Este estudo foi idealizado para avaliar as características clinicas e laboratoriais de uma população de narcolépticos atendidos num centro de referência na cidade de São Paulo (Brasil). MÉTODO: 28 pacientes realizaram polissonografia e teste de múltiplas latências do sono segundo critérios internacionais. O alelo HLADQB1*0602 foi identificado por PCR. A Hipocretina-1 no líquido cefalorradiano (LCR) foi mensurada por radioimunoensaio. Os pacientes foram divididos em 2 grupos conforme o nível de Hipocretina-1. Normal (N) - Hypocretin-1 >110pg/ml e baixa (B) - Hypocretina-1 <110pg/ml. RESULTADOS: Somente 4 pacientes do grupo N tinham cataplexia quando comparados com 14 pacientes do grupo B (p=0,0002). DISCUSSÃO: Estes resultados foram comparáveis com outros autores, confirmando a utilidade do uso de biomarcadores específicos (HLA-DQB1*0602 e nível da hipocretina-1 no LCR) em narcolepsia com cataplexia. Porém, o alelo HLADQB1*0602 e a dosagem da Hipocretina-1 são insuficientes para o diagnóstico da narcolepsia sem cataplexia.

This study was thought to characterized clinical and laboratory findings of a narcoleptic patients in an out patients unit at São Paulo, Brazil. METHOD: 28 patients underwent polysomnographic recordings (PSG) and Multiple Sleep Latency Test (MSLT) were analyzed according to standard criteria. The analysis of HLADQB1*0602 allele was performed by PCR. The Hypocretin-1 in cerebral spinal fluid (CSF) was measured using radioimmunoassay. Patients were divided in two groups according Hypocretin-1 level: Normal (N) - Hypocretin-1 higher than 110pg/ml and Lower (L) Hypocretin-1 lower than 110 pg/ml. RESULTS: Only 4 patients of the N group had cataplexy when compared with 14 members of the L group (p=0.0002). DISCUSSION: This results were comparable with other authors, confirming the utility of using specific biomarkers (HLA-DQB1*0602 allele and Hypocretin-1 CSF level) in narcolepsy with cataplexy. However, the HLADQB1*0602 allele and Hypocretin-1 level are insufficient to diagnose of narcolepsy without cataplexy.

Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1) in people with extreme diurnal preferences (morning or evening). We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology.

OBJETIVO: Revisar resumidamente a literatura dos últimos 36 anos de pesquisa em cronobiologia molecular a fim de informar aos profissionais de saúde os avanços obtidos nesta área e os potenciais para aplicação na clínica médica. MÉTODO: Buscas na literatura foram realizadas utilizando as bases de dados PubMed e Scopus usando como palavras-chave "clock genes, circadian rhythms, diurnal preference, delayed sleep phase syndrome, advanced sleep phase syndrome, photoperiod and mood disorder". DISCUSSÃO: Atualmente, o mecanismo molecular da regulação da ritmicidade circadiana é compreendido em grande detalhe. Muitos estudos publicados mostram associações de polimorfismos nos genes relógio com transtornos do ritmo circadiano e com transtornos do humor. CONCLUSÕES: De maneira geral, o progresso obtido na área de cronobiologia molecular traz um melhor entendimento da regulação do sistema de temporização biológico. O desenvolvimento de estudos nesta área tem o potencial de ser aplicável ao tratamento dos transtornos dos ritmos circadianos e certos transtornos do humor, além de prevenir riscos à saúde causados por viagens intercontinentais (Jet Lag) e por trabalhos noturnos e por turnos.

