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The Genetics of Sleep Disorders in Childhood and Adolescence a Genética Dos Distúrbios Do Sono Na Infância E Adolescência Magda Lahorgue Nunes1, Oliviero Bruni2

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The Genetics of Sleep Disorders in Childhood and Adolescence a Genética Dos Distúrbios Do Sono Na Infância E Adolescência Magda Lahorgue Nunes1, Oliviero Bruni2 0021-7557/08/84-04-Supl/S27 Jornal de Pediatria Copyright © 2008 by Sociedade Brasileira de Pediatria ARTIGO DE REVISÃO The genetics of sleep disorders in childhood and adolescence A genética dos distúrbios do sono na infância e adolescência Magda Lahorgue Nunes1, Oliviero Bruni2 Resumo Abstract Objetivo: O objetivo deste artigo é revisar a literatura sobre a Objective: To review the literature regarding the genetics of genética dos distúrbios do sono na infância e adolescência. sleep disorders in childhood and adolescence. Fontes dos dados: As palavras-chave "sono" e "genética" foram Sources: Articles published in the past 5 years were searched usadas para pesquisar por artigos publicados nos últimos cinco anos no banco de dados MEDLINE. A seguir, seus resumos foram on MEDLINE using the keywords sleep and genetics. Abstracts were analisados. A pesquisa também incluiu artigos clássicos, com a then analyzed. Classical articles with the first description of genes primeira descrição dos genes. were also included. Síntese dos dados: A recorrência familiar de muitos distúrbios Summary of the findings: We often find familial recurrence in do sono é um achado freqüente, mas loci genéticos foram many sleep disorders. However, gene loci were discovered for only a descobertos para poucos deles. Descrevemos aqui distúrbios do sono few of them. We describe sleep disorders transmitted by genetic transmitidos por herança genética e também aqueles que heritance and also those in that, although a gene was not found, apresentam altos índices de recorrência familiar, apesar de nenhum gene específico haver sido encontrado. familial recurrence is high. Conclusões: Apesar da maioria dos distúrbios do sono ainda Conclusion: Although most of the sleep disorders do not have não terem uma base molecular identificada, técnicas modernas são by now an identified molecular basis, modern techniques are being cada vez mais utilizadas para determinar a contribuição dos genes increasingly applied to determine the contribution of genes to sleep ao sono e aos seus distúrbios associados. A importância clínica destas and its associated disorders. The clinical importance of these descobertas pode estar relacionada com a melhoria de métodos discoveries may relate not only to improving diagnostic methods but diagnósticos, mas também como alvo para o desenvolvimento de also as a target for drug development. medicações específicas. J Pediatr (Rio J). 2008;84(4 Supl):S27-32: Sono, genética, J Pediatr (Rio J). 2008;84(4 Suppl):S27-32: Sleep, genetics, narcolepsia, síndrome das pernas inquietas, parassônias, infância. narcolepsy, restless leg syndrome, parasomnias, childhood. Introdução base molecular do sono normal4-7. A pergunta sobre qual seria 5 Os distúrbios do sono (DS) são relatados freqüentemente a função do sono segue sem resposta na Biologia . durante a infância e adolescência. A história familiar positiva Muitos distúrbios do sono apresentam recorrência fami- é comum1. Devido a sua elevada prevalência podem repre- liar, mas até hoje a pesquisa sobre a genética molecular dos sentar uma epidemia mundial emergente2. distúrbios do sono continua sendo, surpreendentemente, um dos últimos campos ativos2. A importância do diagnóstico e tratamento dos distúrbios Os estudos genéticos geralmente se restringem à narco- do sono em crianças depende, entre outros fatores, dos acha- lepsia, à síndrome das pernas inquietas (SPI) e a apnéia obs- dos sobre a influência do sono e do temperamento na vida trutiva do sono. escolar3. Nos últimos anos, muitos genes foram associados a mui- Em contraste com o progresso impressionante da gené- tas doenças. O mapeamento destas alterações facilitou a iden- tica molecular dos ritmos circadianos, pouco se sabe sobre a tificação de pessoas afetadas, melhorou a compreensão de 1. MD, PhD. Associate professor, Faculdade de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS. 2. MD. Assistant professor, Center for Pediatric Sleep Disorders, Department of Developmental Neurology and Psychiatry, Faculty of Medicine, Sapienza Univer- sity, Rome, Italy. Apoio financeiro: O primeiro autor recebe apoio do CNPq (processo nº 300742 -2007). Não foram declarados conflitos de interesse associados à publicação deste artigo. Como citar este artigo: Nunes ML, Bruni O. The genetics of sleep disorders in childhood and adolescence. J Pediatr (Rio J). 2008;84(4 Suppl):S27-32. doi:10.2223/JPED.1786 S27 28S28 Jornal de Pediatria - Vol. 84, Nº 4 (Supl), 2008 Genética dos distúrbios do sono - Nunes ML & Bruni O seu prognóstico e funcionou como novos alvos para o desen- qualquer momento e determine os ataques catalépticos9. volvimento de medicações. Estes achados permitem uma nova compreensão da patofi- siologia da narcolepsia: uma característica genética especí- O objetivo deste artigo é revisar a literatura sobre a gené- fica (a mutação de HLA no cromossomo 6) pode aumentar a tica dos distúrbios do sono na infância e adolescência para susceptibilidade dos neurônios que contêm hipocretina a ata- permitir a melhor compreensão destes distúrbios e para orien- ques imunes. A hipótese mais provável para a narcolepsia é tar o pediatra generalista em direção ao seu diagnóstico e um processo auto-imune que atinge os neurônios de hipocre- prognóstico. tina em resposta a fatores ambientais desconhecidos Metodologia 9-11,13,14. Dentro desta perspectiva, os neurologistas e pedia- Foi realizada revisão da literatura sobre o tema no banco tras devem estar cientes que o tratamento inicial com imuno- de dados MEDLINE, usando-se uma combinação das palavras- globulinas em crianças e adolescentes recém-diagnosticados chave "sono" e "genética", e a seguir uma busca isolada pelas com narcolepsia pode atrasar o avanço da doença e até palavras-chave "narcolepsia", "apnéia do sono" e "síndrome mesmo limitar ou evitar a necessidade de tratamento crônico das pernas inquietas". Os resumos foram analisados e os arti- com anfetaminas, agentes promotores de vigília (modafinil) 15 gos que continham informações sobre a faixa etária pediá- ou antidepressivos . trica foram incluídos. A pesquisa também incluiu artigos Recentemente, foi proposto que a regulação negativa do clássicos, com a primeira descrição dos genes envolvidos em gene Mx2 nas células brancas do sangue de pacientes narco- DS. lépticos e a expressão do gene NLC1-A em uma região espe- Resultados cífica do cromossomo 21 (21q22.3) são novos fatores 16,17 Narcolepsia genéticos relacionados com a narcolepsia . No entanto, o gene DQB1*0602 continua sendo o melhor marcador de HLA A narcolepsia é um distúrbio crônico do sono que ocorre para todos os grupos étnicos8,18. com predominância levemente maior em indivíduos do sexo masculino, entre a infância e a quinta década de vida, atin- Síndrome do avanço da fase do sono e síndrome do gindo seu clímax na segunda década. A doença é caracteri- atraso da fase do sono zada por uma tétrade de sintomas relativos à ocorrência de O sono é regulado por um processo homeostático que sono REM (sono com movimento rápido dos olhos) em determina sua necessidade e por um processo circadiano que momentos inadequados: sonolência diurna excessiva, cate- determina sua freqüência19. O ciclo vigília-sono é controlado plexia (queda abrupta com perda de tônus muscular, sem pelo relógio circadiano, e o primeiro gene do relógio a ser iso- perda de consciência, geralmente provocada por emoções lado (Clock, per) foi identificado em uma mosca drosophila. como riso, raiva ou surpresa), paralisia do sono (experiência Mais tarde, contrapartes homólogas foram encontradas em aterradora que ocorre ao início do sono ou ao acordar,em que mamíferos20. o paciente se descobre subitamente incapaz de se mover,falar ou respirar profundamente) e alucinações hipnagógicas/ Recentemente, dois genes envolvidos em distúrbios cir- hipnopômpicas (sonhos vívidos que podem ser difíceis de dis- cadianos do sono foram descobertos 21. A síndrome do atraso tinguir da realidade e alucinações auditivas, visuais ou de fase do sono (SAFS) é caracterizada pelo atraso do início cenestopáticas que ocorrem no começo do sono , tanto diurno do sono e pela demora para acordar (3-6 horas) em relação como noturno)8,9. aos horários convencionais para as duas ações. Os pacientes A ocorrência familiar de narcolepsia-cataplexia foi rela- típicos normalmente não adormecem antes das 2h da manhã tada pela primeira vez em 1877, por Westphal8. No entanto, e não acordam antes das 10-12h, apesar da arquitetura do a observação da associação da narcolepsia com o antígeno sono poder ser considerada normal. Os pacientes normal- do leucócito humano (HLA) DR2 foi relatada pela primeira vez mente relatam estarem mais alertas durante a noite do que no Japão, cem anos depois8. Mais de 85% de todos os narco- durante a manhã. Quando o paciente é forçado a acordar mais lépticos com cataplexia definida compartilham de uma muta- cedo devido a compromissos escolares, o resultado pode ser ção (um alelo de HLA) no cromossomo 6, seja apenas no HLA a insuficiência crônica de sonoeoexcesso de sonolência DQB1*0602 ou em conjunto com HLA DR15. Mais tarde, em diurna. Esta é uma das reclamações mais freqüentes na ado- 1999, um segundo gene, a orexina (hipocretina), localizado lescência, associada também a problemas de desempenho no cromossomo 12, foi relacionado com a narcolepsia em um escolar1,20. O atraso de fase de sono está associado ao poli- modelo canino8. As hipocretinas/orexinas são novos neuro- morfismo em Per3. A síndrome do avanço de fase do sono é peptídeos hipotalâmicos envolvidos nas funções neuroendó- caracterizada por horários de início de sono e de acordar habi- crina e de homeostase de energia10. A deficiência de ligação tual e involuntariamente mais cedo do que a média da socie- de hipocretina é observada em muitos pacientes narcolépti- dade. Esta síndrome, menos comum do que a SAFS, cos com cataplexia 11,12. Já que a hipocretina geralmente par- geralmente ocorre na faixa etária pediátrica19 e é causada por ticipa da manutenção da vigília, a perda dos neurônios que uma mutação pontual em um gene do relógio biológico liberam este peptídeo pode permitir que o sono REM ocorra a (Per2)21.
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