.2016.12.005

14. Dubucs C., Aziza J., Sartor A., Heitz F., Sevely A., Sternberg D., et al. Severe antenatal hypertrophic cardiomyopathy secondary to ACAD9-related mitochondrial complex I deficiency. Mol. Syndromol. 2023; 14(2): 101–8. https://doi.org/10.1159/000526022

15. Kadoya T., Sakakibara A., Kitayama K., Yamada Y., Higuchi S., Kawakita R., et al. Successful treatment of infantile-onset ACAD9-related cardiomyopathy with a combination of sodium pyruvate, beta-blocker, and coenzyme Q10. J. Pediatr. Endocrinol. Metab. 2019; 32(10): 1181–5. https://doi.org/10.1515/jpem-2019-0205

16. He M., Rutledge S.L., Kelly D.R., Palmer C.A., Murdoch G., Majumder N., et al. A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Am. J. Hum. Genet. 2007; 81(1): 87–103. https://doi.org/10.1086/519219

17. Fragaki K., Chaussenot A., Boutron A., Bannwarth S., Rouzier C., Chabrol B., et al. Assembly defects of multiple respiratory chain complexes in a child with cardiac hypertrophy associated with a novel ACAD9 mutation. Mol. Genet. Metab. 2017; 121(3): 224–6. https://doi.org/10.1016/j.ymgme.2017.05.002

18. Aintablian H.K., Narayanan V., Belnap N., Ramsey K., Grebe T.A. An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach. Mol. Genet. Metab. Rep. 2016; 10: 38–44. https://doi.org/10.1016/j.ymgmr.2016.12.005

19. Savost’yanov K.V., Namazova-Baranova L.S., Basargina E.N., Vashakmadze N.D., Zhurkova N.V., Pushkov A.A., et al. The new genome variants in Russian children with genetically determined cardiomyopathies revealed with massive parallel sequencing. Vestnik Rossiyskoy akademii meditsinskikh nauk. 2017; 72(4): 242–53. https://doi.org/10.15690/vramn872 https://elibrary.ru/zfourx (in Russian)

20. Broad Institute. Genome Analysis Toolkit. Available at: https://gatk.broadinstitute.org

21. Savost'yanov K.V. Advanced Algorithms for Genetic Diagnosis of Rare Hereditary Diseases in Russian Patients [Sovremennye algoritmy geneticheskoy diagnostiki redkikh nasledstvennykh bolezney u rossiyskikh patsientov]. Moscow: Poligrafist i izdatel'; 2022. 452 p. ISBN 978-5-6047928-7-2. (in Russian)

22. Human Gene Mutation Database (HGMD). Available at: https://www.hgmd.cf.ac.uk/docs/new_back.html

23. Gerards M., van den Bosch B.J., Danhauser K., Serre V., van Weeghel M., Wanders R.J., et al. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain. 2011; 134(Pt. 1): 210–9. https://doi.org/10.1093/brain/awq273

24. Kanabus M., Heales S.J., Rahman S. Development of pharmacological strategies for mitochondrial disorders. Br. J. Pharmacol. 2014; 171(8): 1798–817. https://doi.org/10.1111/bph.12456

25. Leont’eva I.V., Nikolaeva E.A. Mitochondrial cardiomyopathies. Rossiyskiy vestnik perinatologii i pediatrii. 2016; 61(3): 22–30. https://doi.org/10.21508/1027-4065-2016-61-3-22-30 https://elibrary.ru/wbzstj (in Russian)

26. Triepels R.H., Van Den Heuvel L.P., Trijbels J.M., Smeitink J.A. Respiratory chain complex I deficiency. Am. J. Med. Genet. 2001; 106(1): 37–45. https://doi.org/10.1002/ajmg.1397

27. Gandaeva L.A., Basargina E.N., Kondakova O.B., Kaverina V.G., Pushkov A.A., Zharova O.P. A new nucleotide variant in the ELAC2 gene in a young child with a ventricular hypertrophy. Rossiyskiy vestnik perinatologii i pediatrii. 2022; 67(4): 120–6. https://doi.org/10.21508/1027-4065-2022-67-4-120-126 https://elibrary.ru/tpigml (in Russian)