Clinical and genetic characteristic of narcolepsy typed I patients with HLA negative

Background and rationale: Narcolepsy type 1 (NT1) is the most known central hypersomnia, with an overall prevalence of 200-500/million and it is characterized by an irresistible excessive daytime sleepiness and cataplexy, brief episodes of loss of muscle control, triggered by emotions while consciousness is preserved. Genetic markers of NT1 so far identified include HLA-DQB1*06:02, common variants in T cell receptor alpha and beta, P2RY11 and a few other immune-related genes. Furthermore, in more than 95% of NT1 patients hypocretin-1 (Hcrt-1) levels in cerebrospinal fluid (CSF) are significantly decreased (<110 pg/ml) or undetectable. This is the most sensitive and specific test for diagnosing NT1. A difficult diagnostic challenge is the identification of narcoleptic patients with the unusual association between HLA DQB1*06:02 negative and hypocretin/orexin deficiency, which is reported in less than 2% of cases. This variant has been described in secondary form of narcolepsy type I (lesional) and in association to HLA subtype DPB1*0901, and homologous DPB1*10:01 subtype, with severe and spontaneous not triggered cataplexy. Using two different and sensitive approaches, hypocretin-specific CD4+ T cells; T cells specific for tribbles homologue 2-another self-antigen of hypocretin neurons, hypocretin-specific CD8+ T Hcrt- and Trib2-reactive CD4+ and CD8+ T cells have been recently identified in the blood and cerebrospinal fluid of NT1 patients analyzed (3/14 HLA-DQB1*06:02 negative), solidifying the autoimmune etiology of narcolepsy. Our hypothesis is that this rare variant is underdiagnosed. The clinical phenotype, outcome, management might be different from the usual NT1 positive to HLA DQB1 06-02 and needs to be better define. Objectives and specific aims: We aim to describe the clinical phenotype, outcome, management of this variant of NTI, according to sleep parameters, symptoms, and genetic assessment. Methods: Clinical data, genetic markers, and liquor assessments will be collected from patients with a diagnosis of NTI with hypocretin deficiency, and HLA DQB1*06:02 negative, recruited from our Sleep Center and compared to those recruited from the Host Sleep Center, retrospectively collected within the last 3 years. The number of total patients diagnosed with narcolepsy in the same period of time will be calculated from the same Sleep Centers, to calculate the relative percentage of this variant. Expected outcomes: According to the new criteria of diagnosis of NT1 (ICSD-III), an increased percentage of this subtype is expected to be found, with an increase percentage of paediatric onset, with a different clinical phenotype from the classical NT1. Impact: increasing the criteria of diagnosis and management of this rare disease.