As disruption of orexin (hypocretin) signaling is a primary defect in narcolepsy with cataplexy, we investigated whether markers of cholinergic synaptic transmission might be altered in mice constitutively lacking orexin receptors (double receptor knockout; DKO). mRNA for Choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and the high-affinity choline transporter (CHT1) but not acetylcholinesterase (AChE) was significantly higher in samples from DKO than wild-type (WT) mice.
130 patients with narcolepsy-cataplexy (mean ± SD age 20 ± 10 yrs, 69% male) and 117 controls (22 ± 6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (δV'(E))/carbon dioxide tension (δP(CO(2))) L·min(-1)·mmHg(-1)) and hypoxic (δV'(E) /change in arterial oxygen saturation measured by probe oximetry (δS(p,O(2))) L·min(-1) per %S(p,O(2))) responsiveness, and by spirometry.
As disruption of orexin (hypocretin) signaling is a primary defect in narcolepsy with cataplexy, we investigated whether markers of cholinergic synaptic transmission might be altered in mice constitutively lacking orexin receptors (double receptor knockout; DKO). mRNA for Choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and the high-affinity choline transporter (CHT1) but not acetylcholinesterase (AChE) was significantly higher in samples from DKO than wild-type (WT) mice.
Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1).
Sporadic narcolepsy with cataplexy is a disabling disease that is strongly associated with the major histocompatibility class II allele HLA DQB1*0602 and is characterized by profound reduction in the cerebrospinal fluid (CSF) concentration of hypocretin 1 levels.
About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity.
Seventeen young adults with a sole diagnosis of HLA DQB1 0602 positive narcolepsy with cataplexy (25.1 +/- 4.6 years old) and 17 healthy comparison subjects (26.8 +/- 4.8 years old).
These ELISA assay results do not support the hypothesis that HLA DQB1*0602-positive narcolepsy with cataplexy is associated with serum antibodies against preprohypocretin or its cleavage products.
Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy.
The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism.
Narcolepsy with cataplexy is a lifelong disease resulting from the loss of hypocretin neurons in the hypothalamus; structural changes are not, however, limited only to the hypothalamus.
Impaired neurotransmission of hypocretin/orexin (neuropeptides of the lateral hypothalamus) is involved in the neurobiology of narcolepsy with cataplexy (NT1).
White matter alterations related to hypocretin pathway have been less evaluated in patients who have narcolepsy with cataplexy (NC), as compared to the identified exploration of gray matter and have varied among structural brain magnetic resonance imaging studies.
The gold standard exam of narcolepsy with cataplexy is Hypocretin-1 dosage, but in patients without cataplexy and idiopathic hypersomnia, there are no specific diagnostic lab findings.
Biological markers of narcolepsy with cataplexy (classical narcolepsy) include sleep-onset REM periods (SOREM) on multiple sleep latency tests (MSLT), HLA-DQB1*0602 positivity, low levels of cerebrospinal fluid (CSF) hypocretin-1 (orexin A), increased body mass index (BMI), and high levels of CSF leptin.
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.