![]() 7 The likely cause of narcolepsy in humans was found to be a degeneration of Hcrt neurons. This was consistent with a previous report from Mignot’s group that 7 out of 9 narcoleptic patients studied had low CSF Hcrt. In situ hybridization studies revealed an absence of Hcrt mRNA in the hypothalami of narcoleptic patients, and radioimmunoassays showed low levels of Hcrt in the CNS. 6 What they did find, however, was a global deficiency in Hcrt. In 2000, Mignot’s group reported one Hcrt mutation in a case of early onset narcolepsy out of 74 narcoleptic patients studied. This is not surprising as most human narcolepsy is not familial and is discordant in identical twins. The search for genetic alterations in human narcolepsy has demonstrated that Hcrt and Hcrtr mutations are rare. There has been a flurry of activity since the Hcrt-narcolepsy link was made in 1999. EEG studies ruled out the possibility of seizure disorders and confirmed a disruption of REM sleep. 5 Null mutation of Hcrt produced an autosomal recessive phenotype remarkably similar to human narcolepsy, in which the mice would experience sudden narcoleptic attacks with a characteristic collapse of the head and neck and buckling of the limbs. Only 2 weeks later, Masashi Yanagisawa’s group at the University of Texas Southwestern Medical Center published a report describing a narcolepsy-like phenotype in Hcrt knockout mice. 4 later showed that Hcrt ligand levels in the brain and cerebral spinal fluid (CSF) of Doberman pinschers were within normal range, supporting the theory that in canines, narcolepsy develops as a result of a mutation in the receptor gene. 3 Mutation analysis of 17 narcoleptic Doberman pinschers revealed the same insertion mutation in Hcrtr2 the insertion was absent in all 36 comparison dogs tested. Mignot’s group at Stanford University used positional cloning to identify an autosomal recessive mutation in one of the Hcrt receptor genes, Hcrtr2, in narcoleptic canines. In 1999, two American groups simultaneously published data linking the Hcrt peptide system with narcolepsy. Hypocretin and orexin are considered synonymous. They were named “orexin-A” and “orexin-B,” orexin coming from orexis, which refers to appetite. ![]() 2 described two novel neuropeptides that increased appetite when given to rats. At least one of the Hcrt peptides was found to be neuroexcitatory to hypothalamic cells but its precise function was not known. These peptides were restricted to neuronal bodies in the dorsal and lateral hypothalamus with fibers projecting to multiple targets in the hypothalamus, thalamus, and brainstem. Using directional tag PCR subtraction, they discovered a hypothalamus-specific mRNA that was thought to encode the peptides Hcrt-1 and Hcrt-2. 1 The name was coined from the words hypo thalamus, referring to the anatomic location of neurotransmitter, and se cretin, the gastric peptide with which hypocretin (Hcrt) was thought to share considerable homology. ![]() H ypocretin was first described in 1998 by De Lecea et al. ![]()
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