Įxcessive daytime sleepiness and cataplexy are keys for the diagnosis of narcolepsy, although many comorbidities are frequently observed in narcolepsy patients. It has been proposed that a process of molecular mimicry must be involved given the observed increase of NT1 prevalence after the H1N1 influenza pandemic in 2009–2010. The autoantigen Trib2 is involved in human narcolepsy with anti-Tribble antibodies acting on hypocretin-producing neurons, leading to their disappearance and consequent Hcrt deficiency. Genes that affect the CD4 + T cells antigen response influence the interaction of DQB1*06:02 and specific T cell receptors (TCRs). In narcolepsy type 1 (NT1), the higher prevalence of allele HLA-DQB1*06:02 and Hypocretin (Hcrt) deficiency, supports the immunological theory for the cause of NT1. In the present study we compared the whole genomes of a monozygotic twin pair discordant for NT1 to provide data and analysis to contribute to the understanding of NT1 genetic basis. Recently, several findings strongly suggest immunological causes for excessive daytime sleepiness, cataplexy, and other REM disturbances. Genetic, degenerative, and immunological hypotheses try to explain the pathophysiology of narcolepsy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2 narcolepsy. Individuals affected by narcolepsy find it difficult to stay awake for long periods, causing serious disruptions in their daily routine. Narcolepsy is a rare neurological disease. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. To describe the genetic background for the NT1 discordant manifestations in this case, we present the whole-genome analysis of this monozygotic twin pair. The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). We present the case of a pair of 17-year-old male, monozygotic twins discordant for NT1. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |