TSC1 as a Novel Gene for Sleep-Related Hypermotor Epilepsy: A Child with a Mild Phenotype of Tuberous Sclerosis.

Sleep-related hypermotor epilepsy (SHE) is a rare syndrome that presents with hyperkinetic asymmetric tonic/dystonic seizures with vegetative signs, vocalization, and emotional facial expression, mainly during light non-rapid eye movement sleep stages. The role of various genes (CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, NPRL2, NPRL3, and PRIMA1) has previously been reported, though genetic etiology is assessed in less than 10% of cases. We report the case of a 5-year-old female carrying the TSC1 variant c.843del p.(Ser282Glnfs*36) who presented with a mild phenotype of tuberous sclerosis, including carbamazepine-responsive SHE, normal neurocognitive functioning, hypomelanotic macules, no abnormalities outside the central nervous system, and tubers at neuroimaging. The presented case extends the list of SHE-related genes to include TSC1, thus suggesting a central pathogenic role of mammalian target of rapamycin (mTOR) cascade dysfunction in SHE and introducing a possible use of mTOR inhibitors in this epileptic syndrome.

Encephalopathy related to status epilepticus during sleep due to a de novo KCNA1 variant in the Kv-specific Pro-Val-Pro motif: phenotypic description and remarkable electroclinical response to ACTH.

Although the classic phenotype of episodic ataxia type 1 (EA1) caused by variants in KCNA1 includes episodic ataxia and myokymia, further genotype-phenotype correlations are difficult to establish due to highly heterogeneous clinical presentations associated with KCNA1 pathogenic variants. De novo variants in the paralogous Pro-Val-Pro motif (PVP) of KCNA2, an essential region for channel gating, have been reported to be associated with severe epilepsy phenotypes, including developmental and epileptic encephalopathies (DEE). Here, we describe the first patient with a DEE who developed an encephalopathy related to status epilepticus during sleep (ESES) and cerebellar signs, harbouring a variant in the Kv-specific PVP motif of the KCNA1 gene. Interestingly, he showed a remarkable long-term electroclinical response to IM ACTH therapy. This report extends the range of phenotypes associated with KCNA1 variants to include that of ESES, and suggests that ACTH therapy is likely to have a positive effect in patients with these variants.

Impaired glycinergic transmission in hyperekplexia: a model of parasomnia overlap disorder.

We report sleep phenotypes and polysomnographic findings in two siblings with a novel homozygous variant of the GLRA1 gene causing hereditary hyperekplexia (HH). Both sisters had startles during wakefulness and sleep, sleep terrors, and one had symptoms of REM sleep behavior disorder (RBD). Frequent startles were found in NREM sleep associated with NREM parasomnias in deep sleep. In REM sleep, both had motor behaviors and increased phasic/tonic muscle activities confirming RBD. Clonazepam improved startles, motor behaviors, and muscle activities in REM sleep. Impaired glycinergic transmission in human HH could be involved in the pathophysiology of RBD and NREM parasomnias.

Non-REM Parasomnia: The Promise of Precision Medicine.

Our understanding of non-REM parasomnias is just beginning to unfold the potential biomarkers and underlying pathophysiologic processes that lead to these events. Biomarkers need further investigation and will help us to understand better ways to develop risk models and possible mechanisms. Similarly, as we develop more accurate pathophysiologic-based diagnostic testing for non-REM parasomnias, we will begin the evolution toward a physiologic-based classification scheme that aids the application of precision medicine. This article explores currently known characteristics and exploratory features that may aid in this transition to better understanding our individual patients with non-REM parasomnias and tailoring their treatments.

A stereo EEG study in a patient with sleep-related hypermotor epilepsy due to DEPDC5 mutation.

