A clinical case of a hypertrophic phenotype of cardiomyopathy in a child with a combined deficiency of oxidative phosphorylation type 3 associated with a mutation of the TSFM gene

Combined oxidative phosphorylation deficiency type 3 is a rare mitochondrial disease caused by pathogenic variants in the mitochondrial elongation factor (TSFM) gene. The function of this protein is highly active in cardiomyocytes and neurons, so the manifestations of the disease are neurological and cardiac symptoms. Heart damage occurs predominantly as concentric hypertrophy of the left ventricle. From the nervous system, the most observed are muscle hypotonia and choreo-like dyskinesis. In this article, we present a clinical case of combined type 3 oxidative phosphorylation deficiency, which was characterized by the early onset of neurological symptoms and subsequent myocardial hypertrophy at the age of 10 years. This is the second case of the C919T:p.Gln307Ter mutation in the TSFM gene in the literature we studied. Today, the disease is characterized by high mortality at onset from birth and stabilization of the clinical course with asymptomatic or late onset of the disease. The small number of cases of combined oxidative phosphorylation type 3 deficiency leaves many clinical questions, and the description of each genetically confirmed case is extremely important.

1. Meyers DE, Basha HI, Koenig MK. Mitochondrial cardiomyopathy: pathophysiology, diagnosis, and management. Tex Heart Inst J. 2013;40(4):385–394.

2. Debray FG, Lambert M, Chevalier I, et al. Longterm outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics. 2007;119(4):722–733. DOI:10.1542/peds.2006-1866.

3. Garbern JC, Lee RT. Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes. Stem Cell Res Ther. 2021;12(1):177. Published 2021 Mar 12. DOI:10.1186/s13287-021-02252-6.

4. Lioncino M, Monda E, Caiazza M, et al. Cardiovascular Involvement in mtDNA Disease: Diagnosis, Management, and Therapeutic Options. Heart Fail Clin. 2022;18(1):51–60. DOI:10.1016/j.hfc.2021.07.003.

5. Online Mendelian Inheritance in Man (OMIM). Combined oxidative phosphorylation deficiency 3; COXPD3: OMIM # 610505. Baltimore, MD: Johns Hopkins University; 2019. Available from: https://www.omim.org/entry/610505I

6. Emperador S, Bayona-Bafaluy M, FernándezMarmiesse A, et al. Molecular-genetic characterization and rescue of a TSFM mutation causing childhoodonset ataxia and nonobstructive cardiomyopathy. Eur J Hum Genet. 2017; 25: 153–156. https://doi.org/10.1038/ejhg.2016.124

7. Perli E, Pisano A, Glasgow RIC, et al. Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement. Sci Rep. 2019;9(1):5108. Published 2019 Mar 25. DOI:10.1038/s41598-019-41483-9.

8. Scala M, Brigati G, Fiorillo C, et al. Novel homozygous TSFM pathogenic variant associated with encephalocardiomyopathy with sensorineural hearing loss and peculiar neuroradiologic fi Neurogenetics. 2019;20(3):165–172. DOI:10.1007/s10048-019-00582-5.

9. Yang JO, Shaybekyan H, Zhao Y, et al. Case Report: Whole Exome Sequencing Identifies Compound Heterozygous Variants in TSFM Gene Causing Juvenile Hypertrophic Cardiomyopathy. Front Cardiovasc Med. 2022;8:798985. Published 2022 Jan 6. DOI:10.3389/fcvm.2021.798985.

10. van Riesen AK, Biskup S, Kühn AA, et al. Novel Mutation in the TSFM Gene Causes an Early-Onset Complex Chorea without Basal Ganglia Lesions. Mov Disord Clin Pract. 2021;8(3):453–455. Published 2021 Feb 5. DOI:10.1002/mdc3.13144.

11. Smeitink JA, Elpeleg O, Antonicka H, et al. Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet. 2006;79(5):869–877. DOI:10.1086/508434.

12. Ahola S, Isohanni P, Euro L, et al. Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy,andopticatrophy.Neurology.2014;83(8):743– 751. DOI:10.1212/WNL.0000000000000716.

13. Calvo SE, Compton AG, Hershman SG, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012;4(118):118ra10. DOI:10.1126/scitranslmed.30033100.

14. Vedrenne V, Galmiche L, Chretien D, et al. Mutation in the mitochondrial translation elongation factor EFTs results in severe infantile liver failure. J Hepatol. 2012;56(1):294–297. DOI:10.1016/j.hep.2011.06.014.

15. Seo GH, Oh A, Kim EN, et al. Identification of extremely rare mitochondrial disorders by whole exome sequencing. J Hum Genet. 2019;64(11):1117–1125. DOI:10.1038/s10038-019-0660-y.

16. Traschütz A, Hayer SN, Bender B, et al. TSFM mutations cause a complex hyperkinetic movement disorder with strong relief by cannabinoids. Parkinsonism Relat Disord. 2019;60:176–178. DOI:10.1016/j.parkreldis.2018.09.031.

17. Smits P, Antonicka H, van Hasselt PM, et al. Mutation in subdomain G’ of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle. Eur J Hum Genet. 2011;19(3):275–279. DOI:10.1038/ejhg.2010.208.

18. Fontanesi F, Tigano M, et al. Chapter 2 — Human mitochondrial transcription and translation. In: ed. Giuseppe Gasparre, Anna Maria Porcelli’s The Human Mitochondrial Genome. Academic Press. 2020, 35–70. https://doi.org/10.1016/B978-0-12-819656-4.00002

19. Savvatis K, Vissing CR, Klouvi L, et al. Cardiac Outcomes in Adults with Mitochondrial Diseases. J Am Coll Cardiol. 2022;80(15):1421–1430. DOI:10.1016/j.jacc.2022.08.716.