Russian Journal of Child NeurologyRussian Journal of Child NeurologyРусский журнал детской неврологии2073-88032412-9178Publishing House ABV Press22810.17650/2073-8803-2017-12-3-58-67CLINICAL OBSERVATIONSКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯMUTATIONS IN THE ARX GENE: CLINICAL, ELECTROENCEPHALOGRAPHIC AND NEUROIMAGING FEATURES IN 3 PATIENTSМутации в гене ARX: клинические, электроэнцефалографические и нейровизуализационные особенности у 3 пациентовIvanovaI. V.ИвановаИ. В.
Russian Federation

5 Nagornaya St., Troitsk, Moscow 108840

108840 Москва, Троицк, ул. Нагорная, 5

driraivanova@gmail.comMukhinK. Yu.МухинК. Ю.
Russian Federation

5 Nagornaya St., Troitsk, Moscow 108840

108840 Москва, Троицк, ул. Нагорная, 5;

119579 Москва, ул. Академика Анохина, 9

PylaevaO. A.ПылаеваО. А.
Russian Federation

5 Nagornaya St., Troitsk, Moscow 108840

108840 Москва, Троицк, ул. Нагорная, 5;

119579 Москва, ул. Академика Анохина, 9

BobylovaM. Yu.БобыловаМ. Ю.
Russian Federation

9 Akademika Anokhina St., Moscow 119579

108840 Москва, Троицк, ул. Нагорная, 5;

119579 Москва, ул. Академика Анохина, 9

KvaskovaN. E.КвасковаН. Е.
Russian Federation

5 Nagornaya St., Troitsk, Moscow 108840

108840 Москва, Троицк, ул. Нагорная, 5

PetrukhinA. S.ПетрухинА. С.
Russian Federation

9 Akademika Anokhina St., Moscow 119579

119579 Москва, ул. Академика Анохина, 9

Svt. Luka’s Institute of Child Neurology and EpilepsyООО «Институт детской неврологии и эпилепсии им. Святителя Луки»ООО «Институт детской и взрослой неврологии и эпилепсии им. Святителя Луки»Svt. Luka’s Institute of Child Neurology and EpilepsyООО «Институт детской неврологии и эпилепсии им. Святителя Луки»Svt. Luka’s Institute of Child and Adult Neurology and EpilepsyООО «Институт детской и взрослой неврологии и эпилепсии им. Святителя Луки»ООО «Институт детской неврологии и эпилепсии им. Святителя Луки»1507201712358670112201701122017Copyright ©; 2017, ABV-PressCopyright ©; 2017, АБВ-пресс2017ABV-PressАБВ-прессhttps://rjdn.abvpress.ru/jour/about/editorialPolicieshttps://rjdn.abvpress.ru/jour/article/view/228

The Aristaless-related homeobox (ARX) gene is a member of the paired-type homeodomain transcription factor family with critical roles in embryonic development, particularly in the developing brain. Mutations in ARX gene demonstrate striking intra- and interfamilial pleiotropy together with genetic heterogeneity and lead to a broad spectrum of diseases. They give rise to 4 key phenotypic features: a different types of brain malformation, abnormal genitalia, epilepsy and intellectual disability. Authors present 3 clinical cases: a girl with duplication on the short arm of X-chromosome (Xp11.22-p22.33), which include genes ARX and CDKL5; a girl and a boy with a missense mutation in ARX gene that have not been previously described (chrX:25031522C>A), causes the substitution of an amino acid in the 197 protein position (p.Gly197Val, NM_139058.2). All patients suffer from severe epilepsy, that is refractory to antiepileptic drugs, and all of them have different degrees of psychomotor delay. The patients with missense mutation also have movement disorders: stereotypic movements in the girl and choreo athetosis and dystonia in the boy. Electroencephalographic abnormalities have been identified in all patients, and there were not significant abnormalities on magnetic resonance imaging in all cases. The described cases broaden the clinical spectrum of mutations in ARX gene.

ARX geneduplicationmissense-mutationepilepsyintellectual disabilitymovement disordersген ARXдупликациямиссенс-мутацияэпилепсияумственная отсталостьдвигательные нарушения1. Белоусова Е.Д. Генетика эпилепсии: зачем и как обследовать детей с эпилепсией. Неврология, нейропсихиатрия, психосоматика 2014;(спецвыпуск 1):4–8. [Belousova E.D. Genetics of epilepsy: why and how to examine children with epilepsy. Neurology, neuropsychiatry, psychosomatics 2014;(special issue 1):4–8. (In Russ.)].Белоусова Е.Д. Генетика эпилепсии: зачем и как обследовать детей с эпилепсией. Неврология, нейропсихиатрия, психосоматика 2014;(спецвыпуск 1):4–8. [Belousova E.D. Genetics of epilepsy: why and how to examine children with epilepsy. Neurology, neuropsychiatry, psychosomatics 2014;(special issue 1):4–8. (In Russ.)].2. Мухин К.Ю., Миронов М.Б., Петрухин А.С. Эпилептические синдромы. Диагностика и терапия. 3-е изд. М.: ООО «Системные решения», 2014. С. 353–364. [Mukhin K.Yu., Mironov M.B., Petrukhin A.S. Epileptic syndromes. Diagnostics and therapy. 3rd edn. Moscow: Systemnye Resheniya LLC, 2014. Pp. 353–364. (In Russ.)].Мухин К.Ю., Миронов М.Б., Петрухин А.С. Эпилептические синдромы. Диагностика и терапия. 3-е изд. М.: ООО «Системные решения», 2014. С. 353–364. [Mukhin K.Yu., Mironov M.B., Petrukhin A.S. Epileptic syndromes. Diagnostics and therapy. 3rd edn. Moscow: Systemnye Resheniya LLC, 2014. Pp. 353–364. (In Russ.)].3. Холин А.А., Мухин К.Ю. Ранняя (неонатальная) миоклоническая энцефалопатия. В кн.: Эпилептические энцефалопатии и схожие синдромы у детей. М.: АртСервис ЛТД, 2011. 680 с. [Kholin A.A., Mukhin K.Yu. Early (neonatal) myoclonic encephalopathy. In: Epileptic encephalopathies and similar syndromes of children. Moscow: ArtService LTD, 2011. 680 p. (In Russ.)].Холин А.А., Мухин К.Ю. Ранняя (неонатальная) миоклоническая энцефалопатия. В кн.: Эпилептические энцефалопатии и схожие синдромы у детей. М.: АртСервис ЛТД, 2011. 680 с. [Kholin A.A., Mukhin K.Yu. Early (neonatal) myoclonic encephalopathy. In: Epileptic encephalopathies and similar syndromes of children. Moscow: ArtService LTD, 2011. 680 p. (In Russ.)].4. Bienvenu T., Poirier K., Friocourt G. et al. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 2002;11(8):981–91. PMID: 11971879.Bienvenu T., Poirier K., Friocourt G. et al. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 2002;11(8):981–91. PMID: 11971879.5. Colasante G., Sessa A., Crispi S. et al. ARX acts as a regional key selector gene in the ventral telencephalon mainly through its transcriptional repression activity. Dev Biol 2009;334(1):59–71. DOI: 10.1016/j.ydbio.2009.07.014.Colasante G., Sessa A., Crispi S. et al. ARX acts as a regional key selector gene in the ventral telencephalon mainly through its transcriptional repression activity. Dev Biol 2009;334(1):59–71. DOI: 10.1016/j.ydbio.2009.07.014.6. Curie A., Nazir T., Brun A. et al. The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia. Orphanet J Rare Dis 2014;9:25. DOI: 10.1186/1750-1172-9-25.Curie A., Nazir T., Brun A. et al. The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia. Orphanet J Rare Dis 2014;9:25. DOI: 10.1186/1750-1172-9-25.7. Ekşioğlu Y.Z., Pong A.W., Takeoka M. A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay and ambiguous genitalia in males and neuropsychiatric disorders in females. Epilepsia 2011;52(5):984–92. DOI: 10.1111/j.1528-1167.2011.02980.x.Ekşioğlu Y.Z., Pong A.W., Takeoka M. A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay and ambiguous genitalia in males and neuropsychiatric disorders in females. Epilepsia 2011;52(5):984–92. DOI: 10.1111/j.1528-1167.2011.02980.x.8. Escamilla-Del-Arenal M., da Rocha S.T., Heard E. Evolutionary diversity and developmental regulation of X-chromosome inactivation. Hum Genet 2011;130(2):307–27. DOI: 10.1007/s00439-011-1029-2.Escamilla-Del-Arenal M., da Rocha S.T., Heard E. Evolutionary diversity and developmental regulation of X-chromosome inactivation. Hum Genet 2011;130(2):307–27. DOI: 10.1007/s00439-011-1029-2.9. Fulp C.T., Cho G., Marsh E.D. et al. Identification of ARX transcriptional targets in the developing basal forebrain. Hum Mol Genet 2008;17(23):3740–60. DOI: 10.1093/hmg/ddn271.Fulp C.T., Cho G., Marsh E.D. et al. Identification of ARX transcriptional targets in the developing basal forebrain. Hum Mol Genet 2008;17(23):3740–60. DOI: 10.1093/hmg/ddn271.10. Gecz J., Cloosterman D., Partington M. ARX: a gene for all seasons. Curr Opin Genet Dev 2006;16(3):308–16. DOI: 10.1016/j.gde.2006.04.003.Gecz J., Cloosterman D., Partington M. ARX: a gene for all seasons. Curr Opin Genet Dev 2006;16(3):308–16. DOI: 10.1016/j.gde.2006.04.003.11. Guerrini R., Moro F., Kato M. et al. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology 2007;69(5):427–33. DOI: 10.1212/01.wnl.0000266594.16202.c1.Guerrini R., Moro F., Kato M. et al. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology 2007;69(5):427–33. DOI: 10.1212/01.wnl.0000266594.16202.c1.12. Hartmann H., Uyanik G., Gross C. et al. Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene. Neuropediatrics 2004;35(3):157–60. DOI: 10.1055/s-2004-817919.Hartmann H., Uyanik G., Gross C. et al. Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene. Neuropediatrics 2004;35(3):157–60. DOI: 10.1055/s-2004-817919.13. Kato M., Das S., Petras K. et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype–phenotype correlation. Hum Mutat 2004;23(2):147–59. DOI: 10.1002/ humu.10310.Kato M., Das S., Petras K. et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype–phenotype correlation. Hum Mutat 2004;23(2):147–59. DOI: 10.1002/ humu.10310.14. Kitamura K., Yanazawa M., Sugiyama N. et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 2002;32(3):359–69. DOI: 10.1038/ng1009.Kitamura K., Yanazawa M., Sugiyama N. et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 2002;32(3):359–69. DOI: 10.1038/ng1009.15. Kwong A.K., Ho A.C., Fung C.W., Wong V.C. Analysis of mutations in 7 genes associated with neuronal excitability and synaptic transmission in a cohort of children with non-syndromic infantile epileptic encephalopathy. PLoS One 2015;10(5):e0126446. DOI: 10.1371/journal.pone.0126446.Kwong A.K., Ho A.C., Fung C.W., Wong V.C. Analysis of mutations in 7 genes associated with neuronal excitability and synaptic transmission in a cohort of children with non-syndromic infantile epileptic encephalopathy. PLoS One 2015;10(5):e0126446. DOI: 10.1371/journal.pone.0126446.16. Mirzaa G.M., Paciorkowski A.R., Marsh E.D. et al. CDKL5 and ARX mutations in males with early-onset epilepsy. Pediatr Neurol 2013;48(5):367–77. DOI: 10.1016/j.pediatrneurol.2012.12.030.Mirzaa G.M., Paciorkowski A.R., Marsh E.D. et al. CDKL5 and ARX mutations in males with early-onset epilepsy. Pediatr Neurol 2013;48(5):367–77. DOI: 10.1016/j.pediatrneurol.2012.12.030.17. Miura H., Yanazawa M., Kato K., Kitamura K. Expression of a novel Aristaless-related homeobox gene ARX in the vertebrate telencephalon, diencephalon and floor plate. Mech Dev 1997;65(1–2):99–109. PMID: 9256348.Miura H., Yanazawa M., Kato K., Kitamura K. Expression of a novel Aristaless-related homeobox gene ARX in the vertebrate telencephalon, diencephalon and floor plate. Mech Dev 1997;65(1–2):99–109. PMID: 9256348.18. Oegema R., Maat-Kievit A., Lequin M.H. et al. Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX. Am J Med Genet A 2012;158A(6):1472–6. DOI: 10.1002/ajmg.a.35365.Oegema R., Maat-Kievit A., Lequin M.H. et al. Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX. Am J Med Genet A 2012;158A(6):1472–6. DOI: 10.1002/ajmg.a.35365.19. Olivetti P.R., Noebels J.L. Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Curr Opin Neurobiol 2012;22(5):859–65. DOI: 10.1016/j.conb.2012.04.006.Olivetti P.R., Noebels J.L. Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Curr Opin Neurobiol 2012;22(5):859–65. DOI: 10.1016/j.conb.2012.04.006.20. Partington M.W., Turner G., Boyle J., Gécz J. Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. Clin Genet 2004;66(1):39–45. DOI: 10.1111/j.0009-9163.2004.00268.x.Partington M.W., Turner G., Boyle J., Gécz J. Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. Clin Genet 2004;66(1):39–45. DOI: 10.1111/j.0009-9163.2004.00268.x.21. Popovici C., Busa T., Boute O. et al. Whole ARX gene duplication is compatible with normal intellectual development. Am J Med Genet A 2014;164A(9):2324–7. DOI: 10.1002/ajmg.a.36564.Popovici C., Busa T., Boute O. et al. Whole ARX gene duplication is compatible with normal intellectual development. Am J Med Genet A 2014;164A(9):2324–7. DOI: 10.1002/ajmg.a.36564.22. Sherr E.H. The ARX story (epilepsy, mental retardation, autism and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr 2003;15(6):567–71. PMID: 14631200.Sherr E.H. The ARX story (epilepsy, mental retardation, autism and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr 2003;15(6):567–71. PMID: 14631200.23. Shoubridge C., Fullston T., Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat 2010;31(8):889–900. DOI: 10.1002/humu.21288.Shoubridge C., Fullston T., Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat 2010;31(8):889–900. DOI: 10.1002/humu.21288.24. Strømme P., Mangelsdorf M.E., Scheffer I.E., Gécz J. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless-related homeobox gene, ARX. Brain Dev 2002;24(5):266–8. PMID: 12142061.Strømme P., Mangelsdorf M.E., Scheffer I.E., Gécz J. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless-related homeobox gene, ARX. Brain Dev 2002;24(5):266–8. PMID: 12142061.25. Strømme P., Mangelsdorf M.E., Shaw M.A. et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 2002;30(4):441–5. DOI: 10.1038/ng862.Strømme P., Mangelsdorf M.E., Shaw M.A. et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 2002;30(4):441–5. DOI: 10.1038/ng862.26. Sunnen C.N., Simonet J.C., Marsh E.D., Golden J.A. ARX is required for specification of the zonaincerta and reticular nucleus of the thalamus. J Neuropathol Exp Neurol 2014;73(3):253–61. DOI: 10.1097/NEN.0000000000000048.Sunnen C.N., Simonet J.C., Marsh E.D., Golden J.A. ARX is required for specification of the zonaincerta and reticular nucleus of the thalamus. J Neuropathol Exp Neurol 2014;73(3):253–61. DOI: 10.1097/NEN.0000000000000048.27. Uyanik G., Aigner L., Martin P. et al. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology 2003;61(2):232–5. PMID: 12874405.Uyanik G., Aigner L., Martin P. et al. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology 2003;61(2):232–5. PMID: 12874405.28. Vogt D., Hunt R.F., Mandal S. et al. Lhx6 directly regulates ARX and CXCR7 to determine cortical interneuron fate and laminar position. Neuron 2014;82(2):350–64. DOI: 10.1016/j.neuron.2014.02.030.Vogt D., Hunt R.F., Mandal S. et al. Lhx6 directly regulates ARX and CXCR7 to determine cortical interneuron fate and laminar position. Neuron 2014;82(2):350–64. DOI: 10.1016/j.neuron.2014.02.030.29. Wallerstein R., Sugalski R., Cohn L. et al. Expansion of the ARX spectrum. Clin Neurol Neurosurg 2008;110(6):631–4. DOI: 10.1016/j.clineuro.2008.03.007.Wallerstein R., Sugalski R., Cohn L. et al. Expansion of the ARX spectrum. Clin Neurol Neurosurg 2008;110(6):631–4. DOI: 10.1016/j.clineuro.2008.03.007.30. Yue W., Cheng W., Liu Z. et al. Genomewide DNA methylation analysis in obsessive-compulsive disorder patients. Sci Rep 2016;6:31333. DOI: 10.1038/srep31333.Yue W., Cheng W., Liu Z. et al. Genomewide DNA methylation analysis in obsessive-compulsive disorder patients. Sci Rep 2016;6:31333. DOI: 10.1038/srep31333.