Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 79
Filtrar
1.
Indian Pediatr ; 56(9): 792-794, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31638014

RESUMO

BACKGROUND: Bainbridge-Ropers syndrome is a rare autosomal dominant genetic disorder. CASE CHARACTERISTICS: A 26-day-old neonate presented with feeding difficulties, excessive sleeping, and hirsutism over forehead and lumbosacral skin. OUTCOME: Whole-exome sequencing identified a novel nonsense mutation. MESSAGE: We report a novel mutation in a Chinese neonate with Bainbridge-Ropers syndrome.


Assuntos
Códon sem Sentido , Anormalidades Craniofaciais/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Hipotonia Muscular/diagnóstico , Transtornos Psicomotores/diagnóstico , Fatores de Transcrição/genética , Anormalidades Craniofaciais/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Feminino , Marcadores Genéticos , Hirsutismo/diagnóstico , Hirsutismo/genética , Humanos , Recém-Nascido , Hipotonia Muscular/genética , Transtornos Psicomotores/genética , Síndrome
2.
Proc Natl Acad Sci U S A ; 116(32): 16062-16067, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31337678

RESUMO

The regulatory network of genes and molecules in sleep/wakefulness remains to be elucidated. Here we describe the methodology and workflow of the dominant screening of randomly mutagenized mice and discuss theoretical basis of forward genetics research for sleep in mice. Our high-throughput screening employs electroencephalogram (EEG) and electromyogram (EMG) to stage vigilance states into a wake, rapid eye movement sleep (REMS) and non-REM sleep (NREMS). Based on their near-identical sleep/wake behavior, C57BL/6J (B6J) and C57BL/6N (B6N) are chosen as mutagenized and counter strains, respectively. The total time spent in the wake and NREMS, as well as the REMS episode duration, shows sufficient reproducibility with small coefficients of variance, indicating that these parameters are most suitable for quantitative phenotype-driven screening. Coarse linkage analysis of the quantitative trait, combined with whole-exome sequencing, can identify the gene mutation associated with sleep abnormality. Our simulations calculate the achievable LOD score as a function of the phenotype strength and the numbers of mice examined. A pedigree showing a mild decrease in total wake time resulting from a heterozygous point mutation in the Cacna1a gene is described as an example.


Assuntos
Testes Genéticos/métodos , Sono/genética , Vigília/genética , Animais , Canais de Cálcio Tipo N/genética , Simulação por Computador , Cruzamentos Genéticos , Distúrbios do Sono por Sonolência Excessiva/genética , Etilnitrosoureia , Feminino , Genes Dominantes , Homozigoto , Escore Lod , Masculino , Camundongos Endogâmicos C57BL , Mutação/genética , Linhagem , Fenótipo , Reprodutibilidade dos Testes
3.
Respir Res ; 20(1): 125, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208424

RESUMO

BACKGROUND: Obstructive sleep apnoea (OSA) is one of the major sources of the excessive daily sleepiness, cognitive dysfunction, and it increases cardiovascular morbidity and mortality. Previous studies suggested a possible genetic influence, based on questionnaires but no objective genetic study was conducted to understand the exact variance underpinned by genetic factors. METHODS: Seventy-one Hungarian twin pairs involved from the Hungarian Twin Registry (48 monozygotic, MZ and 23 dizygotic, DZ pairs, mean age 51 ± 15 years) underwent overnight polysomnography (Somnoscreen Plus Tele PSG, Somnomedics GMBH, Germany). Apnoea hypopnea index (AHI), respiratory disturbance index (RDI) and oxygen desaturation index (ODI) were registered. Daytime sleepiness was measured with the Epworth Sleepiness Scale (ESS). Bivariate heritability analysis was applied. RESULTS: The prevalence of OSA was 41% in our study population. The heritability of the AHI, ODI and RDI ranged between 69% and 83%, while the OSA, defined by an AHI ≥5/h, was itself 73% heritable. The unshared environmental component explained the rest of the variance between 17% and 31%. Daytime sleepiness was mostly determined by the environment, and the variance was influenced in 34% by the additive genetic factors. These associations were present after additional adjustment for body mass index. CONCLUSION: OSA and the indices of OSA severity are heritable, while daytime sleepiness is mostly influenced by environmental factors. Further studies should elucidate whether close relatives of patients with OSA may benefit from early family risk based screening.


