A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Sleep and rhythm consequences of a genetically induced loss of serotonin.

BACKGROUND: A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa-responsive fluctuating generalized dystonia-parkinsonism. The non-motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. OBJECTIVE: We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. PATIENT: The patient was a 28-year-old man with fluctuating generalized dystonia-parkinsonism caused by sepiapterin reductase deficiency. METHODS: A sleep interview, wrist actigraphy, sleep log over 14 days, 48-h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5-hydroxytryptophan (the precursor of serotonin) and levodopa were performed. RESULTS: Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8 +/- 5.3 h), organic hyperphagia, attentionlexecutive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5-hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep-wake rhythm (sleep occurred every 24 +/- 1.7 h, P < 0.0001), and improved cognition. CONCLUSION: In this unique genetic paradigm, the melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep-wake rhythm.

Polysomnographic abnormalities in succinic semialdehyde dehydrogenase (SSADH) deficiency.

OBJECTIVES: Patients with SSADH deficiency, a disorder of chronically elevated endogenous GABA and GHB, were studied for sleep symptoms and polysomnography. We hypothesized that patients would have excessive daytime somnolence and decreased REM sleep. DESIGN: Polysomnography and MSLT were performed on patients enrolled for comprehensive clinical studies of SSADH deficiency. SETTING: Sleep studies were obtained in the sleep laboratories at CNMC and NIH. PATIENTS: Sleep recordings were obtained in 10 patients with confirmed SSADH deficiency. INTERVENTIONS: Thirteen overnight polysomnograms were obtained in 10 patients (7 male, 3 female, ages 11-27 y). Eleven MSLT studies were completed in 8 patients. MEASUREMENTS AND RESULTS: Polysomnograms showed prolongation of REM stage latency (mean 272 +/- 89 min) and decreased percent stage REM (mean 8.9%, range 0.3% to 13.8%). Decreased mean sleep latency was present in 6 of 11 MSLTs. CONCLUSIONS: SSADH deficiency is associated with prolonged latency to stage REM and decreased percent stage REM. This disorder represents a model of chronic GABA and GHB accumulation associated with suppression of REM sleep.

Prostaglandin D synthase (beta trace) levels in sleep apnea patients with and without sleepiness.

BACKGROUND: Excessive daytime sleepiness (EDS) occurs often in patients with obstructive sleep apnea syndrome (OSAS). However, not all patients present EDS. We hypothesized that the prostaglandin D2 system (PGD2) may be involved in the pathogenesis of EDS associated with OSAS. METHODS: We measured the levels of lipocalin-type PGD synthase (L-PGDS), the enzyme that produces PGD2, in the serum of 47 patients with OSAS (26 with and 21 without EDS) and 18 healthy controls. RESULTS: Patients with EDS had higher levels of L-PGDS (0.73+/-0.06 mg/L) than patients without EDS (0.58+/-0.03 mg/L, p<0.05) and controls (0.62+/-0.02 mg/L, p<0.05). L-PGDS levels in patients without EDS and controls were similar. CONCLUSION: The increased levels of circulating L-PGDS detected in OSAS patients with EDS suggest a possible role of the prostaglandin D system in the pathophysiology of daytime sleepiness in these patients.

Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency.

Sepiapterin reductase deficiency (SRD) is a rare, treatable disorder of monoamine metabolism with cognitive delay and l-dopa responsive movement disorder. We describe a patient with SRD and distinctive phenotypic feature of marked hypersomnolence. Our patient showed improvement with therapies directed at both serotonergic and dopaminergic deficiencies. This case illustrates symptoms that characterize the SRD phenotype and demonstrates the importance of systematic treatment trials addressing the various biochemical abnormalities present.

Sex differences in susceptibility to oxidative injury and sleepiness from intermittent hypoxia.

STUDY OBJECTIVES: Adult male mice exposed to long-term intermittent hypoxia (LTIH), modeling sleep apnea oxygenation patterns, develop nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent residual hypersomnolence and oxidative injury in select brain regions, including wake-active regions. Premenopausal females are less susceptible to selective oxidative brain injuries. We sought to determine whether female mice exposed to LTIH would confer resistance to LTIH-induced wake impairments and oxidative injuries. SUBJECTS AND SETTING: Young adult male and female C57BI/6J mice were studied in a university laboratory. INTERVENTIONS: Mice were randomly assigned to either LTIH or sham LTIH for 8 weeks. Total (24-h) wake time and mean sleep latency were measured under 2 conditions: rested and following 6 hours of enforced wakefulness. NADPH oxidase activation, carbonylation, and lipid peroxidation assays were also performed to assess sex differences in oxidative responses to LTIH. RESULTS: In contrast with the significant LTIH-induced wake impairments observed in male mice, females following LTIH showed normal wake times and sleep latencies. Female mice revealed less baseline carbonylation and less carbonylation following LTIH but showed robust NADPH oxidase activation and lipid peroxidation. In contrast with the female relative resistance to LTIH sleepiness, female mice showed more-pronounced sleepiness and delta response after enforced wakefulness. CONCLUSIONS: Despite a robust oxidative response to LTIH, age-matched female mice may be protected, at least temporarily, from LTIH wake impairments by lower basal carbonylation. In contrast, females show greater wake impairments after sleep deprivation. We hypothesize sex differences in polysomnographic predictors of sleepiness and residual sleepiness in humans with sleep apnea.

Interaction of modafinil and clomipramine as comedication in a narcoleptic patient.

Modafinil is a psychostimulant compound that is just now becoming available in many countries for treatment of narcoleptic and hypersomnic patients. Whereas sleep attacks and drowsiness can be effectively improved, the drug does not sufficiently reduce cataplectic seizures. It therefore is often used in combination with tricyclic antidepressant medication, although little is known about the possible interactions. This case report describes a narcoleptic patient chronically treated with clomipramine who started receiving modafinil. The blood concentrations of clomipramine and its metabolite showed a significant dose-dependent and reversible increase under modafinil. Since the patient was genotypically and phenotypically a cytochrome P450 2D6 poor metabolizer, the authors attribute the relevant pharmacokinetic interaction to another clomipramine-metabolizing enzyme.