Narcolepsy Solved, Ready for Specific Treatment
Abstracts & Commentary
Synopsis: Chicurel provides a reader-friendly summary of the main investigators’ work to solve the cell-molecular-behavior secrets of narcolepsy during the recent decade. Nishino et al present the first article to identify the neuropeptide, hypocretin, in normal cerebral spinal fluid. By contrast, the peptide was absent from the CSF in seven of nine patients with cataplexy. Peyron et al report that in six human narcoleptic post-mortem brains, severe microscopic reductions of hypocretin-generated cells were found in the hypothalamus as well as its axon terminals in the brain and the pons. In a meticulous way, Thannickal et al microscopically addressed the post-mortem hypothalamus of four narcolepsy patients 4-12 years after death. Like Peyron et al’s report, the number of hypocretin cells in the lateral hypothalamic was reduced by 85-95% compared to normals. Van den Pol provides a commentary on the above and other publications with an experienced preparation that might interest the scholarly neurologist.
Sources: Chicurel M. Neuroscience. The sandman’s secrets. Nature 2000;407:554-556; Nishino S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000;355:39-40; Peyron C, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6:991-997; Thannickal TC, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27:469-474; Van den Pol AN. Narcolepsy: A neurodegenerative disease of the hypocretin system? Neuron 2000;27:415-418.
Narcolepsy is an overwhelmingly, distressing, randomly timed, every day, pathologic sleep disorder—the scientific mechanisms of which were unknown a decade or so ago. The primary clinical condition consists of abrupt, repetitive, episodic and imperative daytime sleep epochs. More serious dysfunction includes: cataplexy (sudden hypotonic muscle paralysis accompanied by feelings of sharp emotion); frightening hypnotic hallucinations; and abnormal patterns of REM sleep. It is said that age of onset ranges from 3 years to older than 70, but 90% or more patients develop their full symptoms between the onset of adolescence to 30 years of age. Once expressed, any affected persons remain dysfunctional and are unable to carry out complicated employment for their remaining lives. Automobile accidents are frequent among the sufferers.
Narcolepsy, the most distressing of all sleep disorders, affects approximately 150,000 Americans of various ethnic ancestors. More than 90% of those with the disease express the HLA-DR2/DQ1* 0602 gene which also is carried by about 30% of the entire, nonnarcoleptic human population. Interestingly, selective genetic representation and, somewhat similar spontaneous behavior, can affect many animals, including dogs, cats, horses, and "knockout" mice. Human familial co-incidence stands at less than 5%, with expression in dominant twins climbing to 25%.
Mignot (in 1989) pioneered neurobiological studies of narcolepsy by identifying and analyzing immune qualities and chromosomal gene markers in affected strains of Doberman pinscher dogs. Several years later, a general commercial interest arose to create more effective sedatives for the benignly sleepless public. Two independent teams of investigators, both interested in the subject, embarked upon discovering new visceral-related proteins expressed by the hypothalamus. During these efforts, each main investigator independently found two interesting and identical peptides produced from a single precursor protein in the lateral hypothalamus. Sulcliffe, from Scripps Research Center in La Jolla, California called the two peptide receptors hypo-cretins 1 and 2. Simultaneously, but unknowingly, Yanagisawa at the University of Texas Southwestern Medical Center in Dallas found an identical protein to Sulcliffe’s which generated the same two hypocretin peptides. From that start, Yanagisawa called the peptides Orexins type 1 and type 2. Yanagisawa proceeded to develop "knockout" mice that repeatedly demonstrated nocturnal collapse attacks resembling cataplexy when orexin-2 was deleted. Two weeks before in August 1999, Mignot had also published his findings on a lack of hypocretin in narcoleptic dogs.
Most recently, strong evidence based on neuropeptides and human narcolepsy has emerged. Mignot’s group has identified the normal presence of hypocretin-1 in the cerebral spinal fluid of eight healthy persons. Among nine patients with catoplexy, however, only two showed any hypocretin in their CSF (see Nishino et al’s study).
Peyron et al in Mignot’s group and Thannickal et al provide the crowning information of what causes narcolepsy. Among 10 narcoleptic brains preserved for several years post mortem, all demonstrated severe losses of hypocretin neurons in the tubero-lateral area of the hypothalamus. Peyron et al’s post-mortem findings in narcoleptics include one infant with an onset of narcolepsy by the mutation of arginine into the hypocretin signal peptide. Peyron et al also studied five other narcoleptic brains obtained after long fixation and Thannickal et al examined four more. Possibly one or two of the brains banked for several years after death were examined, and may have been studied by both parties during their several years postmortem. In any event, both teams found a severe reduction (80-85% by Thannickal et al) of the hypocretin cells normally located in the lateral hypothalamus. Peyron et al also indicated that two (the only ones studied) of her narcolepsy cases showed that hypocretin cells in the pons and one in the cerebrum contained abnormally low concentrations of hypocretin peptides. Whether or not the positive absence of hypocretin was involved in the locus ceruleus was not stated. Both observers indicated that intermixed melanin-concentrating cells in regional areas remained unchanged.
Commentary
The above, over-condensed Neurology Alert represents another triumph for the decade of the brain. In 1989, Mignot identified narcolepsy as genetic in cataplexic dogs and started the concentrated search for the genetic transmammalian mechanisms that underlie this merciless illness. Two teams, one being Sutcliffe and the other Yanagisawa starting in 1993-1994, identified two previously unknown different hypothalamic peptides, each of which were derived from the same gene but were named differently by their finders. Sutcliffe identified them as hypocretin, 1 and 2, while Yanagisawa called them orexin A and B. Each of the peptides generate important autonomic or neuro-endochronologic systems throughout the brain and spinal cord. Hypocretin 1, (orexin A) relates mainly to be a feeding-stimulating, melanin-concentrating hormone and physiologically contributes to cardiovascular regulation. Hypocretin 2 (orexin B) relates to sleep regulation and specifically projects to catecholaminergic cells in the brain stem, especially the locus coeruleus (LC) (Horvath TL, et al. J Comp Neurol 1999;415:145-159). A year before, Peyron et al (J Neurosci 1998;18:9996-10015) had identified the preprohypocretin-positive neurons in the dorso-lateral hypocampus. They identified widespread projections from the hypothalamus all the way to the medullary reticular formation and other systems. The loss of these important connections to the normal sleep cycle, as well as to the explosive abnormal LC attacks, condemn narcoleptic persons to live a life of permanent, internal fear. —Fred Plum
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