Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.

Four patients with clinically and genetically confirmed Prader-Willi syndrome (PWS) underwent nocturnal polysomnograpy (PSG), multiple sleep latency test (MSLT), human leukocyte antigens (HLA) typing and estimation of cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) level to investigate if a role of hypothalamic dysfunction and sleep disturbance might be functionally connected through the hypocretin (orexin) system. In all four patients physical examination confirmed extreme obesity (increasing with age) with dysmorphogenetic features. Excessive daytime sleepiness (EDS) was manifested in only two subjects without any imperative feature. None of the patients under study suffered from cataplexy. Nocturnal PSG revealed fragmented sleep with low efficiency, the hypopnea and apnea indexes increasing from borderline up to very high values in direct proportion to the patients' age. MSLT latency was shortened in two patients with clinically expressed EDS, only one sleep onset rapid eye movements (REM) period (SOREM) was found. HLA typing showed DQB1*0602 positivity in two patients; the further two were negative. Mean value of CSF Hcrt-1 in the patients group was down to 164 +/- 46.8 pg/ml (in comparison with 265.8 +/- 48.8 pg/ml in 10 young healthy subjects, P=0.02). The deficiency of CSF Hcrt-1 level correlated in PWS patients with their EDS severity.

The findings suggest that lysozomal storage abnormalities in Niemann-Pick disease patients may impact the hypothalamus and, more specifically, hypocretin-containing cells. These changes might be partially responsible for sleep abnormalities and cataplexy in patients with Niemann-Pick disease.

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