PURPOSE: Dishevelled EGL-10 and pleckstrin domain-containing protein 5 (DEPDC5) mutations are found in a wide spectrum of focal epilepsies ranging from epilepsy caused by malformation of cortical development to non-lesional epilepsy, including sleep-related hypermotor epilepsy (SHE). A surgical approach has been anecdotally reported in patients with DEPDC5 mutations, but most of these cases had a lesional etiology. METHODS: We describe a stereo-EEG (SEEG) study in a patient with drug-resistant/non-lesional SHE. Patient was screened for known mutations associated with SHE. RESULTS: SEEG disclosed bilateral synchronous and independent activity prevailing on the right central-anterior cingulate cortex, without a clear spatially defined epileptogenic zone. Due to the lack of a clear epileptogenic zone, surgery was contraindicated. Years later a DEPDC5 mutation was identified. CONCLUSION: We suggest that genetic analysis should be considered before performing SEEG study in a patient with drug resistant non-lesional SHE, in the presence of seizures in wakefulness and unclear anatomo-electroclinical correlation. If DEPDC5 mutations are identified, the presurgical evaluation should be tailored to look for MRI-negative focal cortical dysplasia and a wide epileptogenic network. The appropriate management and potential benefit of surgery for genetic non-lesional epilepsy have yet to be clarified.

Aberrant Axonal Arborization of PDF Neurons Induced by Aß42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model.

Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aß42 AD model, we show that Aß42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aß42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aß42 flies. Finally, inhibition of JNK activation in Aß42 flies restores nighttime sleep loss, decreases Aß42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aß42 burden, a key initiator of a complex pathogenic cascade in AD.

Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas.

UNLABELLED: Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep-wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior. SIGNIFICANCE STATEMENT: Serotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep-wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder.

Early pathology in sleep studies of patients with familial Creutzfeldt-Jakob disease.

In this study, we aimed to assess sleep function in patients with recent-onset familial Creutzfeldt-Jakob disease (fCJD). The largest cluster of fCJD patients is found in Jews of Libyan origin, linked to the prion protein gene (PRNP) E200K mutation. The high index of suspicion in these patients often leads to early diagnosis, with complaints of insomnia being a very common presenting symptom of the disease. The study included 10 fCJD patients diagnosed by clinical manifestations, magnetic resonance imaging (MRI) scan of the brain, elevated tau protein in the cerebrospinal fluid (CSF) and positive PRNP E200K mutation. Standard polysomnography was performed after a brief interview confirming the presence of sleep disturbances. All patients showed a pathological sleep pattern according to all scoring evaluation settings. The sleep stages were characterized by (i) disappearance of sleep spindles; (ii) outbursts of periodic sharp waves and shallowing of sleep consisting in increased Stage 2 and wake periods during the night, as well as decrease of slow-wave sleep and rapid eye movement (REM) sleep. Recordings of respiratory functions reported irregular breathing with central and obstructive apnea and hypopnea. The typical hypotonia occurring during the night and atonia during REM sleep were replaced by hyperactive sleep consisting of multiple jerks, movements and parasomnia (mainly talking) throughout the night. In conclusion, we report unique pathological sleep patterns in early fCJD associated with the E200K mutation. Specific respiratory disturbances and lack of atonia could possibly serve as new, early diagnostic tools in the disease.

Not Only Sleepwalking But NREM Parasomnia Irrespective of the Type Is Associated with HLA DQB1*05:01.

STUDY OBJECTIVES: Despite the high prevalence and clinical relevance of NREM parasomnias, data on supportive genetic markers are scarce, and mainly refer to sleepwalking only. METHODS: We retrospectively analyzed clinical, polysomnographic, and HLA findings of 74 adults (37 men) with NREM parasomnia gathered from four neurological sleep centers. Parasomniac events were classified according to ICSD-2 criteria. HLA DQB1 genotyping was compared to regional-matched reference allele-frequencies. RESULTS: Fifty-six patients had more than 2 different parasomnia type: 11 sleepwalking, 4 sleep terrors, 3 confusional arousals only. Parasomniac events were documented during video-polysomnography (V-PSG) in 70% (49/70) of subjects (71.4% confusional arousals, 8.2% sleep terrors, 4.1% sleepwalking, 16.3% ≥ 2 NREM parasomnia types). Violent behavior during V-PSG occurred in 8.5% (6/71). NREM parasomnia onset was reported after the age of 30 years in 6.8% (5/74). The HLA DQB1*05:01 allele was present in 41% (29/71) compared to 24.2% in the regional-matched reference allele group (p < 0.05). This haplotype prevalence did not differ within the NREM parasomnia type. Epworth Sleepiness Score was 10 or higher in 28.6%. CONCLUSIONS: This is a large polysomnography-based case series of patients with NREM parasomnia. In patients with suspected sleepwalking or sleep terrors, polysomnography is highly useful in detecting arousals from NREM sleep as a marker of NREM parasomnia. We confirmed previous findings by demonstrating a high prevalence of the HLA DQB1*05:01 genotype for different types of NREM parasomnias. Our findings therefore support a common genetic background, and corroborate the importance of video-polysomnography in the work-up of parasomnia.

Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function.

OBJECTIVE: We assessed the mutation frequency in nicotinic acetylcholine receptor (nAChR) subunits CHRNA4, CHRNB2, and CHRNA2 in a cohort including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and sporadic nocturnal frontal lobe epilepsy (NFLE). Upon finding a novel mutation in CHRNA2 in a large family, we tested in vitro its functional effects. METHODS: We sequenced all the coding exons and their flanking intronic regions in 150 probands (73 NFLE, 77 ADNFLE), in most of whom diagnosis had been validated by EEG recording of seizures. Upon finding a missense mutation in CHRNA2, we measured whole-cell currents in human embryonic kidney cells in both wild-type and mutant α2ß4 and α2ß2 nAChR subtypes stimulated with nicotine. RESULTS: We found a c.889A>T (p.Ile297Phe) mutation in the proband (≈0.6% of the whole cohort) of a large ADNFLE family (1.2% of familial cases) and confirmed its segregation in all 6 living affected individuals. Video-EEG studies demonstrated sleep-related paroxysmal epileptic arousals in all mutation carriers. Oxcarbazepine treatment was effective in all. Whole-cell current density was reduced to about 40% in heterozygosity and to 0% in homozygosity, with minor effects on channel permeability and sensitivity to nicotine. CONCLUSION: ADNFLE had previously been associated with CHRNA2 dysfunction in one family, in which a gain of function mutation was demonstrated. We confirm the causative role of CHRNA2 mutations in ADNFLE and demonstrate that also loss of function of α2 nAChRs may have pathogenic effects. CHRNA2 mutations are a rare cause of ADNFLE but this gene should be included in mutation screening.

Benign neonatal sleep myoclonus: an autosomal dominant form not allelic to KCNQ2 or KCNQ3.

Benign neonatal sleep myoclonus is an uncommon, nonepileptic disorder characterized by myoclonic jerks appearing in the neonatal period that occur predominantly during sleep. Although self-limiting, the disorder is frequently confused with epileptic neonatal seizures. A few familial cases have been reported; however the genetics has not been studied. We ascertained 3 families with 2 or more affected individuals and analyzed the pedigrees. We used microsatellite markers to determine if the disorder was possibly linked to KCNQ2 or KCNQ3, the 2 genes that cause most cases of benign familial neonatal seizures, a disorder that it could be easily confused with. The 3 pedigrees, including one with 4 affected individuals, were suggestive of autosomal dominant inheritance. The loci for KCNQ2 and KCNQ3 were excluded in the 2 larger families. We conclude that benign neonatal sleep myoclonus can show autosomal dominant inheritance and is not allelic with benign familial neonatal seizures.

Parasomnias and nocturnal frontal lobe epilepsy (NFLE): lights and shadows--controversial points in the differential diagnosis.

