Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy.

STUDY OBJECTIVES: We examined body mass index (BMI) changes associated with sodium oxybate treatment (SXB) in pediatric patients with narcolepsy with cataplexy who participated in a double-blind, placebo-controlled, randomized withdrawal study and an open-label continuation period. METHODS: Participants were aged 7-16 years at screening. SXB-naive participants titrated to twice-nightly dosing of SXB then entered a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period. After a 2-week randomized withdrawal period, all participants entered an open-label safety period (OLP; main study duration: ≤ 52 weeks). Participants who completed the OLP were allowed to enter the open-label continuation period (an additional 1-2 years). BMI percentile categories were defined as underweight (< 5th), normal (5th to < 85th), overweight (≥ 85th to < 95th), and obese (≥ 95th). RESULTS: Median BMI percentile decreased from baseline to OLP week 52 in SXB-naive participants who were normal weight at baseline (decreased from 77.0 to 35.0) or overweight/obese at baseline (98.0 to 86.7). Median BMI percentile decreased to a lesser extent in participants taking twice-nightly SXB at study entry who were normal weight at baseline (54.6 to 53.0) or overweight/obese at baseline (96.5 to 88.9). Shifts in BMI category from baseline to week 52 were sometimes noted. In SXB-naive participants, 9/10 (90.0%) who were overweight became normal weight, 7/25 (28.0%) who were obese became normal weight, 3/25 (12.0%) who were obese became overweight, and 1/16 (6.3%) who was normal weight became obese. In participants taking SXB at baseline, 5/8 (62.5%) who were overweight became normal weight, 3/6 (50.0%) who were obese became overweight, 1/14 (7.1%) who was normal weight became overweight, and 2/14 (14.3%) who were normal weight became underweight. Median BMI percentiles at months 6 and 12 of the open-label continuation period were similar to those at OLP end (OLP week 52). In SXB-naive participants, the evident BMI z-score decrease over time was relative to the screening values. CONCLUSIONS: Decreases in BMI percentile and z-score, and downward shifts in BMI category, were observed within 1 year of SXB treatment in pediatric participants with narcolepsy with cataplexy. BMI decreases plateaued after approximately 1 year. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem With an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy; URL: https://clinicaltrials.gov/study/NCT02221869; Identifier: NCT02221869. CITATION: Dauvilliers Y, Lammers GJ, Lecendreux M, et al. Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy. J Clin Sleep Med. 2024;20(3):445-454.

The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss of imaginal discs in the larva. Loss of drosha in eye clones causes small and rough eyes in adult flies. One of the identified DROSHA variants (p.Asp1219Gly) behaves as a strong loss-of-function allele in flies, while another variant (p.Arg1342Trp) is less damaging in our assays. In worms, a knock-in that mimics the p.Asp1219Gly variant at a worm equivalent residue causes loss of miRNA expression and heterochronicity, a phenotype characteristic of the loss of miRNA. Together, our data show that the DROSHA variants found in the individuals presented here are damaging based on functional studies in model organisms and likely underlie the severe phenotype involving the nervous system.

Impact of daily caffeine intake and timing on electroencephalogram-measured sleep in adolescents.

STUDY OBJECTIVES: Caffeine use is ubiquitous among adolescents and may be harmful to sleep, with downstream implications for health and development. Research has been limited by self-reported and/or aggregated measures of sleep and caffeine collected at a single time point. This study examines bidirectional associations between daily caffeine consumption and electroencephalogram-measured sleep among adolescents and explores whether these relationships depend on timing of caffeine use. METHODS: Ninety-eight adolescents aged 11-17 (mean =14.38, standard deviation = 1.77; 50% female) participated in 7 consecutive nights of at-home sleep electroencephalography and completed a daily diary querying morning, afternoon, and evening caffeine use. Linear mixed-effects regressions examined relationships between caffeine consumption and total sleep time, sleep-onset latency, sleep efficiency, wake after sleep onset, and time spent in sleep stages. Impact of sleep indices on next-day caffeine use was also examined. RESULTS: Increased total caffeine consumption was associated was increased sleep-onset latency (ß = .13; 95% CI = .06, .21; P < .001) and reduced total sleep time (ß = -.17; 95% confidence interval [CI] = -.31, -.02; P = .02), sleep efficiency (ß = -1.59; 95% CI = -2.51, -.67; P < .001), and rapid eye movement sleep (ß = -.12; 95% CI = -.19, -.05; P < .001). Findings were driven by afternoon and evening caffeine consumption. Reduced sleep efficiency was associated with increased afternoon caffeine intake the following day (ß = -.006; 95% CI = -.012, -.001; P = .01). CONCLUSIONS: Caffeine consumption, especially afternoon and evening use, impacts several aspects of adolescent sleep health. In contrast, most sleep indicators did not affect next-day caffeine use, suggesting multiple drivers of adolescent caffeine consumption. Federal mandates requiring caffeine content labeling and behavioral interventions focused on reducing caffeine intake may support adolescent sleep health. CITATION: Lunsford-Avery JR, Kollins SH, Kansagra S, Wang KW, Engelhard MM. Impact of daily caffeine intake and timing on electroencephalogram-measured sleep in adolescents. J Clin Sleep Med. 2022;18(3):877-884.

Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features.

The Polycomb group (PcG) gene RNF2 (RING2) encodes a catalytic subunit of the Polycomb repressive complex 1 (PRC1), an evolutionarily conserved machinery that post-translationally modifies chromatin to maintain epigenetic transcriptional repressive states of target genes including Hox genes. Here, we describe two individuals, each with rare de novo missense variants in RNF2. Their phenotypes include intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Population genomics data suggest that RNF2 is highly constrained for loss-of-function (LoF) and missense variants, and both p.R70H and p.S82R variants have not been reported to date. Structural analyses of the two alleles indicate that these changes likely impact the interaction between RNF2 and BMI1, another PRC1 subunit or its substrate Histone H2A, respectively. Finally, we provide functional data in Drosophila that these two missense variants behave as LoF alleles in vivo. The evidence provide support for deleterious alleles in RNF2 being associated with a new and recognizable genetic disorder. This tentative gene-disease association in addition to the 12 previously identified disorders caused by PcG genes attests to the importance of these chromatin regulators in Mendelian disorders.

Sleep Disorders in Adolescents.

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.

Polysomnography Findings and Sleep Disorders in Children With Alternating Hemiplegia of Childhood.

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.

IRF2BPL Is Associated with Neurological Phenotypes.

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.

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

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.

Epilepsy in neurofibromatosis type 1.

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.

A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.

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.

A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.

Epilepsy in KCNH1-related syndromes.

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. 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. 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. 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.

Longitudinal polysomnographic findings in infantile Pompe disease.

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.

Polysomnographic findings in infantile Pompe disease.

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.

Nocturnal temazepam in the treatment of narcolepsy.

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).

Alternating hemiplegia of childhood.

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.