Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C.
METHODS
Subjects with Niemann-Pick disease, type C have been reported to display narcolepsylike symptoms, including cataplexy. In this study, 5 patients with juvenile Niemann-Pick disease were evaluted for sleep abnormalities using nocturnal polysomnography, clinical evaluation, and the Multiple Sleep Latency Test. HLA typing and cerebrospinal fluid hypocretin levels were also evaluated in 4 patients. Niemann-Pick disease diagnosis was confirmed in all cases biochemically and by the presence of foam cells in the bone marrow.


RESULTS
Deterioration of intellectual function; the presence of pyramidal, dystonic and cerebellar features; and splenomegaly were observed in all cases. Cataplexy was reported in 1 patient. Nocturnal polysomnography revealed disrupted sleep in all patients. Total sleep time, sleep efficiency, rapid eye movement sleep, and delta sleep amounts were decreased when compared to age-matched controls. Altered sleep patterns included sudden increases in muscle tone during delta sleep, electroencephalographic sigma activity connected with rapid eye movements and muscle atonia, atypical K-complexes and spindle activity, and the presence of alpha-delta sleep. All Niemann-Pick disease cases exhibited fragmentary myoclonus. Shortened mean sleep latencies were observed in 3 patients during the Multiple Sleep Latency Test, but sleep-onset rapid eye movement periods were observed only in the case with cataplexy. This patient was HLA DQB1*0602 positive, while the other subjects were HLA negative. Cerebrospinal fluid hypocretin-1 levels were reduced in 2 patients (1 with cataplexy) while in the 2 other patients, the levels were at the lower range of the normal values. Hypocretin levels in the Niemann-Pick disease group (204.8 +/- 39.3 pg/mL) were significantly reduced when compared to controls (265.8 +/- 48.8 pg/mL).


CONCLUSIONS
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.
Vankova
Jitka
J
Department of Neurology, 1st Medical Faculty, Charles University, Prague. vankjit@seznam.cz
Stepanova
Iva
I
Jech
Robert
R
Elleder
Milan
M
Ling
Lig
L
Mignot
Emmanuel
E
Nishino
Seiji
S
Nevsimalova
Sona
S
D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000134:cerebrospinal fluid; D005260:Female; D006683:HLA-DQ Antigens / Q000276:immunology; D059866:HLA-DQ beta-Chains; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009479:Neuropeptides / Q000134:cerebrospinal fluid / Q000172:deficiency*; D009542:Niemann-Pick Diseases / Q000134:cerebrospinal fluid* / Q000150:complications* / Q000276:immunology; D000068797:Orexins; D012894:Sleep Stages / Q000502:physiology; D012893:Sleep Wake Disorders / Q000209:etiology*; D014851:Wakefulness
D002352:Carrier Proteins; C000596229:HCRT protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins