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Chronic sleep deprivation is a common, treatable condition among adolescents. Growing literature supports a myriad consequences that impact overall health, behavior, mood, and academic performance in this vulnerable age group during a time when there are rapid changes in physical development and emotional regulation. This article reviews the epidemiology and health effects of sleep deprivation in adolescents as well as common disorders leading to sleep loss and evidence to support treatment. Although a variety of important sleep disorders may disrupt quality of sleep in adolescents, such as obstructive sleep apnea, restless leg syndrome, and narcolepsy, this article will focus on common disorders that affect the quantity of sleep, such as poor sleep hygiene, circadian rhythm disorders, and insomnia.

The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.

Objectives To describe the characteristics of epilepsy in patients with Neurofibromatosis type 1 (NF1). Methods Analysis of a cohort of consecutive NF1 patients seen in our NF1 clinic during a three-year period. Results Of the 184 NF1 patients seen during that period, 26 had epilepsy and three had febrile seizures. Of the 26, 17 (65%) had localization-related epilepsy, seven of whom (41%) were drug resistant. Six (23%) had apparently primary generalized epilepsy (0/6 drug resistant), two (8%) Lennox-Gastaut syndrome, and one (4%) West syndrome (all three were drug-resistant). As compared to the patients with no epilepsy, those with epilepsy were more likely to have MRI findings of mesial temporal sclerosis (MTS) (23% vs. 5%, p = 0.0064), and cerebral hemisphere tumors (31% vs. 10%, p = 0.0079), but not of the other MRI findings including neurofibromatosis bright objects, or optic gliomas. Three of the six patients with MTS underwent temporal lobectomy with subsequent control of their seizures with confirmation of MTS on pathology in 3/3 and presence of coexisting focal cortical dysplasia (FCD) in 2/3. We also have observed three additional patients outside the above study with the association of NF1, MTS, and intractable epilepsy. Significance Epilepsy is relatively common in NF1, often occurs in patients with brain tumors or with MTS which can coexist with FCD, can be associated with multiple types of epilepsy syndromes, and when localization-related is often drug-resistant. Patients with NF1 and MTS can respond to medial temporal lobectomy and may have coexisting medial temporal lobe cortical dysplasia.

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( NACC1 ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 −14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1 .

The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.

Aim. KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations.Methods. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres.Results. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient.Conclusions. Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

STUDY OBJECTIVES: Patients with alternating hemiplegia of childhood (AHC) experience bouts of hemiplegia and other paroxysmal spells that resolve during sleep. Patients often have multiple comorbidities that could negatively affect sleep, yet sleep quality and sleep pathology in AHC are not well characterized. This study aimed to report sleep data from both polysomnography (PSG) and clinical evaluations in children with AHC. METHODS: We analyzed nocturnal PSG and clinical sleep evaluation results of a cohort of 22 consecutive pediatric patients with AHC who were seen in our AHC multidisciplinary clinic and who underwent evaluations according to our comprehensive AHC clinical pathway. This pathway includes, regardless of presenting symptoms, baseline PSG and evaluation by a board-certified pediatric sleep specialist. RESULTS: Out of 22 patients, 20 had at least one type of sleep problem. Six had obstructive sleep apnea as documented on polysomnogram, of whom two had no prior report of sleep-disordered breathing symptoms. Patients had abnormal mean overall apnea-hypopnea index of 5.8 (range 0–38.7) events/h and an abnormal mean arousal index of 15.0 (range 4.8–46.6) events/h. Based on sleep history, 16 patients had difficulty falling asleep, staying asleep, or both; 9 had behavioral insomnia of childhood; and 2 had delayed sleep-wake phase syndrome. CONCLUSIONS: Sleep dysfunction is common among children with AHC. Physicians should routinely screen for sleep pathology, with a low threshold to obtain a nocturnal PSG. CITATION: Kansagra S, Ghusayni R, Kherallah B, Gunduz T, McLean M, Prange L, Kravitz RM, Mikati MA. Polysomnography findings and sleep disorders in children with alternating hemiplegia of childhood. J Clin Sleep Med. 2019;15(1):65–70.

