Cerebrospinal Fluid Orexin A Levels and Autonomic Function in Kleine-Levin Syndrome

Wang, Jing Yu; Han, Fang; Dong, Song; Li, Jing; An, Peng; Zhang, Xiao Zhe; Chang, Yun Woo; Zhao, Liang; Zhang, Xue Li; Liu, Ya Nan; Yan, Han; Li, Qing Hua; Hu, Yan; Lv, Chang; Gao, Zhan

doi:10.5665/sleep.5642

Cited by 43 publications

(24 citation statements)

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“…Potential implication of hypocretins (namely, a decreased cerebrospinal fluid [CSF] level during the hypersomnia period) was reported (Lopez, Barateau, Chenini, & Dauvilliers, ). A recent study in 44 Chinese KLS patients also reported that the CSF hypocretin‐1 levels were 31% lower during relapse (Wang et al, ). In addition to hypocretin neurons, LMOD3 was also found to be expressed in the tuberomammillary locus, locus coeruleus, ventral tegmental area and substantia nigra, as well as in the raphe nucleus, all critically involved in the maintenance of wakefulness.…”

Section: Discussionmentioning

confidence: 93%

Kleine‐Levin syndrome is associated with LMOD3 variants

Shareef

Basit

et al. 2018

Journal of Sleep Research

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Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first-degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individuals is lacking. Here we performed whole genome single-nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected members. The identified gene with a mutation was resequenced in 38 sporadic KLS patients and the expression of the gene product was mapped in the mouse brain. Linkage analysis mapped the disease locus to chromosome 3 and exome analysis identified a heterozygous missense variant in LMOD3 (p.E142D) in the linkage interval. The variant was found to segregate in all affected and one presumably unaffected member of the family. Resequencing LMOD3 in 38 other KLS patients and their families revealed three other low frequency or rare missense variants in seven cases that were inherited with incomplete penetrance. LMOD3 is expressed in the brain and colocalized with major structures involved in the regulation of vigilance states. LMOD proteins are structural proteins and seem to be developmentally regulated. Our findings suggest that KLS might be a structural/neurodevelopmental brain disease.

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Section: Discussionmentioning

confidence: 93%

Kleine‐Levin syndrome is associated with LMOD3 variants

Shareef

Basit

et al. 2018

Journal of Sleep Research

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“…The psychiatric symptomatology during KLS episodes has been previously described in several studies (Arnulf, Zeitzer, File, Farber, & Mignot, ; Arnulf et al., ; Huang et al., ; Lavault et al., ; Wang et al., ), but has sometimes been based on questionnaires rather than on psychiatric interviews (Arnulf et al., ). It most resembled clinical features of mood disorders and psychotic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…The episodes are frequently triggered by infections and separated by asymptomatic periods (Arnulf, Rico, & Mignot, ; Huang et al., ). Behavioural disturbances (hypersexuality, megaphagia or loss of appetite, aggressiveness and regressive behaviour) and psychiatric symptomatology (depressed mood, hallucinations, delusions and psychomotor excitement) are present during episodes in approximately half of patients (Arnulf et al., ; Wang et al., ). However, the characteristics of these symptoms are incompletely known.…”

Section: Introductionmentioning

confidence: 99%

Emerging psychiatric disorders in Kleine‐Levin syndrome

Groos

Chaumereuil

Flamand

et al. 2018

Journal of Sleep Research

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In Kleine-Levin syndrome (KLS), episodes of hypersomnia and cognitive, psychiatric and behavioural disturbances alternate with asymptomatic periods in adolescents. We evaluated whether psychiatric disorders would emerge during asymptomatic periods in a naturalistic, uncontrolled clinical cohort. Patients with primary KLS underwent psychiatric interviews at diagnosis and every year for 1-10 years, leading to diagnosis of former and present comorbid psychiatric disorders. Among the 115 patients (65.2% male and aged 16.1 ± 4.8 years at KLS onset), 19 (16.5%) had a history of psychiatric disorder prior to KLS onset, which persisted afterwards in 10. Twenty-five (21%) patients developed a new, comorbid psychiatric disorder 1-6 years after KLS onset, during 'asymptomatic' periods, including mood disorders (n = 14; including major depressive episodes, n = 8; recurrent depressive episodes, n = 2; bipolar I disorder, n = 1; dysthymic disorder, n = 1; adjustment disorder with depressive mood, n = 1; and mood disorder not otherwise specified, n = 1), anxiety disorders (n = 7), eating disorders (n = 2), psychotic disorders not otherwise specified (n = 2), schizoaffective disorder (n = 1) and cannabis dependence (n = 1). Six patients attempted suicide: two before and two after KLS onset, and two during episodes. Female sex, longer disease course, longer time incapacitated (356 ± 223 versus 155 ± 186 days) and more frequent psychiatric symptoms during episodes (but no family or personal history of psychiatric disorders) were associated with emerging psychiatric disorders. Contrary to the alleged benignity of KLS and normality between episodes, one KLS patient in five suffers from emerging psychiatric disorders. These disorders may depend on personal vulnerability and, most probably, on psychiatric symptoms during episodes.

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“…Algunos autores consideran una variante cuando se produce asociado al síndrome menstrual [8]. A pesar de haberse encontrado alteraciones en la neuroimagen funcional [13,14] y una orexina A (hipocretina 1) en el límite bajo en el líquido cefalorraquídeo de los pacientes durante los episodios [15], no existe actualmente una prueba diagnóstica.…”

Section: Discussionunclassified

Síndrome de Kleine-Levin: diagnóstico diferencial en los síndromes encefalíticos recurrentes del adolescente

Duat-Rodríguez¹,

Martinez-Albadalejo²,

Perez-Sebastian³

et al. 2017

RevNeurol

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Introducción. El síndrome de Kleine-Levin es una enfermedad rara de causa desconocida que se caracteriza por episodios recurrentes autolimitados de hipersomnia acompañados de alteración cognitiva y conductual. Entre los episodios, los pacientes tienen un patrón de sueño y cognitivo normal. Casos clínicos. Se presentan tres pacientes de 14 años, dos chicos y una chica. Comenzaron tras un desencadenante (vacuna, una infección respiratoria por influenza B; en el caso de la chica, coincidían con la menstruación). En el episodio agudo mostraban tendencia al sueño y en vigilia destacaba bradipsiquia, inquietud motora y gran labilidad emocional, con tendencia al llanto y necesidad de la presencia de los familiares. Presentaron una duración aproximada de 10-15 días y periodicidad mensual, y se mostraron asintomáticos entre los episodios. Los tres pacientes fueron valorados por pediatras, diagnosticados y tratados de encefalitis autoinmune. Sólo uno cumplía la tríada típica de hipersomnia, hiperfagia e hipersexualidad, pero ninguno de los tres datos se había recogido en la historia clínica inicial y la familia sólo lo refería tras una anamnesis dirigida. Conclusiones. En el síndrome de Kleine-Levin, los síntomas neurológicos durante el cuadro agudo son aún más frecuentes que los psiquiátricos. La tendencia al sueño y el hecho de que durante la vigilia no estén asintomáticos y se muestren lentos, apáticos, lábiles e irascibles, sitúa en primer lugar la sospecha de síndrome encefalítico. Debemos tener presente esta entidad en encefalitis recurrentes de etiología no filiada.

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Cerebrospinal Fluid Orexin A Levels and Autonomic Function in Kleine-Levin Syndrome

Abstract: There are lower orexin A levels in the symptomatic phase than in remission and a fall and rise in blood pressure and heart rate, suggesting a role for orexin dysregulation in KLS pathophysiology.

Cited by 43 publications

References 36 publications

Kleine‐Levin syndrome is associated with LMOD3 variants

Kleine‐Levin syndrome is associated with LMOD3 variants

Emerging psychiatric disorders in Kleine‐Levin syndrome

Síndrome de Kleine-Levin: diagnóstico diferencial en los síndromes encefalíticos recurrentes del adolescente

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