OBJECTIVE: The aim of this study was to review the molecular chronobiology studies in the last 36 years in order Eto point out the advances in this area to health professionals. METHOD: We searched in the PubMed and Scopus data banks for articles related with human molecular chronobiology. The keywords used were "clock genes, circadian rhythms, diurnal preference, delayed sleep phase syndrome, advanced sleep phase syndrome, photoperiod and mood disorder". DISCUSSION: The knowledge about molecular mechanism of circadian rhythms increased a lot in the last years and now we are able to better understand the details of molecular processes involved in circadian and sleep regulation. Studies show that polymorphisms in clock genes are associated with sleep and mood disorders. These studies will be helpful to further elucidate the regulation of molecular mechanisms of circadian rhythms. CONCLUSIONS: The development of these studies in molecular chronobiology can be helpful to treat circadian and mood disorders and to prevent health risks caused by intercontinental flights (Jet Lag), nocturnal or shift work schedule.

A narcolepsia é caracterizada por sonolência excessiva diurna e cataplexia. Pouco se sabe sobre as diferenças fisiopatológicas entre pacientes com e sem cataplexia. OBJETIVO: Quantificar os linfócitos T CD4, T CD8 e B e a presença do alelo HLA-DQB1*0602 nos subgrupos de pacientes com narcolepsia. MÉTODO: O estudo foi prospectivo e controlado (transversal) com 22 pacientes portadores de narcolepsia e 23 sujeitos controle. Os pacientes realizaram polissonografia (PSG) de noite inteira e teste de múltiplas latências do sono (TMLS). O alelo do antígeno de histocompatibilidade (HLA-DQB1*0602) e os linfócitos T CD4, T CD8 e B foram quantificados nos pacientes e sujeitos controle. RESULTADOS: O alelo HLA-DQB1*0602 foi encontrado em 10 (62,5%) dos 16 pacientes com cataplexia e em 2 (33,3%) dos 6 pacientes sem cataplexia (p=0,24). Nos sujeitos controle, o alelo HLA-DQB1*0602 foi encontrado em 5 sujeitos (20%). Um aumento significativo de linfócitos T CD4 e uma diminuição de linfócitos B foi observado no grupo de pacientes com cataplexia freqüente quando comparado ao grupo de pacientes sem cataplexia. CONCLUSÃO: Doenças auto-imunes como lupus eritematoso sistêmico e artrite reumatóide têm sido associadas com diminuição de linfócitos T CD4 e B. Na artrite reumatóide, diminuição de linfócitos B e presença do alelo HLA-DRB1 tem sido associada a pior evolução. Para essa doença, a teoria de um maior consumo de linfócitos B em suas fases de maturação tem sido aventada. Os achados do nosso estudo reforçam a teoria imunológica da narcolepsia.

Narcolepsy is characterized by excessive daytime sleep and cataplexy. Little is known about the possible difference in pathophysiology between patients with or without cataplexy. OBJECTIVE: To quantify T CD4, T CD8 and B lymphocytes in subgroups of patients with narcolepsy and the presence or absence of the HLA-DQB1*0602 allele between groups. METHOD: Our study was prospective and controlled (transversal) with 22 narcoleptic patients and 23 health control subjects. Patients underwent an all-night polysomnographic recording (PSG) and a multiple sleep latency Test (MSLT). The histocompatibility antigen allele (HLA-DQB1*0602), T CD4, CD8 and B lymphocytes were quantified in control subjects and in narcoleptics. RESULTS: The HLA-DQB1*0602 allele was identified in 10 (62.5%) of our 16 cataplexic subjects and in 2 (33.3%) of the 6 patients without cataplexy (p=0.24). In control subjects, HLA-DQB1*0602 allele was identified in 5 (20%). A significant decrease in T CD4 and B lymphocytes was found in narcoleptic patients with recurrent cataplexy when compared with our patients without cataplexy. CONCLUSION: Autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis were associated with a decrease in sub-group of T CD4 and B lymphocytes. A drop in B lymphocytes count in reumathoid arthritis might, it is posited, be correlated to the presence of HLA-DRB1 allele along with an overall worsened outcome of the affliction. The theory of an increase in consumption of B lymphocytes over the maturation phase has likewise been put forward. Our study reinforces the view that narcolepsy should be considered from an immunological perspective.