Item does not contain fulltext Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Infantile Pompe disease is a rare, metabolic disorder due to deficiency of the enzyme acid α-glucosidase that degrades lysosomal glycogen. The deficiency leads to multisystem dysfunction. Neuromuscular weakness due to metabolic myopathy is present, which predisposes children to sleep-disordered breathing. With the advent of enzyme replacement therapy (ERT), children are living longer, and there is a new natural history that is emerging. In a prior paper on our cohort of infantile Pompe disease patients, we reported a high incidence of both hypoventilation and obstructive sleep apnea (OSA). In this retrospective study, we analyzed longitudinal nocturnal polysomnography results from 10 patients with infantile-onset Pompe disease, all of which were on enzyme replacement therapy for a mean of 34.9 months at the time of follow-up study. Patients demonstrated relative stability in sleep disordered breathing, with a trend towards improvement in both OSA and central sleep apnea. ERT may help in the treatment of sleep apnea in this cohort. © 2015 Wiley Periodicals, Inc.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

Infantile Pompe disease is a rare, autosomal recessive disorder due to deficiency of the enzyme acid α-glucosidase that degrades lysosomal glycogen. Clinical features of diffuse hypotonia, cardiomyopathy, and weakness are present within the first days to months of life in patients with classic infantile Pompe disease. Progression of the disease often leads to respiratory failure. Although sleep apnea is reported in late-onset Pompe disease, sleep pathology is not well characterized in infantile disease. In this retrospective study, we analyzed nocturnal polysomnography results from 17 patients with infantile-onset Pompe disease. Obstructive sleep apnea and hypoventilation were common among this cohort, even in those that did not have symptoms of sleep-disordered breathing. All patients with infantile-onset Pompe disease should undergo polysomnography as a routine part of their care.

We describe the electroencephalographic and clinical seizure manifestations of pyridoxal 5'-phosphate-dependent epilepsy (PLP-DE) in two patients [diagnosis confirmed by low cerebrospinal fluid (CSF) PLP, complete resolution of previously intractable seizures with PLP supplementation, negative pyridoxine-dependent epilepsy CSF biomarkers, and/or positive disease causing pyridox(am)ine 5'-phosphate oxidase gene mutation] along with a comprehensive review of the literature. One patient presented with neonatal tonic status epilepticus with subsequent generalized tonic-clonic seizures, and the second, with refractory complex partial seizures starting at 2 years of age. The pretreatment EEG revealed, interictally, burst suppression, multifocal independent sharp waves, and electrical status epilepticus in sleep. Ictally and interictally, it revealed runs of unilateral spike/slow waves. Previously reported features include burst suppression, myoclonus, tonic seizures, clonic seizures, and spasms. In the appropriate clinical scenario, the aforementioned features should raise the possibility of PLP-DE and appropriate treatment should be initiated. The first late-onset case (at 2 years) of PLP-DE is reported.

We report four patients with no preexisting movement disorders who developed oculogyric crises secondary to lamotrigine toxicity and had resolution of these crises after dose reduction. Episode numbers ranged from 1-20 per day and episode duration from 2 s to several hours. Mean plasma concentration of lamotrigine at the time of oculogyric crisis was 15.5 μg/mL, with a mean dose of 16 mg/kg per day.

Summary Obstructive sleep apnea is a frequently overlooked, treatable disorder that is common among children. This article discusses 5 important aspects of this disorder that might not be known to the general pediatric practitioner or pediatric neurologist. These aspects are important in screening, properly evaluating, and treating children with obstructive sleep apnea.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by loss of REM sleep atonia and clinical manifestations of dream reenactment. Patients typically present at the request of bed partners due to the often violent and dangerous nature of this nighttime disorder. RBD can present at any age, and is frequently associated with narcolepsy in the younger population. Older patients presenting with idiopathic RBD have a significant risk of developing neurodegenerative conditions. RBD is associated with other changes in the central nervous system (CNS) such as decreased olfaction, visuospatial issues, and mild slowing on electroencephalography (EEG). Treatment involves ensuring environmental safety, eliminating predisposing factors, and initiating medications such as clonazepam and melatonin. Given the relationship of RBD to neurodegenerative conditions, RBD represents a unique opportunity to understand the neuroanatomical basis for REM sleep-related mechanisms and may be a leading indicator for patients who may benefit from neuroprotective treatments for these neurodegenerative diseases.

Alternating hemiplegia of childhood (AHC) is a very rare disease characterized by recurrent attacks of loss of muscular tone resulting in hypomobility of one side of the body. The etiology of the disease due to ATP1A3 gene mutations in the majority of patients. Few familial cases have been described. AHC has an onset in the first few months of life. Hemiplegic episodes are often accompanied by other paroxysmal manifestations, such as lateral eyes and head deviation toward the hemiplegic side and a very peculiar monocular nystagmus. As the attack progresses, hemiplegia can shift to the other side of the body. Sometimes the attack can provoke bilateral paralysis, and these patients may have severe clinical impairment, with difficulty in swallowing and breathing. Hemiplegic attacks may be triggered by different stimuli, like bath in warm water, motor activity, or emotion. The frequency of attacks is high, usually several in a month or in a week. The duration is variable from a few minutes to several hours or even days. Sleep can stop the attack. Movement disorders such as dystonia and abnormal movements are frequent. Cognitive delay of variable degree is a common feature. Epilepsy has been reported in 50% of the cases, but seizure onset is usually during the third or fourth year of life. Many drugs have been used in AHC with very few results. Flunarizine has the most supportive anecdotal evidence regarding efficacy.

Acute necrotizing encephalopathy is a rare, clinically distinct entity characterized by multiple, symmetric areas of edema and necrosis in the thalamus, cerebellum, brainstem, and white matter. It is postulated to arise from uncontrolled cytokine release during a febrile illness, and is most often seen in East Asia. We describe a rare North American case of acute necrotizing encephalopathy attributable to human herpes virus-6 is a 9-month-old white male. The infant moved to the United States from Hong Kong, 3 months before disease onset. A workup revealed elevations in serum interleukin-1β, interleukin-2, and interleukin-10, with normal values of interleukin-6 and tumor necrosis factor-α after the initiation of high-dose steroids. This profile is unique compared with previous cytokine profiles of this disease, possibly because of the effects of steroid therapy. A rare North American case with a history of birth in East Asia underscores the possibility of a role for environmental pathogens in this disease.

Aim. Assess quality-of-life after vagal nerve stimulation and determine patient characteristics associated with improvement in quality-of-life. Methods. Sixteen patients (11 children, 5 adults) who had vagal nerve stimulation at our center were studied. Quality-of-life was assessed pre- and post-vagal nerve stimulation using the Quality-of-Life in Childhood Epilepsy questionnaire for children and the Epilepsy Surgery Inventory-55 for adults. Results. Sixteen patients who did not qualify for resective surgery were included; seven (43.75%) were males and 9 (56.25%) were females. Mean age at onset of seizures was 3.96 ± 4.00 years and at surgery was 15.78 ± 10.78. Follow-up time was 1.26 ± 0.92 years. Fourteen patients (87.5%) were mentally retarded. Ten (62.5%) had cryptogenic etiology and 6 patients (37.5%) symptomatic etiology. Fifty percent had localization-related epilepsy. Six of 7 patients with generalized cryptogenic etiology (85.71%) had Lennox-Gastaut syndrome. Seizures dropped from 122.31 ± 159.49 to 67.84 ± 88.22 seizures/month. Seizure reduction (> 50%) correlated with improvement in total quality-of-life (p = 0.034). Post-vagal nerve stimulation, the total group scored significantly higher in the social domain (p = 0.039). In patients with localization-related epilepsy, significant improvements were detected in the social domain (p = 0.049) and in total quality-of-life (p = 0.042). Conclusion. Despite a diverse and small population size, we observed significant improvements in the social domain 1.26 years post-vagal nerve stimulation. In addition, there was an improvement in total quality-of-life amongst patients with partial seizures. Finally, seizure reduction was associated with quality-of-life improvement. Our results support previous studies from the West reporting improvement in quality-of-life following vagal nerve stimulation, contradict those studies that did not show such differences, and are the first coming from a developing country.

Narcolepsy is characterized by fragmented nighttime sleep and frequent arousals. One treatment approach to improve daytime symptoms is to consolidate nighttime sleep through decreasing arousals. Sodium oxybate is the first FDA-approved medication that follows this approach. Benzodiazepines are known to also decrease arousals at night and have been proposed to help with sleep fragmentation. In one report, clonazepam was shown to improve cataplexy in 10 of 14 patients with narcolepsy although no improvement in daytime sleepiness was reported. The purpose of this case review was to share our experience of nocturnal temazepam on daytime sleepiness in patients with narcolepsy as measured by the Epworth Sleepiness Scale (ESS).

The effects of vagus nerve stimulation on weight in individuals with epilepsy are not fully characterized. A retrospective review was performed of all pediatric patients who underwent placement of a vagus nerve stimulator at Duke University Medical Center. Baseline body mass index (BMI) percentile was compared with percentile on follow-up visits. We studied 23 patients who had undergone VNS placement during the period 2001–2009. Baseline BMI percentile was 61.7 ± 34.3. We had a power of 81% to detect a difference of 20 in BMI percentile from baseline to last follow-up. At the 1-year follow-up (mean = 345 ± 112 days) and last follow-up (mean 4.2 ± 2.4 years) the average BMI percentile was 61.6 ± 31.88 and 56.09 ± 30.83, respectively. There was no significant difference in BMI percentile as compared with baseline at the 1-year and last follow-up visits ( P = 0.992 and 0.681, respectively). Long-term pediatric VNS therapy did not have a major clinically significant effect on BMI percentile during an average follow-up of more than 4 years.