Skip to main content Accessibility help

Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature

  • Stella Mazurova (a1), Martin Magner (a1), Vendula Kucerova-Vidrova (a1), Alzbeta Vondrackova (a1), Viktor Stranecky (a2), Anna Pristoupilova (a2), Josef Zamecnik (a3), Hana Hansikova (a1), Jiri Zeman (a1), Marketa Tesarova (a1) and Tomas Honzik (a1)...


Cardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.


Corresponding author

Correspondence to: Associate Professor T. Honzik, MD, PhD, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, 128 08, Praha 2, Prague, Czech Republic. Tel: +420 224 367 792; Fax: +420 224 967 113; E-mail:


Hide All
1. Honzik, T, Tesarova, M, Magner, M, et al. Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. J Inherit Metab Dis 2012; 35: 749759.
2. Finsterer, J, Kothari, S. Cardiac manifestations of primary mitochondrial disorders. Int J Cardiol 2014; 177: 754763.
3. Powell, CA, Kopajtich, R, D’Souza, AR, et al. TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet 2015; 97: 319328.
4. Chung, WK, Martin, K, Jalas, C, et al. Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy. J Med Genet 2015; 52: 627635.
5. Stroud, DA, Maher, MJ, Lindau, C, et al. COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2. Hum Mol Genet 2015; 24: 54045415.
6. Lax, NZ, Alston, CL, Schon, K, et al. Neuropathologic characterization of pontocerebellar hypoplasia type 6 associated with cardiomyopathy and hydrops fetalis and severe multisystem respiratory chain deficiency due to novel RARS2 mutations. J Neuropathol Exp Neurol 2015; 74: 688703.
7. Alston, CL, Ceccatelli Berti, C, Blakely, EL, et al. A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency. Hum Genet 2015; 134: 869879.
8. Haack, TB, Jackson, CB, Murayama, K, et al. Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol 2015; 2: 492509.
9. Shehata, BM, Cundiff, CA, Lee, K, et al. Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy. Am J Med Genet A 2015; 167A: 21142121.
10. Brecht, M, Richardson, M, Taranath, A, Grist, S, Thorburn, D, Bratkovic, D. Leigh syndrome caused by the MT-ND5 m.13513G>a mutation: a case presenting with WPW-like conduction defect, cardiomyopathy, hypertension and hyponatraemia. JIMD Rep 2015; 19: 95100.
11. Brisca, G, Fiorillo, C, Nesti, C, et al. Early onset cardiomyopathy associated with the mitochondrial tRNALeu((UUR)) 3271T>C MELAS mutation. Biochem Biophys Res Commun 2015; 458: 601604.
12. Holmgren, D, Wahlander, H, Eriksson, BO, Oldfors, A, Holme, E, Tulinius, M. Cardiomyopathy in children with mitochondrial disease; clinical course and cardiological findings. Eur Heart J 2003; 24: 280288.
13. Yaplito-Lee, J, Weintraub, R, Jamsen, K, Chow, CW, Thorburn, DR, Boneh, A. Cardiac manifestations in oxidative phosphorylation disorders of childhood. J Pediatr 2007; 150: 407411.
14. Scaglia, F, Towbin, JA, Craigen, WJ, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004; 114: 925931.
15. Wahbi, K, Bougouin, W, Behin, A, et al. Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. Eur Heart J 2015; 36: 28862893.
16. Honzik, T, Tesarova, M, Mayr, JA, et al. Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation. Arch Dis Child 2010; 95: 296301.
17. Mazurova, S, Tesarova, M, Magner, M, et al. Novel mutations in the TAZ gene in patients with Barth syndrome. Prague Med Rep 2013; 114: 139153.
18. Magner, M, Dvorakova, V, Tesarova, M, et al. TMEM70 deficiency: long-term outcome of 48 patients. J Inherit Metab Dis 2015; 38: 417426.
19. Chanprasert, S, Wang, J, Weng, SW, et al. Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Mol Genet Metab 2013; 110: 153161.
20. Gotz, A, Tyynismaa, H, Euro, L, et al. Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet 2011; 88: 635642.
21. Taylor, RW, Pyle, A, Griffin, H, et al. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA 2014; 312: 6877.
22. Darley-Usmar, VM, Rickwood, D, Wilson, MT. Mitochondria, A Practical Approach. IRL Press, Oxford and Washington, DC, 1987, xvi, 321pp.
23. Rustin, P, Chretien, D, Bourgeron, T, et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 1994; 228: 3551.
24. Srere, PA, Brooks, GC. The circular dichroism of glucagon solutions. Arch Biochem Biophys 1969; 129: 708710.
25. Schagger, H, von Jagow, G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal Biochem 1991; 199: 223231.
