Polymorphism of the clinical manifestations of progressive mitochondrial encephalomyopathy associated with POLG1 gene mutation
https://doi.org/10.21508/1027-4065-2016-61-3-51-57
Abstract
The common cause of mitochondrial diseases is mutations in the POLG1 gene encoding the catalytic subunit of DNA-polymerase gamma that is responsible for the replication and repair of mitochondrial DNA. Diseases associated with POLG1 gene defects are characterized by obvious clinical polymorphism and may resemble some mitochondrial syndromes and other hereditary and nonhereditary diseases, which gives rise to diagnostic difficulties. Another characteristic feature is that phenotypic manifestations are of diversity in various patients having the same mutation in the POLG1 gene. The paper describes mitochondrial encephalomyopathy, caused by homozygous mutation in the polymerase gamma (POLG1, p.L304R), with different clinical manifestations and a poor outcome in patients from two different families.
About the Authors
M. I. Yablonskaya
Academician Yu.E. Veltishchev Research Clinical Institute of Pediatrics, N.I. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation
Russian Federation
Moscow
Russian Federation
Moscow
E. A. Nikolaeva
Academician Yu.E. Veltishchev Research Clinical Institute of Pediatrics, N.I. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation
Russian Federation
Moscow
Russian Federation
Moscow
P. A. Shatalov
Academician Yu.E. Veltishchev Research Clinical Institute of Pediatrics, N.I. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation
Russian Federation
Moscow
Russian Federation
Moscow
M. N. Kharabadze
Academician Yu.E. Veltishchev Research Clinical Institute of Pediatrics, N.I. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation
Russian Federation
Moscow
Russian Federation
Moscow
References
1. Haas R.H., Parikh S., Falk M.J. et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007; 120: 6: 1326–1333.
2. Poole O.V., Hanna M.G., Pitceathly R.D. Mitochondrial disorders: disease mechanisms and therapeutic approaches. Discov Med 2015; 20: 111: 325–331.
3. Martikainen M.H., Chinnery P.F. Mitochondrial disease: mimics and Chameleons. Pract Neurol 2015; 15: 6: 424–435. doi:10.1136/practneurol-2015-001191.
4. Tang S., Wanq J., Lee N.C. et al. Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet 2011; 48: 10: 669–681. doi: 10.1136/jmedgenet-2011-100222.
5. Ashley N., O’Rourke A., Smith C. et al. Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations. Hum Mol Genet 2008; 17: 16: 2496–2506. doi: 10.1093/hmg/ddn150.
6. Neeve V.C.M., Samuels J., Bindoff L.A. et al. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr? Brain 2012. 135: 12: 3614–3626. doi:10.1093/brain/aws298.
7. Macao B., Uhler J.P., Siibak T. et al. The exonuclease activity of DNA polymerase γ is required for ligation during mitochondrial DNA replication. Nat Commun 2015. 6: 7303. Published online 2015 Jun 22. doi: 10.1038/ncomms8303
8. Stump J.D., Saneto R.P., Copeland W.C. Clinical and Molecular Features of POLG-Related Mitochondrial Disease. Cold Spring Harb Perspect Biol 2013; 5: 4: a011395. doi: 10.1101/cshperspect.a011395.
9. Human DNA Polymerase gamma Mutation Databasee https://tools.niehs.nih.gov/polg/
10. Михайлова С.В., Захарова Е.Ю., Цыганкова П.Г. и др. Клинический полиморфизм митохондриальных энцефаломиопатий, обусловленных мутациями гена полимеразы гамма. Рос вестн перинатол и педиатр 2012; 57: 4: 2: 51–61. Mikhailova S.V., Zakharova E.Yu., Tsygankova P.G. et al. Clinical polymorphism of mitochondrial encephalomyopathies caused by polymerase gamma gene mutations. Ros Vestn Perinatol i Pediatr 2012; 57: 4: 2: 51–61.
11. Lamantea E., Tiranti V., Bordoni A. et al. Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann Neurol 2002; 52: 2: 211–219. doi: 10.1002/ana.10278.
12. Horvath R., Hudson G., Ferrari G. et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006; 129: 7: 1674–1684. doi: 10.1093/brain/awl088.
13. Luoma P., Melberg A., Rinne J.O. et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 2004; 364: 9437: 875–882. doi: 10.1016/S0140-6736(04)16983-3.
14. Nguyen K.V., Ostergaard E., Ravn S.H. et al. POLG mutations in Alpers syndrome. Neurology 2005; 65: 9: 1493–1495. doi: 10.1212/01.wnl.0000182814.55361.70
15. Tzoulis C., Engelsen B.A., Telstad W. et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 2006; 129: 7: 1685–1692. doi: 10.1093/brain/awl097.
16. Hansen N., Zwarg T., Wanke I. et al. MELAS/SANDO overlap syndrome associated with POLG1 mutations. Neurol Sci 2012; 33: 1: 209–212. doi: 10.1007/s10072-011-0631-3.
17. Pitceathly R.D., Tomlinson S.E., Hargreaves I. et al. Distal myopathy with cachexia: an unrecognised phenotype caused by dominantly-inherited mitochondrial polymerase gamma mutations. J Neurol Neurosurg Psychiatry 2013; 84: 1: 107–110. doi: 10.1136/jnnp-2012-303232.
18. Rajakulendran S., Pitceathly R.D.S., Taanman J-W. et al. A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease. PLoS One 2016; 11: 1: e0145500. doi: 10.1371/journal.pone.0145500.
19. 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: 749–759.
20. Николаева Е.А., Новиков П.В. Проблема диагностики и дифференциальной диагностики митохондриальных заболеваний у детей. Педиатрия 2014; 6: 75–83. (Nikolaeva E.А., Novikov P.V. Problem of diagnostics and differential diagnosis of mitochondrial diseases at children. Pediatriya 2014; 6: 75–83.)
21. Farnum G.A., Nurminen A., Kaguni L.S. Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype–phenotype correlations for the complete spectrum of POLG syndromes. Biochim Biophys Acta 2014; 1837: 7: 1113–1121. doi:10.1016/j.bbabio.2014.01.021.
22. Martikainen M.H., Päivärinta M., Jääskeläinen S. et al. Successful treatment of POLG-related mitochondrial epilepsy with antiepileptic drugs and low glycaemic index diet. Epileptic Disord 2012; 14: 4: 438–441. Doi: 10.1684/epd.2012.0543.
Review
For citations:
Yablonskaya M.I., Nikolaeva E.A., Shatalov P.A., Kharabadze M.N. Polymorphism of the clinical manifestations of progressive mitochondrial encephalomyopathy associated with POLG1 gene mutation. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2016;61(3):51-57. (In Russ.) https://doi.org/10.21508/1027-4065-2016-61-3-51-57
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