Nocturnal frontal lobe epilepsy (NFLE) is characterized by seizures with complex, often bizarre, violent behaviour arising only or mainly during sleep. These unusual seizures and their occurrence during sleep are often accompanied by normal EEG tracings and neuroradiological findings, making it difficult to distinguish NFLE seizures from other non-epileptic nocturnal paroxysmal events, namely parasomnias. NFLE was described for the first time in 1981, but, as its epileptic origin was controversial, the condition was called nocturnal paroxysmal dystonia. Even though many aspects of parasomnias and NFLE have been clarified in the last two decades, the problem of differential diagnosis remains a challenge for clinicians. This paper discusses some controversial points still under debate. The difficulties in distinguishing nocturnal epileptic seizures from parasomnias reflect just one aspect of the intriguing issue of the pathophysiological relationships between all types of paroxysmal motor behaviours during sleep.

NREM parasomnias.

Considerable progress has been made in the systematic study of nonrapid eye movement (NREM) sleep parasomnias. This chapter focuses on the clinical features, prevalence, pathophysiology, associated sleep parameters, and clinical variants of the prototypic NREM sleep parasomnias, namely confusional arousals, sleepwalking, and sleep terrors. Whereas the occurrence of NREM parasomnias in children is frequently viewed as relatively benign, these disorders often pose greater problems, including sleep-related injuries, in affected adults. Most episodes arise from sudden but incomplete arousal from slow-wave sleep and sometimes from stage 2 sleep. Factors that deepen or fragment sleep can facilitate or precipitate NREM parasomnias in predisposed individuals. NREM parasomnias can be associated with various primary sleep disorders or with medical conditions. Diagnosis of NREM parasomnias can often be made based on a detailed history, although some patients may require more extensive evaluations, including polysomnographic study with an expanded EEG montage. Sleep deprivation and the presentation of auditory stimuli during slow-wave sleep are two techniques that can increase the occurrence of behavioral manifestations under laboratory conditions. A variety of nonpharmacological treatments have been recommended for long-term management of NREM parasomnias, whereas pharmacological agents should be considered only if the behaviors are hazardous or extremely disruptive.

Genes del sueño / Sleep Genes

Resumen. Introducción. El sueño es una estrategia adaptativa no aprendida que depende de la expresión de diversos neurotransmisores y otras moléculas. La expresión de varias de estas moléculas depende de diversos genes. Alteraciones del dormir se asocian con una inadecuada expresión de algunas moléculas, que indican entonces que estos genes que codifican estas moléculas participan en la regulación del sueño normal. Objetivo. Discutir la evidencia de la regulación de los genes sobre la ocurrencia del sueño y su arquitectura, así como de alteraciones del sueño, que sustenta la participación de genes específicos. Desarrollo. Se describe la evidencia sobre el sueño en mamíferos, particularmente en humanos, así como estudios con gemelos que evidencian la influencia genética en la regulación del sueño. Posteriormente, se discuten algunas alteraciones del sueño, que en esta revisión sólo sirven para enfatizar cómo ciertos genes específicos, en condiciones normales, participan en la expresión del sueño. Además, se da evidencia sobre otras moléculas, como los endocannabinoides, que participan en la regulación del sueño. Por último, se describen los estudios con diferentes cepas de ratones que manifiestan diferencias en la cantidad de sueño que expresan, posiblemente como epifenómeno de sus diferentes cargas genéticas. Conclusiones. Se han descrito diversos genes que nos hacen dormir, aunque dormir también depende de la interacción con el medio ambiente. Esta interacción es la que nos hace expresar el sueño en los momentos más convenientes para sobrevivir (AU)

Summary. Introduction. Sleep is a non-learned adaptive strategy that depends on the expression of several neurotransmitters and other molecules. The expression of some of these molecules depends on a number of different genes. Sleep disorders are associated with an inadequate expression of some molecules, which therefore indicates that these genes that code for these molecules participate in the regulation of normal sleep. Aim. To discuss the evidence on gene regulation over the occurrence of sleep and its architecture, as well as of sleep disorders, which supports the participation of specific genes. Development. We describe the evidence on sleep in mammals, particularly in humans, in addition to studies with twins that demonstrate the influence of genes on sleep regulation. We also discuss several sleep disorders, which in this study only serves to emphasise how certain specific genes, under normal conditions, participate in the expression of sleep. Furthermore, evidence is also provided for other molecules, such as endocannibinoids, involved in sleep regulation. Lastly, we report on studies conducted with different strains of mice that show differences in the amount of sleep they express, possibly as an epiphenomenon of their different genetic loads. Conclusions. A number of different genes have been described as those responsible for making us sleep, although sleeping also depends on our interaction with the environment. This interaction is what makes us express sleep at times that are best suited to favouring our survival (AU)

Parasomnias of childhood.

