Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report.

BACKGROUND: Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1. CASE PRESENTATION: We present the case of a pair of 17-year-old male, monozygotic twins discordant for NT1. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. To describe the genetic background for the NT1 discordant manifestations in this case, we present the whole-genome analysis of this monozygotic twin pair. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). CONCLUSIONS: The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease.

Testing sleepiness and vigilance in the sleep laboratory.

PURPOSE OF REVIEW: Excessive daytime sleepiness (EDS) is common and a potentially devastating public health challenge. EDS has been implicated as a contributing factor to workplace injury, motor vehicle accidents, cardiovascular disease, and impaired quality of life. Subjective self-report measures have failed to sufficiently quantify EDS. The use of objective tools found in sleep laboratories is therefore fundamental in the management of patients with EDS. The purpose of this review is to provide an overview of the current methods used to quantify sleepiness, and to highlight recent advances. RECENT FINDINGS: The Multiple Sleep Latency Test (MSLT), normally used for the diagnosis of narcolepsy, can be a useful tool in recognizing other forms of sleepiness. The Maintenance of Wakefulness Test (MWT) has also been confirmed as an important test to identify EDS, as well as to provide an indicator of future risk of accidents. Modifications and newer tests have been discussed with potential applications for the future. SUMMARY: Objective tests such as the MSLT and MWT are useful in the diagnosis and management of patients with EDS. However, the relatively high cost can restrict their overall usefulness in clinical medicine. Newer simple tests are under development.

Lisdexamfetamine to improve excessive daytime sleepiness and weight management in narcolepsy: a case series.

OBJECTIVE: To report the successful use of lisdexamfetamine in the management of narcolepsy. METHODS: Five narcoleptic patients received lisdexamfetamine, at different dosages and for different periods, for management of excessive daytime sleepiness and weight control. RESULTS: All patients experienced improvement of excessive daytime sleepiness and lost weight without side effects. CONCLUSION: Lisdexamfetamine appears promising for the treatment of two of the most common symptoms of narcolepsy: excessive daytime sleepiness and weight gain.

Lisdexamfetamine to improve excessive daytime sleepiness and weight management in narcolepsy: a case series

Objective: To report the successful use of lisdexamfetamine in the management of narcolepsy. Methods: Five narcoleptic patients received lisdexamfetamine, at different dosages and for different periods, for management of excessive daytime sleepiness and weight control. Results: All patients experienced improvement of excessive daytime sleepiness and lost weight without side effects. Conclusion: Lisdexamfetamine appears promising for the treatment of two of the most common symptoms of narcolepsy: excessive daytime sleepiness and weight gain.

Benefit of repeat multiple sleep latency testing in confirming a possible narcolepsy diagnosis.

PURPOSE: The clinical diagnosis of narcolepsy is usually uncomplicated in the presence of cataplexy. Objective testing is more important in ambiguous disease. The gold-standard objective test in these cases is the multiple sleep latency test (MSLT). Repeat testing can be burdensome but is reasonable when faced with a diagnostic dilemma. However, there is limited evidence to support this approach. In this study, we assessed the diagnostic utility of a repeat MSLT in patients suspected of narcolepsy whose first MSLT result was nonconfirmatory. METHODS: Of 125 patients who underwent an MSLT between 2004 and 2009, we identified 10 (9.6%) who had undergone repeat studies. We analyzed changes in MSLT parameters while taking account of other relevant differences between testing. RESULTS: Two patients (20%) met narcolepsy criteria during the second MSLT. Nine patients (90%) met sleepiness criteria (mean sleep latency <8 minutes) during the second MSLT while only 5 did during the first (P = 0.05). CONCLUSIONS: We demonstrate that a repeat MSLT confirmed the diagnosis of narcolepsy in 20% of patients whose results had been nonconfirmatory on a first MSLT. This study provides support for a repeat MSLT in cases where clinical suspicion for narcolepsy is high despite an ambiguous first test.