Assuntos
Doenças em Gêmeos/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Predisposição Genética para Doença/genética , Apneia Obstrutiva do Sono/genética , Sonolência , Adulto , Idoso , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/epidemiologia , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Hungria/epidemiologia , Masculino , Pessoa de Meia-Idade , Polissonografia/métodos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia
4.
Hum Mol Genet ; 28(7): 1153-1161, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535103

RESUMO

Elevated serotonin (5-HT) blood levels, the first biomarker identified in autism research, has been consistently found in 20-30% of patients with Autism Spectrum Disorder (ASD). Hyperserotonemia is mainly due to greater 5-HT uptake into platelets, mediated by the 5-HT transporter (SERT) located at the platelet plasma membrane. The protein complex involved in platelet SERT trafficking and externalization includes integrin ß3, the beta subunit of the platelet membrane adhesive GP IIb/IIIa. Integrin ß3 is encoded by the ITGB3 gene, previously identified as a quantitative trait locus (QTL) for 5-HT blood levels in ASD at single nucleotide polymorphism (SNP) rs2317385. The present study aims to identify the functional ITGB3 gene variants contributing to hyperserotonemia. ITGB3 gene sequencing in 20 individuals selected on the basis of rs2317385 genotypes defined four haplotypes encompassing six SNPs located in the ITGB3 gene promoter region, all in linkage disequilibrium with rs2317385. Luciferase assays in two hematopoietic cell lines, K-562 and HEL 92.1.7, demonstrate that ITGB3 gene promoter activity is enhanced by the presence of the C allele at rs55827077 specifically during differentiation into megakaryocytes (P < 0.01), with modulatory effects by flanking SNPs. This same allele is strongly associated with (a) higher 5-HT blood levels in 176 autistic individuals (P < 0.001), (b) greater platelet integrin ß3 protein expression (P < 0.05) and (c) enhanced SERT trafficking from the cytosol toward the platelet plasma membrane (P = 4.05 × 10-11). Our results support rs55827077 as the functional ITGB3 gene promoter variant contributing to elevated 5-HT blood levels in ASD and define a mechanistic chain of events linking ITGB3 to hyperserotonemia.


Assuntos
Transtorno do Espectro Autista/genética , Integrina beta3/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Adolescente , Adulto , Transtorno Autístico/genética , Criança , Pré-Escolar , Distúrbios do Sono por Sonolência Excessiva/genética , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Haplótipos , Humanos , Integrina beta3/fisiologia , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Transporte Proteico/fisiologia , Serotonina/análise , Serotonina/sangue , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
5.
Behav Sleep Med ; 17(5): 537-551, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29388804

RESUMO

Objective/Background: The impact of midday napping on neurocognitive function in adolescents has not been well established. This study aimed to investigate the relationship between self-reported midday-napping behaviors and neurocognitive function in early adolescents. Participants: The sample was comprised of 363 early adolescents (12.00 ± 0.38 years old) from Jintan, China. Methods: Midday napping, nighttime sleep duration, and sleep quality were measured by self-reported questionnaires. Neurocognitive function was measured by the Penn Computerized Neurocognitive Battery (accuracy and reaction times). Generalized linear regression was used to analyze the relationships. Results: Sixty-four percent of our sample took more than 3 naps per week, and 70.11% reported nap durations of over 30 min. Participants with higher frequencies or longer durations of midday napping reported significantly better nighttime sleep quality (p < 0.05). Adjusted models showed that frequent nappers (5-7d/week) were significantly associated with heightened accuracy on tasks that measured sustained attention and nonverbal reasoning and faster reaction times on spatial memory compared with other frequency groups (ps < 0.05). For napping duration subgroups, early adolescents who took naps of any length were estimated to have faster reaction speeds on the sustained attention task compared with participants who never napped (ps < 0.05). However, only nappers with a moderate duration (31-60 min) tended to achieve both faster speeds (ß = -38.28, p = 0.02) and better accuracy (ß = 3.90, p = 0.04) on the sustained attention task. Conclusions: Our findings suggest that there is an association between habitual midday napping and neurocognitive function in early adolescents, especially in China, where midday napping is a cultural practice.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/genética , Transtornos Neurocognitivos/etiologia , Adolescente , Feminino , Humanos , Masculino , Autorrelato , Inquéritos e Questionários , Fatores de Tempo
6.
Sleep Health ; 4(6): 572-578, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30442327

RESUMO

OBJECTIVES: We searched for interactions between PER3 gene VNTR polymorphism, latitude, sleep duration, diurnal sleepiness, and social jetlag. DESIGN: We selected samples from 3 distinct cities along the latitudinal range of Brazil and comprising the same time zone. SETTING: Undergraduate universities located in 3 major cities of Brazil. PARTICIPANTS: A total of 980 undergraduate students: 276 from Maceio (latitude 9°), 358 from Campinas (latitude 22°), and 346 from Porto Alegre (latitude 30°). MEASUREMENTS: PER3 variable number of tandem repeats genotyping, diurnal sleepiness, sleep duration (weekdays and weekend), chronotype, and social jetlag. RESULTS: Latitude is associated with a differential expression of circadian and sleep profiles. We observed a shift toward eveningness with increased latitude and increased social jetlag and diurnal sleepiness at latitude 30°. Moreover, our results suggest that the PER3 variable number of tandem repeats polymorphism has a modulatory effect on these circadian and sleep profiles: the variant PER34/4 is associated with a smaller difference in the sleep duration on weekdays among different latitudes and is associated with longer sleep duration on weekends just at latitude 30°, even when compared to both other genotypes at the same latitude. On the other hand, irrespective of the genotype, volunteers from latitude 30° expressed increased social jetlag and diurnal sleepiness. CONCLUSIONS: The seasonal variation in the light/dark cycle, tied to latitude, together with the tight social time constraints that young adults are subjected to during weekdays, generates differences in the sleep phenotypes. Volunteers with the PER34/4 variant who live farther from the equator have a greater increase in their weekend sleep duration.


Assuntos
Interação Gene-Ambiente , Proteínas Circadianas Period/genética , Sono/genética , Vigília/genética , Brasil , Distúrbios do Sono por Sonolência Excessiva/genética , Feminino , Genótipo , Geografia , Humanos , Síndrome do Jet Lag/genética , Masculino , Repetições Minissatélites , Polimorfismo Genético , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Fatores de Tempo , Adulto Jovem
7.
J Hum Genet ; 63(12): 1259-1267, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30266950

RESUMO

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.


Assuntos
Carnitina O-Acetiltransferase/genética , Cromossomos Humanos Par 9/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Cadeias beta de HLA-DQ/genética , Polimorfismo de Nucleotídeo Único , Distúrbios do Sono por Sonolência Excessiva/enzimologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino
8.
Sleep ; 41(9)2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29868885

RESUMO

Study Objective: Narcolepsy type 1 (NT1) is considered a chronic, incurable disease. Excessive daytime sleepiness (EDS) is typically the most troublesome symptom, and more difficult to control by pharmacologic treatment than cataplexy. Although many NT1 patients are monitored by regular follow-ups, the purported relentless persistence of EDS has rarely been the object of longitudinal studies. Methods: Retrospective analysis of 26 well-defined hypocretin-deficient NT1 patients who underwent longitudinal assessments of Epworth sleepiness scale (ESS) scores under stable pharmacotherapy. We present detailed case reports of four patients with unusual spontaneous improvement. Results: Over a mean observation period of 5 years, changes in ESS scores between first and last examination were ≤4 points in 19 patients (73%). Three patients deteriorated by 5 points, four patients ameliorated by 7-11 points. Among the latter, subjective sleepiness resolved in all four patients, and three of them continued showing ESS scores <11 after cessation of their pharmacotherapy. Without therapy, two patients did not fulfill anymore the ICSD-3 multiple sleep latency test criteria (mean sleep latency >8 minutes), one of whom did not fall asleep during maintenance of wakefulness test. Multiple linear regression analysis identified higher cerebrospinal fluid (CSF) hypocretin level (p < 0.001) and absence of fragmented nighttime sleep (p = 0.001) as independent associates of EDS improvement. Conclusions: The longitudinal course of NT1-related sleepiness is not invariably stable, but included spontaneous deterioration or improvement in 27%. Spontaneous improvement can persist after treatment discontinuation and resemble remission. Milder hypocretin deficiency and good nighttime sleep may predict a more favorable disease course.


Assuntos
Narcolepsia/genética , Narcolepsia/metabolismo , Orexinas/deficiência , Orexinas/genética , Remissão Espontânea , Latência do Sono/fisiologia , Adulto , Cataplexia/genética , Cataplexia/metabolismo , Cataplexia/fisiopatologia , Distúrbios do Sono por Sonolência Excessiva/genética , Distúrbios do Sono por Sonolência Excessiva/metabolismo , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Narcolepsia/fisiopatologia , Polissonografia/tendências , Estudos Retrospectivos , Sono/fisiologia , Vigília/fisiologia
10.
Scand J Clin Lab Invest ; 77(5): 390-393, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28537447

RESUMO

The hypothalamic peptide hypocretin 1 (orexin A) may be assayed in cerebrospinal fluid to diagnose narcolepsy type 1. This testing is not commercially available, and factors contributing to assay variability have not previously been comprehensively explored. In the present study, cerebrospinal fluid hypocretin concentrations were determined in duplicate in 155 patient samples, across a range of sleep disorders. Intra-assay variability of these measures was analyzed. Inter-assay correlation between samples tested at Emory and at Stanford was high (r = 0.79, p < 0.0001). Intra-assay correlation between samples tested in duplicate in our center was also high (r = 0.88, p < 0.0001); intra-assay variability, expressed as the difference between values as a percentage of the higher value, was low at 9.4% (SD = 7.9%). Although both time the sample spent in the freezer (r = 0.16, p = 0.04) and age of the kit used for assay (t = 3.64, p = 0.0004) were significant predictors of intra-kit variability in univariate analyses, only age of kit was significant in multivariate linear regression (F = 4.93, p = 0.03). Age of radioimmunoassay kit affects intra-kit variability of measured hypocretin values, such that kits closer to expiration exhibit significantly more variability.


Assuntos
Narcolepsia/diagnóstico , Orexinas/genética , Radioimunoensaio/normas , Kit de Reagentes para Diagnóstico/normas , Distúrbios do Sono por Sonolência Excessiva/líquido cefalorraquidiano , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/genética , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Congelamento , Expressão Gênica , Humanos , Hipersonia Idiopática/líquido cefalorraquidiano , Hipersonia Idiopática/diagnóstico , Hipersonia Idiopática/genética , Hipersonia Idiopática/fisiopatologia , Narcolepsia/líquido cefalorraquidiano , Narcolepsia/genética , Narcolepsia/fisiopatologia , Variações Dependentes do Observador , Orexinas/líquido cefalorraquidiano , Reprodutibilidade dos Testes , Síndromes da Apneia do Sono/líquido cefalorraquidiano , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/fisiopatologia , Fatores de Tempo
11.
Neurol Sci ; 38(5): 769-774, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28181067

RESUMO

Sleep disorders are highly prevalent in the population and have dramatic health, social, and economic impacts. However, their treatments may remain symptomatic due to ignorance of molecular factors which may provide fundamental insights into the neurological bases of sleep. Excessive daytime sleepiness (EDS) is a common complaint encountered in neurological practice with significant effects both on individuals and on society. We aimed to investigate the role of monoamine oxidase A (MAOA) as a candidate gene in EDS. Epworth sleepiness scale (ESS) was applied to 221 subjects who were also genotyped for MAOA upstream variable number of tandem repeats (MAOA-uVNTR). Patient group displayed higher ESS values (mean 12.67) when compared with the control group (mean 6.38). However, MAOA-uVNTR genotypes did not show a significant association with ESS scores neither on women nor on men. Finally, these data suggest further replications in different populations. Moreover, the investigation of some other genes together with MAOA and/or some possible regulatory molecular mechanisms may offer a more comprehensive approach in the role of genetic factors contributing to EDS.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/genética , Repetições Minissatélites/genética , Monoaminoxidase/genética , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica
12.
Neurol Neurochir Pol ; 51(2): 190-193, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28209438

RESUMO

A 41-year-old female with history of Graves' disease, bilateral cataract, paroxysmal atrial fibrillation was admitted because of muscle weakness, daytime sleepiness, fatigability, drowsiness, bilateral eyelid ptosis, descending of head and lower jaw. On neurological examination the patient was presented with muscle weakness, muscle atrophy (in face and sternocleidomastoid muscles), features of myotonia and apocamnosis (orbicular muscles). Electromyography revealed myopathic changes, myotonic and pseudomyotonic discharges, positive repetitive nerve stimulation test in proximal muscles. Myotonic dystrophy (MD) diagnosis was confirmed by genetic testing and myasthenia gravis (MG) by a positive titer of cholinergic receptor autoantibodies. In the CSF concentration of hypocretin was significantly decreased.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Doença de Graves/diagnóstico , Miastenia Gravis/diagnóstico , Distrofia Miotônica/diagnóstico , Adolescente , Adulto , Autoanticorpos/sangue , Comorbidade , Distúrbios do Sono por Sonolência Excessiva/genética , Eletromiografia , Feminino , Testes Genéticos , Doença de Graves/genética , Humanos , Masculino , Debilidade Muscular/diagnóstico , Miastenia Gravis/genética , Distrofia Miotônica/genética , Exame Neurológico , Receptores Colinérgicos/imunologia
13.
Neurosci Lett ; 644: 43-47, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28235603

RESUMO

The identification of genes that are risk factors for major depressive disorder remains a main task for global psychiatric research. The Catechol-O-methyltransferase (COMT) gene has been an important candidate risk factor for several psychiatric disorders. Previous studies have shown that a functional polymorphism (Val158Met) in this gene has an effect on several brain circuits and endophenotypes of psychiatric relevance. The aim of this study was to explore the association of a functional polymorphism in the COMT gene with psychological distress, sleep problems and health-related quality of life. Two hundred seventy young Colombian subjects (mean age: 21.3 years; range: 18-57 years) completed the Patient Health Questionnaire-9, the Perceived Stress Scale, the Oviedo Sleep Questionnaire and the 12-Item Short-Form Health Survey and were genotyped for the Val158Met polymorphism (rs4680) in the COMT gene. A linear regression analysis, adjusting for potential confounding factors, was carried out. Subjects that were Met carriers (Val/Met and Met/Met genotypes) showed higher scores for hypersomnia (p=0.001) and lower scores for mental health-related quality of life (p=0.007), these associations remained significant after correcting for multiple testing. These findings support the hypothesis of a broad effect of the Val158Met polymorphism in the COMT gene on several dimensions of behavior and neuropsychiatric symptoms.


Assuntos
Catecol O-Metiltransferase/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Saúde Mental , Qualidade de Vida , Adolescente , Adulto , Colômbia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
14.
Brain Dev ; 39(2): 161-165, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27596361

RESUMO

Deficiency of gamma-amino-butyrate aminotransferase (ABAT) is a rare inherited disorder. A six-month-old girl presented with hyper-somnolence, hyperkinetic movements of distal extremities during wakefulness, hypotonia, bi-pyramidal signs, and impaired response to sound and visual stimuli. Brain MRI at five months showed restricted diffusion along the internal capsule and genu of corpus callosum. A follow up MRI at 18months, showed hyperintensities in brainstem, external and internal capsule, 'trilaminated' appearance of posterior limb of internal capsule and dysmyelination of sub-cortical white matter. MRS showed a peak between 2.2ppm and 2.4ppm, corresponding to glutamine, glutamate and GABA. EEG was normal at six months but showed multifocal epileptiform discharges at 18months. Targeted exome sequencing revealed compound heterozygous missense variations in ABAT resulting in its reduced function. We report the novel association of hypersomnolence and hyperkinetic movement disorder with ABAT variations thus expanding the clinical spectrum of this uncommon neuro-metabolic disorder and discuss the emerging role of GABA in pathways regulating sleep-wake cycle and movement disorders.


Assuntos
4-Aminobutirato Transaminase/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Heterozigoto , Hipercinese/genética , Mutação de Sentido Incorreto , 4-Aminobutirato Transaminase/deficiência , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Diagnóstico Diferencial , Distúrbios do Sono por Sonolência Excessiva/diagnóstico por imagem , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Feminino , Seguimentos , Humanos , Hipercinese/diagnóstico por imagem , Hipercinese/fisiopatologia , Lactente , Homologia de Sequência de Aminoácidos
15.
Sleep ; 39(8): 1535-42, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-27253765

RESUMO

STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is a rare, mostly sporadic disorder, characterized by intermittent episodes of hypersomnia plus cognitive and behavior disorders. Although its cause is unknown, multiplex families have been described. We contrasted the clinical and biological features of familial versus sporadic KLS. METHODS: Two samples of patients with KLS from the United States and France (n = 260) were studied using clinical interviews and human leukocyte antigen (HLA) genotyping. A multiplex family contained two or more first- or second-degree affected relatives (familial cases). RESULTS: Twenty-one patients from 10 multiplex families (siblings: n = 12, including two pairs of monozygotic twins; parent-child: n = 4; cousins: n = 2; uncle-nephews: n = 3) and 239 patients with sporadic KLS were identified, yielding to 4% multiplex families and 8% familial cases. The simplex and multiplex families did not differ for autoimmune, neurological, and psychiatric disorders. Age, sex ratio, ethnicity, HLA typing, karyotyping, disease course, frequency, and duration of KLS episodes did not differ between groups. Episodes were less frequent in familial versus sporadic KLS (2.3 ± 1.8/y versus 3.8 ± 3.7/y, P = 0.004). Menses triggered more frequently KLS onset in the nine girls with familial KLS (relative risk, RR = 4.12, P = 0.03), but not subsequent episodes. Familial cases had less disinhibited speech (RR = 3.44, P = 0.049), less combined hypophagia/hyperphagia (RR = 4.38, P = 0.006), more abrupt termination of episodes (RR = 1.45, P = 0.04) and less postepisode insomnia (RR = 2.16, P = 0.008). There was similar HLA DQB1 distribution in familial versus sporadic cases and no abnormal karyotypes. CONCLUSION: Familial KLS is mostly present in the same generation, and is clinically similar to but slightly less severe than sporadic KLS.


Assuntos
Síndrome de Kleine-Levin/classificação , Síndrome de Kleine-Levin/genética , Distúrbios do Sono por Sonolência Excessiva/complicações , Distúrbios do Sono por Sonolência Excessiva/genética , Saúde da Família , Feminino , França , Genótipo , Teste de Histocompatibilidade , Humanos , Hiperfagia/complicações , Hiperfagia/genética , Síndrome de Kleine-Levin/complicações , Síndrome de Kleine-Levin/fisiopatologia , Masculino , Linhagem , Doenças Raras/complicações , Doenças Raras/genética , Doenças Raras/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/genética , Estados Unidos , Adulto Jovem
16.
J Hum Genet ; 61(10): 873-878, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27305985

RESUMO

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10-48, Pwhole genome without HLA-DQB1*06:02=6.73 × 10-2) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10-2) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10-2). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 10-14, Pwhole genome without HLA-DQB1*06:02=1.34 × 10-1, EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 10-1). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Herança Multifatorial , Narcolepsia/genética , Alelos , Hibridização Genômica Comparativa , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Genótipo , Cadeias beta de HLA-DQ/genética , Humanos , Narcolepsia/diagnóstico , Fenótipo , Polimorfismo de Nucleotídeo Único , Risco
17.
Mol Cell Biochem ; 416(1-2): 11-22, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27023909

RESUMO

Hyper-beta-alaninemia is a rare metabolic condition that results in elevated plasma and urinary ß-alanine levels and is characterized by neurotoxicity, hypotonia, and respiratory distress. It has been proposed that at least some of the symptoms are caused by oxidative stress; however, only limited information is available on the mechanism of reactive oxygen species generation. The present study examines the hypothesis that ß-alanine reduces cellular levels of taurine, which are required for normal respiratory chain function; cellular taurine depletion is known to reduce respiratory function and elevate mitochondrial superoxide generation. To test the taurine hypothesis, isolated neonatal rat cardiomyocytes and mouse embryonic fibroblasts were incubated with medium lacking or containing ß-alanine. ß-alanine treatment led to mitochondrial superoxide accumulation in conjunction with a decrease in oxygen consumption. The defect in ß-alanine-mediated respiratory function was detected in permeabilized cells exposed to glutamate/malate but not in cells utilizing succinate, suggesting that ß-alanine leads to impaired complex I activity. Taurine treatment limited mitochondrial superoxide generation, supporting a role for taurine in maintaining complex I activity. Also affected by taurine is mitochondrial morphology, as ß-alanine-treated fibroblasts undergo fragmentation, a sign of unhealthy mitochondria that is reversed by taurine treatment. If left unaltered, ß-alanine-treated fibroblasts also undergo mitochondrial apoptosis, as evidenced by activation of caspases 3 and 9 and the initiation of the mitochondrial permeability transition. Together, these data show that ß-alanine mediates changes that reduce ATP generation and enhance oxidative stress, factors that contribute to heart failure.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/metabolismo , Mitocôndrias Cardíacas/metabolismo , Doenças Mitocondriais/metabolismo , Miócitos Cardíacos/metabolismo , Convulsões/metabolismo , beta-Alanina/metabolismo , beta-Alanina/toxicidade , Animais , Distúrbios do Sono por Sonolência Excessiva/genética , Distúrbios do Sono por Sonolência Excessiva/patologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Camundongos , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Miócitos Cardíacos/patologia , Consumo de Oxigênio , Ratos , Convulsões/genética , Convulsões/patologia , Taurina/biossíntese , Taurina/genética , beta-Alanina/genética
18.
Arch Immunol Ther Exp (Warsz) ; 64(Suppl 1): 89-98, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28083611

RESUMO

The aim of our study was to analyze the distribution of HLA-DQB1 in Czech patients with central hypersomnias and differences between diagnostic groups of narcolepsy type 1 (NT1), type 2 (NT2), idiopathic hypersomnia (IH) and no central hypersomnia subjects (no-CH). Statistical analysis of DQB1 genotyping was performed on the cohort of 716 patients (375 men, 341 women) with reported excessive daytime sleepiness. DQB1*06:02 allele was present in 94% of the NT1 patients. The decrease of DQB1*06:03 allele was also confirmed. No other DQB1*06 allele nor any other DQB1 allele group was differently distributed in the NT1. In the cohort of NT2 patients DQB1*06:02 allele was present in 43%. Allele group DQB*05 was detected with a significantly higher frequency in this diagnostic unit. Any differences in presence of DQB1*05 alleles in NT2 patients were not reported so far. The cohort of patients with IH did not show any difference in allele distribution of DQB1 alleles/allele groups comparing to healthy controls. DQB1*06:02 allele was significantly increased in the no hypersomnia group. No other DQB1 allele/allele group had any difference in distribution in patients comparing to healthy controls. The different distribution of DQB1*06:02 and other DQB1 alleles/allele groups was detected in analyzed diagnostic groups. These results indicate that DQB1 contributes to the genetic predisposition to NT1, NT2, IH and no-CH in different manners.


