Russian Journal of Child NeurologyRussian Journal of Child NeurologyРусский журнал детской неврологии2073-88032412-9178Publishing House ABV Press35310.17650/2073-8803-2020-15-3-4-65-77REVIEWS AND LECTURESОБЗОРЫ И ЛЕКЦИИCongenital cerebral palsy: genetic cause and nosological integrityВрожденные церебральные параличи: генетическая природа и нозологическая целостностьSokolovP. I.СоколовП. Л.
Russian Federation

38 Aviatorov St., Moscow 119620

119620 Москва, ул. Авиаторов, 38

https://orcid.org/0000-0002-7231-0249ChebanenkoN. V.ЧебаненкоН. В.
Russian Federation

Build. 1, 2/1 Barrikadnaya St., Moscow 125993

Наталья Владимировна Чебаненко

125993 Москва, ул. Баррикадная, 2 / 1, стр. 1

nataqwe@yandex.ruhttps://orcid.org/0000-0002-1401-5479ZykovV. P.ЗыковВ. П.
Russian Federation

Build. 1, 2/1 Barrikadnaya St., Moscow 125993

125993 Москва, ул. Баррикадная, 2 / 1, стр. 1

KanivetsI. V.КанивецИ. В.
Russian Federation

Build. 1, 2/1 Barrikadnaya St., Moscow 125993

8 Podolskoe shosse, Moscow 115093

125993 Москва, ул. Баррикадная, 2 / 1, стр. 1

115093 Москва, Подольское шоссе, 8

PritykoA. G.ПритыкоА. Г.
Russian Federation

38 Aviatorov St., Moscow 119620

119620 Москва, ул. Авиаторов, 38

RomanovP. A.РомановП. А.
Russian Federation

38 Aviatorov St., Moscow 119620

119620 Москва, ул. Авиаторов, 38

V.F. Voyno-Yasenetskiy Research and Practical Center of Specialized Care for Children, Moscow Healthcare DepartmentГБУЗ «Научно-практический центр специализированной медицинской помощи детям им. Н. В. Войно-Ясенецкого Департамента здравоохранения г. Москвы»Russian Medical Academy of Postgraduate Education, Ministry of Health of RussiaФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава РоссииGenomed LLCООО «Геномед»15122020153-465772602202126022021Copyright ©; 2020, ABV-PressCopyright ©; 2020, АБВ-пресс2020ABV-PressАБВ-прессhttps://rjdn.abvpress.ru/jour/about/editorialPolicieshttps://rjdn.abvpress.ru/jour/article/view/353

The review provides an analysis of 73 full-text articles, the source of which was the Medline, OMIM, NCBI, Pubmed, Scopus, eLibrary.ru databases. The data of studies of the main pathogenetic mechanisms of the formation of the cerebral palsy (CP) phenotype, such as chromosomal aberrations, copy number variations, single nucleotide polymorphisms, associated with the development of the CP phenotype, are reviewed and analyzed. Epigenetic effects on the genome, as well as the effects of the genome on the mechanisms of epigenomic regulation, are examined in detail. The data on the genetic determinism of concomitant pathology and reactivity to therapeutic tactics are presented. Based on the study of data from numerous studies, the authors draw the following conclusions:

1) the pathogenesis of the phenotype of CP includes a large number of genes that determine violations of cellular metabolism, neuroontogenesis, brain resistance to hypoxia, etc;

2) genes whose abnormalities form a syndromic pathology are involved in the pathogenesis of CP;

3) the multidirectionality and breadth of the effects of the gene pool with the outcome in a syndrome-specific distinctive picture of the CP allows us to propose the concept of a neurotropic genome;

4) the mechanisms of gene involvement can vary from aberrations to epigenetic imbalances;

5) different groups of genes can differentially influence the formation of individual syndromes in the phenotype of CP;

6) there are data indicating a genetic determinism of the tendency to contracture, pharmacoreactivity to drugs that reduce muscle tone, reactivity to habilitation effects;

7) genomic-epigenomic interactions normally ensure the body’s adaptation to environmental conditions, and with pathology, they increase the likelihood of regulatory breakdowns that lead to the formation of a CP phenotype;

8) the exclusion from the diagnosis of CP of genetically determined cases of phenotype development is incorrect.

The authors present two anthropogenic reasons for the increase in the frequency of occurrence of de novo identified gene abnormalities:

1) anthropogenic impact on the environment, increasing the number of anomalies of the genome de novo; 2) iatrogenic effects of technologies for preserving life, vitality and reproductive ability of carriers of genomic anomalies. This effect leads to the fixation of anomalies in the genome of the population.

A paradox is formulated, according to which, in the presence of technologies capable of preserving the life of carriers of genomic anomalies, in vivo technologies for genome correction are only just beginning to be put into practice. Based on this, it is concluded that it is necessary to intensify the development of methods for prenatal diagnosis and gene therapy of CP.

В обзоре представлен анализ 73 полнотекстовых статей, источником которых были базы Medline, OMIM, NCBI, Pubmed, Scopus, eLibrary.ru. Рассмотрены и проанализированы данные исследований основных патогенетических механизмов формирования фенотипа церебральных параличей (ЦП): несбалансированных хромосомных аномалий, однонуклеотидных структурных вариантов в ядерном и митохондриальном геноме полиморфизмов, ассоциированных с развитием фенотипа ЦП. Подробно рассмотрены эпигенетические влияния на геном, а также влияния генома на механизмы эпигеномного регулирования. Приведены данные о генетической детерминированности сопутствующей патологии и реактивности на лечебные тактики. Детальное изучение использованных материалов позволило авторам прийти к следующим заключениям:

1) в патогенез фенотипа ЦП включено большое количество генов, детерминирующих нарушения клеточного метаболизма, нейроонтогенеза, устойчивость мозга к гипоксии и др.;

2) вовлечению в патогенез ЦП подвержены в том числе гены, аномалии которых формируют описанную синдромальную патологию;

3) разнонаправленность и широта воздействия пула генов с исходом в синдромологически отчетливую конкретную картину ЦП позволяют предложить концепцию нейротропного генома;

4) механизмы вовлечения известного на настоящий момент ассоциированного с ЦП пула генов могут быть различными – от несбалансированных хромосомных аномалий до нарушения регуляции геномно-эпигеномных взаимодействий;

5) различные группы генов могут дифференцированно влиять на формирование отдельных синдромов в общей картине фенотипа ЦП;

6) имеются данные, указывающие на генетическую детерминированность склонности к контрактурообразованию, фармакореактивности на препараты, снижающие мышечный тонус, реактивности на абилитационное воздействие;

7) геномно-эпигеномные взаимовлияния, в норме обеспечивающие максимальную эффективность адаптации организма к условиям окружающей среды, при патологии увеличивают вероятность возникновения регуляторных поломок, которые, затрагивая компетентные гены, приводят к формированию фенотипа ЦП;

8) разделение фенотипов ЦП по принципу генетической детерминированности и исключение из диагноза ЦП генетически детерминированных случаев развития фенотипа некорректно.

В качестве причины увеличения частоты встречаемости ЦП выделяются 2 группы антропогенных влияний на рост числа мутаций и иных генных аномалий, выявляемых de novo в процессе исследований: 1) антропогенное воздействие на окружающую среду, увеличивающее количество аномалий генома de novo; 2) антропогенное (в том числе ятрогенное) воздействие посредством технологий, направленных на сохранение жизни, жизнеспособности и репродуктивной способности носителей аномалий генома, приводящее к фиксации этих аномалий в геноме популяции. Сформулирован парадокс, согласно которому при наличии технологий, способных сохранять жизнь носителям аномального генома, технологии коррекции генома in vivo только начинают вводиться в практику. На основании этого делается вывод о необходимости активизации поисков воздействия на геном и эпигеном как единственно возможных вариантов снижения частоты развития ЦП за счет активного предупреждения на пренатальном этапе и эффективной коррекции формирующегося фенотипа.

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