26. Sheehan, DC, Hrapchak, BB. Theory and practice of histotechnology, 2nd ed. Battelle Press; Distributed by Lipshaw, Columbus, Ohio; Detroit, Michigan, 1987, xiii, 481 pp.
27. Pejznochova, M, Tesarova, M, Honzik, T, Hansikova, H, Magner, M, Zeman, J. The developmental changes in mitochondrial DNA content per cell in human cord blood leukocytes during gestation. Physiol Res 2008; 57: 947955.
28. Schwarz, JM, Cooper, DN, Schuelke, M, Seelow, D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11: 361362.
29. Adzhubei, IA, Schmidt, S, Peshkin, L, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7: 248249.
30. Kumar, P, Henikoff, S, Ng, PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4: 10731081.
31. Copeland, WC. Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol 2012; 47: 6474.
32. Oskoui, M, Davidzon, G, Pascual, J, et al. Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Arch Neurol 2006; 63: 11221126.
33. Mancuso, M, Salviati, L, Sacconi, S, et al. Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA. Neurology 2002; 59: 11971202.
34. Galbiati, S, Bordoni, A, Papadimitriou, D, et al. New mutations in TK2 gene associated with mitochondrial DNA depletion. Pediatr Neurol 2006; 34: 177185.
35. Tyynismaa, H, Sun, R, Ahola-Erkkila, S, et al. Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions. Hum Mol Genet 2012; 21: 6675.
36. Marti, R, Nascimento, A, Colomer, J, et al. Hearing loss in a patient with the myopathic form of mitochondrial DNA depletion syndrome and a novel mutation in the TK2 gene. Pediatr Res 2010; 68: 151154.
37. El-Hattab, AW, Scaglia, F., Mitochondrial, DNA. Depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 2013; 10: 186198.
38. Magner, M, Szentivanyi, K, Svandova, I, et al. Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures. Eur J Paediatr Neurol 2011; 15: 101108.
39. Spinazzola, A, Invernizzi, F, Carrara, F, et al. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis 2009; 32: 143158.
40. Gotz, A, Isohanni, P, Pihko, H, et al. Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome. Brain 2008; 131 (Pt 11): 28412850.
41. Behin, A, Jardel, C, Claeys, KG, et al. Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum. Neurology 2012; 78: 644648.
42. Paradas, C, Gutierrez Rios, P, Rivas, E, Carbonell, P, Hirano, M, DiMauro, S. TK2 mutation presenting as indolent myopathy. Neurology 2013; 80: 504506.
43. Blakely, E, He, L, Gardner, JL, et al. Novel mutations in the TK2 gene associated with fatal mitochondrial DNA depletion myopathy. Neuromuscul Disord 2008; 18: 557560.
44. Knierim, E, Seelow, D, Gill, E, von Moers, A, Schuelke, M. Clinical application of whole exome sequencing reveals a novel compound heterozygous TK2-mutation in two brothers with rapidly progressive combined muscle-brain atrophy, axonal neuropathy, and status epilepticus. Mitochondrion 2015; 20: 16.
45. Alston, CL, Schaefer, AM, Raman, P, et al. Late-onset respiratory failure due to TK2 mutations causing multiple mtDNA deletions. Neurology 2013; 81: 20512053.
46. Stenson, PD et al. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014; 133: 19.
47. Konovalova, S, Tyynismaa, H. Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab 2013; 108: 206211.
48. Sokabe, M, Ose, T, Nakamura, A, et al. The structure of alanyl-tRNA synthetase with editing domain. Proc Natl Acad Sci U S A 2009; 106: 1102811033.
49. McLaughlin, HM, Sakaguchi, R, Giblin, W, et al. A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N). Hum Mutat 2012; 33: 244253.
50. Zhao, Z, Hashiguchi, A, Hu, J, et al. Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy. Neurology 2012; 78: 16441649.
51. Dallabona, C, Diodato, D, Kevelam, SH, et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 2014; 82: 20632071.
52. Sproule, DM, Kaufmann, P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci 2008; 1142: 133158.
53. Euro, L, Konovalova, S, Asin-Cayuela, J, et al. Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation. Front Genet 2015; 6: 21.


Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature

  • Stella Mazurova (a1), Martin Magner (a1), Vendula Kucerova-Vidrova (a1), Alzbeta Vondrackova (a1), Viktor Stranecky (a2), Anna Pristoupilova (a2), Josef Zamecnik (a3), Hana Hansikova (a1), Jiri Zeman (a1), Marketa Tesarova (a1) and Tomas Honzik (a1)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed