perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”perinatology-199Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWSДиагностика и профилактика ядерно-кодируемых митохондриальных заболеваний у детейDiagnostics and prevention of nuclear-encoded mitochondrial diseases in infantsНиколаеваЕ. А.NikolaevaE. A.

д.м.н., гл.н.с. отделения психоневрологии и наследственных заболеваний с нарушением психики Научно-исследовательского клинического института педиатрии

Научно-исследовательский клинический институт педиатрии, МоскваРоссияResearch Clinical Institute of Pediatrics, MoscowRussian Federation2014150320165921928Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20162016Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/199

Представлен анализ публикаций последних лет, посвященных клиническим проявлениям, вопросам диагностики митохон-дриальной патологии, обусловленной дефектами ядерных генов. В научный анализ были включены около 100 генов. В соответствии с кодируемым белком и его функцией выделены 9 групп генов, оказывающих влияние на процессы клеточной биоэнергетики. По срокам манифестации заболевания разделены на группы: болезни раннего возраста (в том числе новорожденных), детского возраста, подростков и взрослых. Обращено внимание на трудность идентификации отдельных форм заболеваний в силу клинического полиморфизма проявлений мутаций отдельных генов и в то же время большого сходства клинических симптомокомплексов, обусловленных разными энзимными и генными дефектами. Представлены дополнительные критерии дифференциальной диагностики заболеваний: 3-метилглутаконовая ацидурия, деплеция и множественные делении митохондриальной ДНК. Сделан вывод о необходимости более широкого внедрения метода полного экзомного секвенирования, позволяющего выявлять не только часто встречающиеся, но и редкие генные мутации ядерной ДНК. Идентификация генного дефекта дает возможность медико-генетического консультирования и профилактики распространения тяжелой патологии в семье.

The paper analyses recent publications on the clinical manifestations and diagnosis of mitochondrial diseases caused by defects in nuclear genes. A scientific analysis included about 100 genes. According to the encoded protein and its function, the author has identified 9 gene groups that affect the processes of cellular bioenergy. By the time of their manifestation, the diseases were divided into groups: those of early childhood (including neonatality), childhood, adolescence, and adulthood. Attention is drawn to difficulties to identify some forms of the diseases in view of the clinical polymorphism of manifestations of mutations in individual genes and, at the same tone, many similarities between clinical symptom complexes caused by different enzyme and gene defects. There are additional criteria for the differential diagnosis of the diseases: 3-methylglutaconic aciduria, depletions and multiple depletions of mitochondrial DNA. It is concluded that it is necessary to more extensively introduce the whole-exome sequencing test that can reveal not only common, but also rare gene mutations in nuclear DNA. Gene defect identification permits medical genetic counselling and prevention of the spread of severe pathology in the family.

детимитохондриальные заболеваниясимптомыядерная ДНКмитохондриальная ДНКдеплециямножественные делеции3-метилглутаконовая ацидуриядиагностикаполное экзомное секвенирование.childrenmitochondrial diseasessymptomsnuclear DNAmitochondrial DNAdepletionmultiple deletions3-methylglutaconic aciduriadiagnosiswhole-exome sequencing test.ReferencesSchaefer A.M., McFarland R., Blakely E.L. et al. Prevalence of mitochondrial DNA disease in adults. Ann Neural 2008; 63: 35-39.Schaefer A.M., McFarland R., Blakely E.L. et al. Prevalence of mitochondrial DNA disease in adults. Ann Neural 2008; 63: 35-39.Chinnery P.F. Elliott H.R., Hudson G. et al. Epigenetics, epidemiology and mitochondrial DNA diseases. Int J Epidemiol 2012; 41: 1: 177-187.Chinnery P.F. Elliott H.R., Hudson G. et al. Epigenetics, epidemiology and mitochondrial DNA diseases. Int J Epidemiol 2012; 41: 1: 177-187.Bannwarth S., Procaccio V., LebreA.S. et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet 2013; 50: 10: 704-714.Bannwarth S., Procaccio V., LebreA.S. et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet 2013; 50: 10: 704-714.Rahman S., Leonard J.V. Mitochondrial disorders. Curr Pediatr 1997; 7: 123—127.Rahman S., Leonard J.V. Mitochondrial disorders. Curr Pediatr 1997; 7: 123—127.Loeffen J., Smeitink J., Triepels R. et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 1998; 63: 1598-1608.Loeffen J., Smeitink J., Triepels R. et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 1998; 63: 1598-1608.Finsterer J. Overview on visceral manifestations of mitochondrial disorders. Netherland J Med 2006; 64: 3: 61-71.Finsterer J. Overview on visceral manifestations of mitochondrial disorders. Netherland J Med 2006; 64: 3: 61-71.Shchelochkov O.A.. Li F.Y., Wang J. et al. Milder clinical course of type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metab 2010; 101: 2—3: 282-285.Shchelochkov O.A.. Li F.Y., Wang J. et al. Milder clinical course of type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metab 2010; 101: 2—3: 282-285.Calvo S.E., Tucker E.J., Compton A.G. et al. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 2010; 42: 10:851—858.Calvo S.E., Tucker E.J., Compton A.G. et al. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 2010; 42: 10:851—858.Rahman S., Thorburn D.R. 189th ENMC International workshop Complex I deficiency: Diagnosis and treatment. 20— 22 April 2012, Naarden, The Netherlands. Neuromuscular Disorders 2013; 23:6:506—515.Rahman S., Thorburn D.R. 189th ENMC International workshop Complex I deficiency: Diagnosis and treatment. 20— 22 April 2012, Naarden, The Netherlands. Neuromuscular Disorders 2013; 23:6:506—515.Taylor R.W., Swalwell H, Kirby D.M. et al. The molecular genetic basis of respiratory chain complex I deficiency: clinical presentations and mtDNA mutations. J Inherit Metab Dis 2006; 29: Suppl. 1: 16.Taylor R.W., Swalwell H, Kirby D.M. et al. The molecular genetic basis of respiratory chain complex I deficiency: clinical presentations and mtDNA mutations. J Inherit Metab Dis 2006; 29: Suppl. 1: 16.Honzik Т., Tesarova M., Magner M. et al. Neonatal onset of mitochondrial dosorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. J Inherit Metab Dis 2012; 35: 749-759.Honzik Т., Tesarova M., Magner M. et al. Neonatal onset of mitochondrial dosorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. J Inherit Metab Dis 2012; 35: 749-759.Prokisch H, Andreoli C, Ahting U. et al. MitoP2: the mitochondrial proteome database—now including mouse data. Nucleic Acids Res 2006; 34: 705—711.Prokisch H, Andreoli C, Ahting U. et al. MitoP2: the mitochondrial proteome database—now including mouse data. Nucleic Acids Res 2006; 34: 705—711.Scharfe C, Homg-ShingLu H., NeuenburgJ.K. etal. Mapping gene associations in human mitochondria using clinical disease phenotypes. PLOS Computational Biology 2009; 5: 4: el000374.Scharfe C, Homg-ShingLu H., NeuenburgJ.K. etal. Mapping gene associations in human mitochondria using clinical disease phenotypes. PLOS Computational Biology 2009; 5: 4: el000374.Valente L., Tiranti V., Marsano R.M. et al. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factorsValente L., Tiranti V., Marsano R.M. et al. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factorsEFG1 and EFTu. Am J Hum Genet 2007; 80: 44—58.EFG1 and EFTu. Am J Hum Genet 2007; 80: 44—58.Cope land W.C. Inherited mitochondrial diseases of DNA replication. Annu Rev Med 2008; 59: 131—146.Cope land W.C. Inherited mitochondrial diseases of DNA replication. Annu Rev Med 2008; 59: 131—146.Angelini C, Bello L., Spinazzi M., Ferrati С Mitochondrial disorders of the nuclear genome Acta myologica 2009; 28: 16-23.Angelini C, Bello L., Spinazzi M., Ferrati С Mitochondrial disorders of the nuclear genome Acta myologica 2009; 28: 16-23.Smith P., Smeitink J., van den Heuvel L. Mitochondrial Translation and Beyond: Processes Implicated in Combined Oxidative Phosphorylation Deficiencies. J Biomed Biotechnol 2010; 2010: 737385. doi: 10.1155/2010/737385.Smith P., Smeitink J., van den Heuvel L. Mitochondrial Translation and Beyond: Processes Implicated in Combined Oxidative Phosphorylation Deficiencies. J Biomed Biotechnol 2010; 2010: 737385. doi: 10.1155/2010/737385.Chrzanowska-Lightowlers Z.M.A., Horvath R, Lightowlers R.N. 175th ENMC International Workshop: Mitochondrial protein synthesis in health and disease. 25—27th June 2010, Naarden, The Netherlands. Neuromuscular Disorders 2011; 21:2:142—147.Chrzanowska-Lightowlers Z.M.A., Horvath R, Lightowlers R.N. 175th ENMC International Workshop: Mitochondrial protein synthesis in health and disease. 25—27th June 2010, Naarden, The Netherlands. Neuromuscular Disorders 2011; 21:2:142—147.DiazF., Kotarsky H., Fellman V., Moraes C.T. Mitochondrial disorders caused by mutations in respiratory chain assembly factors. Semin Fetal Neonatal Med 2011; 16: 4: 197—204.DiazF., Kotarsky H., Fellman V., Moraes C.T. Mitochondrial disorders caused by mutations in respiratory chain assembly factors. Semin Fetal Neonatal Med 2011; 16: 4: 197—204.Kemp J.P., Smith P.M., Pyle A. et al. Nuclear factors involved in mitochondrial translation cause a subgroup of combined respiratory chain deficiency. Brain 2011; 134: Pt 1: 183—195.Kemp J.P., Smith P.M., Pyle A. et al. Nuclear factors involved in mitochondrial translation cause a subgroup of combined respiratory chain deficiency. Brain 2011; 134: Pt 1: 183—195.Koene S., Rodenburg R.J., van der Knaap M.S. et al. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis 2012; 35: 5: 737-747.Koene S., Rodenburg R.J., van der Knaap M.S. et al. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis 2012; 35: 5: 737-747.Wedatilake Y., Brown R.M., McFarland R. et al. SURF1 deficiency: a multi-centre natural history study. Orphanet J Rare Dis 2013; 8: 96. doi: 10.1186/1750-1172-8-96.Wedatilake Y., Brown R.M., McFarland R. et al. SURF1 deficiency: a multi-centre natural history study. Orphanet J Rare Dis 2013; 8: 96. doi: 10.1186/1750-1172-8-96.PatelK.P, O'Brien T.W., Subramony S.H. et al. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012; 105: 1:34-43.PatelK.P, O'Brien T.W., Subramony S.H. et al. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012; 105: 1:34-43.Spinazzola A., Viscomi C, Fernandez-Vizarra E. et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 2006; 38: 570-575.Spinazzola A., Viscomi C, Fernandez-Vizarra E. et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 2006; 38: 570-575.Rodenburg R. Biochemical diagnosis of mitochondrial disorders. J Inherit Metab Dis 2011; 34: 2: 283—292.Rodenburg R. Biochemical diagnosis of mitochondrial disorders. J Inherit Metab Dis 2011; 34: 2: 283—292.Николаева Е.А., Козина А.А., Леонтьева И.В. и др. Системное митохондриалыюе заболевание: проблема дифференциальной диагностики и лечения. Рос вестн пери-натол и педиат 2012; 4: 2: 36—43. (Nikolaeva E.A., Kozina А.А., Leont'eva I.V. et al. System mitochondrial disease: differential diagnosis and treatment problems. Ros vestn perinatol i pediatr 2012; 4: 2: 36—43).Николаева Е.А., Козина А.А., Леонтьева И.В. и др. Системное митохондриалыюе заболевание: проблема дифференциальной диагностики и лечения. Рос вестн пери-натол и педиат 2012; 4: 2: 36—43. (Nikolaeva E.A., Kozina А.А., Leont'eva I.V. et al. System mitochondrial disease: differential diagnosis and treatment problems. Ros vestn perinatol i pediatr 2012; 4: 2: 36—43).Wortmann S.B., Kluijtmans L.A., Rodenburg R.J. et al. 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. J Inherit Metab Dis 2013; 36: 6: 913—921.Wortmann S.B., Kluijtmans L.A., Rodenburg R.J. et al. 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. J Inherit Metab Dis 2013; 36: 6: 913—921.Wortmann S.B., Rodenburg R.J., Jonckheere A. et al. Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain 2009; 132: 1: 136-146.Wortmann S.B., Rodenburg R.J., Jonckheere A. et al. Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain 2009; 132: 1: 136-146.Wortmann S.B., Kluijtmans L.A., Engelke U. et al. The 3-methylglutaconic acidurias: what's new? J Inherit Metab Dis 2012; 35: 1:13-22.Wortmann S.B., Kluijtmans L.A., Engelke U. et al. The 3-methylglutaconic acidurias: what's new? J Inherit Metab Dis 2012; 35: 1:13-22.Spencer СТ., Bryant R.M., Day J. et al. Cardiac and clinical phenotype in Barth syndrome. Pediatrics 2006; 118:2: e337—346.Spencer СТ., Bryant R.M., Day J. et al. Cardiac and clinical phenotype in Barth syndrome. Pediatrics 2006; 118:2: e337—346.Riley L.G., Cooper S., Hickey P. et al. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia—MLASA syndrome. Am J Hum Genet 2010; 87: 1: 52—59.Riley L.G., Cooper S., Hickey P. et al. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia—MLASA syndrome. Am J Hum Genet 2010; 87: 1: 52—59.Николаева Е.А., Мамедов И.С. Дефицит коэнзима Q10 у детей: клинико-генетические варианты, диагностика и лечение. Рос вестн перинатол и педиатр 2012; 2: 77—83. (Nikolaeva E.A., Mamedov I.S. Q10 deficiency in children: clinical and genetic variants, diagnosis and treatment. Ros vestn perinatal i pediatr 2012; 2: 77—83).Николаева Е.А., Мамедов И.С. Дефицит коэнзима Q10 у детей: клинико-генетические варианты, диагностика и лечение. Рос вестн перинатол и педиатр 2012; 2: 77—83. (Nikolaeva E.A., Mamedov I.S. Q10 deficiency in children: clinical and genetic variants, diagnosis and treatment. Ros vestn perinatal i pediatr 2012; 2: 77—83).RahmanS., Clarke СF.,HiranoM. 176thENMCInternational Workshop: Diagnosis and treatment of coenzyme Q10 deficiency. Neuromuscular Disorders 2012; 22: 1: 76—86.RahmanS., Clarke СF.,HiranoM. 176thENMCInternational Workshop: Diagnosis and treatment of coenzyme Q10 deficiency. Neuromuscular Disorders 2012; 22: 1: 76—86.Freisinger P., Futterer N., Lankes E. et al. Hepatocerebral mitochondrial DNA depletion caused by deoxyguanosine kinase (DGUOK) mutations. J Inherit Metab Dis 2006; 29: Suppl. 1: 16.Freisinger P., Futterer N., Lankes E. et al. Hepatocerebral mitochondrial DNA depletion caused by deoxyguanosine kinase (DGUOK) mutations. J Inherit Metab Dis 2006; 29: Suppl. 1: 16.Wong L.J., Naviaux R.K., Brunetti-Pierri N. et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 2008; 29: 9: E150—172.Wong L.J., Naviaux R.K., Brunetti-Pierri N. et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 2008; 29: 9: E150—172.Михайлова СВ., Захарова Е.Ю., Банин А.В. и др. Клинические проявления и молекулярно-генетическая диагностика лейкоэнцефалопатии с преимущественным поражением ствола мозга, спинного мозга и повышенным лактатом у детей. Журн неврол и психиат 2009; 9: 16—22. (Mikhatlova S.V., Zakharova E.Iu., Banin A.V. et al. Clinical and molecular genetic diagnosis of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation in children. Zhurn nevrol i psikhiat 2009; 9: 16—22.)Михайлова СВ., Захарова Е.Ю., Банин А.В. и др. Клинические проявления и молекулярно-генетическая диагностика лейкоэнцефалопатии с преимущественным поражением ствола мозга, спинного мозга и повышенным лактатом у детей. Журн неврол и психиат 2009; 9: 16—22. (Mikhatlova S.V., Zakharova E.Iu., Banin A.V. et al. Clinical and molecular genetic diagnosis of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation in children. Zhurn nevrol i psikhiat 2009; 9: 16—22.)Liu Y.T., Hersheson J., Plagnol V. et al. Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation. J Neurol Neurosurg Psychiatry 2013; doi: 10.1136/jnnp-2013-306483.Liu Y.T., Hersheson J., Plagnol V. et al. Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation. J Neurol Neurosurg Psychiatry 2013; doi: 10.1136/jnnp-2013-306483.Milone M., Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist 2010; 16: 84—91.Milone M., Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist 2010; 16: 84—91.Михайлова СВ., Захарова Е.Ю., Цыганкова П.Г. и др. Клинический полиморфизм митохондриальных энце-фаломиопатий, обусловленных мутациями гена поли-меразы гамма. Рос вестн перинатол и педиат 2012; 4: 2: 36—43. (Mikhajlova S.V., Zakharova E.YU., Tsygankova P.G. et al. Clinical polymorphism of mitochondrial encephalomyopathies due to mutation of polymerase gamma gene. Ros vestn perinatal i pediat 2012; 4: 2: 36—43.)Михайлова СВ., Захарова Е.Ю., Цыганкова П.Г. и др. Клинический полиморфизм митохондриальных энце-фаломиопатий, обусловленных мутациями гена поли-меразы гамма. Рос вестн перинатол и педиат 2012; 4: 2: 36—43. (Mikhajlova S.V., Zakharova E.YU., Tsygankova P.G. et al. Clinical polymorphism of mitochondrial encephalomyopathies due to mutation of polymerase gamma gene. Ros vestn perinatal i pediat 2012; 4: 2: 36—43.)Yu-Wai-Man P., Griffiths P.G., Burke A. et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology 2010; 117: 8: 1538—1546.Yu-Wai-Man P., Griffiths P.G., Burke A. et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology 2010; 117: 8: 1538—1546.Ha A.D., Parratt KL, Rendtorff N.D. et al. The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome. Mov Disord2012; 27: 8: 1034-1040.Ha A.D., Parratt KL, Rendtorff N.D. et al. The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome. Mov Disord2012; 27: 8: 1034-1040.Bohlega S., Van Goethem G., Al SemariA. et al. Novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia and multisystem failure Neuromuscular Disorders 2009; 19: 12: 845—848.Bohlega S., Van Goethem G., Al SemariA. et al. Novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia and multisystem failure Neuromuscular Disorders 2009; 19: 12: 845—848.Lax N.Z., Whittaker R.G., Hepplewhite P.D. et al. Sensory neuronopathy in patients harbouring recessive polymerase Y mutations. Brain 2012; 135: Ptl: 62—71.Lax N.Z., Whittaker R.G., Hepplewhite P.D. et al. Sensory neuronopathy in patients harbouring recessive polymerase Y mutations. Brain 2012; 135: Ptl: 62—71.Massa R., Tessa A., Margollicci M. et al. Late-onset MNGIE without peripheral neuropathy due to incomplete loss ofthymidine phosphorylase activity. Neuromuscular Disorders 2009; 19: 12: 837—840.Massa R., Tessa A., Margollicci M. et al. Late-onset MNGIE without peripheral neuropathy due to incomplete loss ofthymidine phosphorylase activity. Neuromuscular Disorders 2009; 19: 12: 837—840.Al-Owain M., Colak D., Albakheet A. et al. Clinical and biochemical features associated with BCS1L mutation. J Inherit Metab Dis 2013; 36: 5: 813-820.Al-Owain M., Colak D., Albakheet A. et al. Clinical and biochemical features associated with BCS1L mutation. J Inherit Metab Dis 2013; 36: 5: 813-820.Flo J.M., Yadavalli S.S., Euro L. et al. Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum Mol Genet 2012; 21: 20:4521-4529.Flo J.M., Yadavalli S.S., Euro L. et al. Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum Mol Genet 2012; 21: 20:4521-4529.

The authors declare that there are no conflicts of interest present.