PURPOSE OF REVIEW: To enhance the ability of the practitioner to diagnose and manage children with parasomnias in the office setting. RECENT FINDINGS: Over 80% of preschool-age children experience parasomnia events. Instability in the regulation of sleep continuity might underlie sleep walking, sleep terrors, and confusional arousals. Catathernia or nocturnal groaning is a parasomnia that is recognized in adults but frequently has onset during childhood. SUMMARY: Common childhood parasomnias such as hypnic starts, rhythmic movement disorder, sleep paralysis, confusional arousals, sleepwalking, sleep terrors, enuresis, and nightmares are discussed. These events may lead to significant concern and worry for the parents. Most parasomnias are recognizable by history alone, but some may require nocturnal polysomnography for accurate diagnosis and determining an underlying trigger factor. Findings on nocturnal polysomnography are described. Sleep terrors, confusional arousals and sleepwalking may mimic seizures; distinguishing seizures from parasomnias is discussed. There is a genetic predisposition to many childhood parasomnias. Management techniques, including behavioral therapy, are reviewed. Unfortunately, evidence-based recommendations are as yet unavailable. The management of sleep enuresis continues to remain a significant challenge.

A genetic decomposition of the association between parasomnias and dyssomnias in 8-year-old twins.

OBJECTIVE: To estimate genetic and environmental influences on parasomnias and dyssomnias and their association in 8-year-olds. DESIGN: Parents of twins completed the Children's Sleep Habits Questionnaire. SETTING: Families were primarily tested at the Institute of Psychiatry, London, England. PARTICIPANTS: A total of 300 pairs of 8-year-old twins and their parents participated in the study. MAIN OUTCOME MEASURES: Sleep difficulties in children. RESULTS: Individual differences in parasomnias and dyssomnias were largely explained by genes (accounting for 50% and 71% of the variances, respectively). The rest of the variances were mainly due to nonshared environmental influences. A moderate association was found between parasomnias and dyssomnias (r = 0.42), which was mainly accounted for by genetic influences (87%). The genetic correlation between parasomnias and dyssomnias was moderate (r = 0.61). In contrast, the nonshared environmental correlation was small (r = 0.10). CONCLUSIONS: The decomposition of the association between parasomnias and dyssomnias suggests that there may be different manifestations of shared underlying genetic risks for sleep problems partly dependent on nonshared environmental influence.

Are there distinctive sleep problems in Angelman syndrome?

Angelman syndrome is a neurogenetic condition characterized by developmental delay, absence of speech, motor impairment, epilepsy and a peculiar behavioral phenotype that includes sleep problems. It is caused by lack of expression of the UBE3A gene on the maternal chromosome 15q11-q13. Although part of the diagnostic description, 'sleep problems' are not well characterized. A pattern emerges from the available reports. It includes reduced total sleep time, increased sleep onset latency, disrupted sleep architecture with frequent nocturnal awakenings, reduced rapid eye movement (REM) sleep and periodic leg movements. Poor sleep does not significantly interfere with daytime alertness and sleep problems commonly diminish by late childhood, with continuing improvement through adolescence and adulthood. Sleep problems in Angelman syndrome reflect abnormal neurodevelopmental functioning presumably involving dysregulation of GABA-mediated inhibitory influences in thalamocortical interactions. Management may be difficult, particularly in young children; it primarily involves behavioral approaches, though pharmacological treatment may be required. The relationship between sleep and seizure disorder, and between sleep and learning raises critical questions, but more studies are needed to address these relationships adequately.