Assuntos
Cadeias beta de HLA-DQ/genética , Hipersonia Idiopática/genética , Narcolepsia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Criança , Estudos de Coortes , República Tcheca , Distúrbios do Sono por Sonolência Excessiva/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Orexinas/metabolismo , Sono , Distúrbios do Início e da Manutenção do Sono/genética , Vigília
19.
Neuromuscul Disord ; 25(7): 563-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26031904

RESUMO

Perceived fatigue is a prominent symptom in patients with mitochondrial disease but to date its prevalence, impact and aetiology are poorly understood. Our aim was to determine the prevalence and assess for comorbidities associated with clinically relevant fatigue in patients with mitochondrial disease. A cross-sectional postal survey of patients with mitochondrial disease was undertaken using a validated self-completion, patient-reported outcome measures (response rate: 60%; n = 132). The prevalence and perceived functional impact of experienced fatigue were assessed using the Fatigue Impact Scale. Other putative biological mechanisms were evaluated using the Hospital Anxiety Depression scale and Epworth sleepiness scale. Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale ≥ 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale ≥ 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype. Future evaluation of causal factors in mitochondrial disease-associated fatigue is warranted with the potential to guide future treatment modalities.


Assuntos
Fadiga/epidemiologia , Doenças Mitocondriais/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Distúrbios do Sono por Sonolência Excessiva/epidemiologia , Distúrbios do Sono por Sonolência Excessiva/genética , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Fadiga/genética , Fadiga/fisiopatologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Doenças Mitocondriais/psicologia , Debilidade Muscular/epidemiologia , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Percepção , Prevalência , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
20.
Sleep ; 38(1): 119-26, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25325466

RESUMO

STUDY OBJECTIVES: To characterize and compare insomnia symptoms within two common phenotypes of Shift Work Disorder. DESIGN: Observational laboratory and field study. SETTING: Hospital sleep center. PARTICIPANTS: 34 permanent night workers. Subjects were classified by Epworth Sleepiness Scale and Insomnia Severity Index into 3 subgroups: asymptomatic controls, alert insomniacs (AI), and sleepy insomniacs (SI). MEASUREMENTS: Sleep parameters were assessed by sleep diary. Circadian phase was evaluated by dim-light salivary melatonin onset (DLMO). Objective sleepiness was measured using the multiple sleep latency test (MSLT). Brain activity was measured using the N1 event-related potential (ERP). A tandem repeat in PER3 was genotyped from saliva DNA. RESULTS: (1) AI group showed normal MSLT scores but elevated N1 amplitudes indicating cortical hyperarousal. (2) SI group showed pathologically low MSLT scores but normal N1 amplitudes. (3) AI and SI groups were not significantly different from one another in circadian phase, while controls were significantly phase-delayed relative to both SWD groups. (4) AI showed significantly longer sleep latencies and lower sleep efficiency than controls during both nocturnal and diurnal sleep. SI significantly differed from controls in nocturnal sleep parameters, but differences during diurnal sleep periods were smaller and not statistically significant. (5) Genotype × phenotype χ² analysis showed significant differences in the PER3 VNTR: 9 of 10 shift workers reporting sleepiness in a post hoc genetic substudy were found to carry the long tandem repeat on PER3, while 4 of 14 shift workers without excessive sleepiness carried the long allele. CONCLUSIONS: Our results suggest that the sleepy insomnia phenotype is comprehensively explained by circadian misalignment, while the alert insomnia phenotype resembles an insomnia disorder precipitated by shift work.


Assuntos
Fenótipo , Transtornos do Sono do Ritmo Circadiano/complicações , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Fases do Sono/fisiologia , Alelos , Atenção/fisiologia , Encéfalo/fisiologia , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Distúrbios do Sono por Sonolência Excessiva/complicações , Distúrbios do Sono por Sonolência Excessiva/genética , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Potenciais Evocados/fisiologia , Feminino , Humanos , Luz , Masculino , Melatonina/análise , Melatonina/biossíntese , Melatonina/efeitos da radiação , Repetições Minissatélites/genética , Proteínas Circadianas Period/genética , Polissonografia , Saliva , Transtornos do Sono do Ritmo Circadiano/genética , Distúrbios do Início e da Manutenção do Sono/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA