RESUMO
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.
Assuntos
Narcolepsia/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Animais , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Replicação do DNA/genética , Cães , Genótipo , Humanos , Hipotálamo/imunologia , Hipotálamo/patologia , Camundongos , Narcolepsia/imunologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Narcolepsy with cataplexy is characterised by excessive daytime sleepiness, sudden drops of muscle tone triggered by emotions, termed cataplexy, disrupted nocturnal sleep and other dissociated rapid eye movement (REM) sleep phenomena. Narcolepsy has been linked to a loss of hypothalamic neurons producing hypocretins, neuropeptides implicated in the regulation of the arousal system. Neuroimaging and neurometabolic studies have shown the pathophysiological involvement of other brain structures such as cerebral cortex and thalamus, but, overall with inconsistent results. We investigated, by using an advanced quantitative MR technique, proton MR spectroscopy ((1)H-MRS), the distribution of brain neurochemical abnormalities in narcolepsy with cataplexy patients. Single voxel (1)H-MRS study was performed in the thalamus, hypothalamus, and parietal-occipital cortex of hypocretin deficient, narcolepsy with cataplexy patients, HLA-DQB1*0602-positive, drug free. No significant changes were detected in the thalamus and parietal-occipital cortex of the patients. On the other hand, the neuronal marker N-acetyl-aspartate was reduced in the hypothalamus of narcolepsy with cataplexy patients compared to controls. These (1)H-MRS findings further support that in narcolepsy with cataplexy patients, the hypothalamus is the primary site of neural lesions. The absence of (1)H-MRS neurodegenerative changes in the thalamus and cerebral cortex suggests that the abnormalities detected in these brain regions by other neuroimaging techniques are likely of functional nature.