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Aims: Heart rate variability (HRV) reveals information on the functional state of the autonomic nervous system (ANS). This study was initiated to assess the physiological- and maturational development of the ANS by comparing HRV data of healthy prematures with term infants. Methods: Short-term recordings of HRV in 39 premature healthy infants (29-35 weeks' gestation) were performed and compared with normative data of term infants. Frequency domain HRV parameters are computed in three frequency bands. Results: Gestational age of newborn infants is correlated with HRV. Prematures showed significant lower HRV parameters than term infants. The most significant differences were discerned for HRV parameters reflecting parasympathetic activity, whereas the pulse of the baro-receptor reflex was similar for prematures and term infants at 0.07 Hz (0.1 Hz adults). A respiratory peak in the HF-band according to respiratory sinus arrhythmia (RSA), as is common in adults, was not detected for prematures as it is not detected in term infants. Conclusions: Maturation of the ANS is accompanied by increasing HRV with a pronounced increase of parasympathetic activity. These changes are measurable by short-term recordings. The physiological pulses concerning baroreceptor reflex activity and respiratory modulation were similar in prematures and term infants. [ABSTRACT FROM AUTHOR]

Abstract Anaphylaxis to avocado, independent of latex sensitization, has been rarely reported in the literature. This case report describes a 15 year old male who experienced anaphylaxis within half an hour after eating avocado-containing food. Avocado consumption is common in both North America and South America. It is important to consider avocado as a cause of anaphylaxis, even in patients not sensitized to latex.

Background: Magnetic resonance imaging in fetal alcohol spectrum disorder (FASD) children showed altered connectivity, suggesting underlying deficits in networks, which may be related to cognitive outcome. Functional connectivity has been of interest in neurophysiological research with quantitative electroencephalography (QEEG) as useful tool for measuring pathology, not detectable by normal EEG. The aim of this study was to investigate differences in the EEG interhemispheric coherence (ICoh) in children diagnosed with FASD compared with healthy controls and to relate the results to cognitive scores., Method: Analysis of ICoh in 81 FASD children (4-Digit Code) compared with 31 controls. The children underwent cognitive assessment, and EEG was performed and used for analysis. Group comparisons and analysis of covariance interaction models were used to test for differences between FASD and controls but also to look for differences between FASD subgroups. Significant findings were correlated to cognitive scores., Results: Lower ICoh was found in the frontal and temporal derivations in the FASD group. When comparing FASD subgroups, children with fetal alcohol syndrome had lower ICoh occipital. Reduced ICoh in the temporal alpha band was correlated with lower performance IQ in the FASD group., Conclusion: Our findings could imply hypoconnectivity between the hemispheres with impact on cognition. We suggest that EEG coherence analysis could be a sensitive parameter in the detection of electrophysiological abnormalities in FASD with possible clinical relevance. These results may indicate that QEEG could be used as biomarker for FASD. However, further research is needed to determine the role of QEEG analysis in the diagnosis of FASD., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Fetal alcohol spectrum disorder (FASD) comprises a combination of developmental, cognitive, and behavioral disabilities that occur in children exposed to alcohol prenatally. A higher prevalence of epilepsy and pathological electroencephalographic (EEG) features have also been reported in individuals with FASD. We examined the frequency of epilepsy, pathological EEG findings, and their implications for cognitive and adaptive functioning in children with FASD., Methods: We conducted a cross-sectional study of 148 children with FASD who underwent a multidisciplinary assessment and a 120-min EEG recording. Group comparisons and regression analyses were performed to test the associations between epilepsy and pathological EEG findings, FASD subgroups and neurocognitive test results and adaptive functioning., Results: The frequency of epilepsy was 6%, which compares with 0.7% in Norway overall. Seventeen percent of children without epilepsy had pathological EEG findings. Attention-deficit hyperactivity disorder (ADHD) was diagnosed in 64% of the children. Children with epilepsy and/or pathological EEG findings had comparable cognitive and adaptive scores to those with normal EEG. However, children with frontal EEG pathology (without epilepsy) had significantly lower scores on the IQ indices Processing speed and Working memory than FASD children without such findings, irrespective of ADHD comorbidity., Conclusions: There was a greater prevalence of epilepsy among children with FASD than in the general Norwegian population. A greater frequency of EEG pathology was also evident in children without epilepsy, across all FASD subgroups. Irrespective of epilepsy, ADHD comorbidity, and FASD subgroup, children with frontal EEG pathology, despite having a normal total IQ, showed significantly slower processing speed and poorer working memory, which may indicate specific executive function deficits that could affect learning and adaptive functioning., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy that has a cumulative incidence of 0.015 to 0.7% in infants [1]. The most common allergens causing FPIES reactions include cow's milk, followed by soy, grains, and rice [1, 3]. Increasing clinical awareness of FPIES has resulted in the expansion of emerging triggers of FPIES, including fruit antigens., Case Presentation: We describe an infant diagnosed with FPIES to prune., Conclusion: Fruit allergens are an emerging group of triggers for FPIES, both in their fresh and dried forms. To our knowledge, this case is the first presentation of FPIES to prunes (dehydrated plum). This case highlights that careful history taking can avoid unnecessary investigations and delay in diagnosing FPIES., (© 2023. The Author(s).)

Background: Fetal alcohol spectrum disorder (FASD) describes a combination of developmental, cognitive, and behavioral disabilities in children with prenatal exposure to alcohol. The literature suggests that there are higher rates of sleep disturbances in these children. Few studies have investigated sleep disturbances in relation to common comorbidities of FASD. We examined the prevalence of disturbed sleep and the relationship between parent-reported sleep problems in different FASD subgroups and comorbidities like epilepsy or attention-deficit hyperactivity disorder (ADHD) and impact on clinical functioning., Methods: In this prospective cross-sectional survey, caregivers of 53 children with FASD completed the Sleep Disturbance Scale for Children (SDSC). Information about comorbidities was collected, and EEG and assessment of IQ, daily-life executive and adaptive functioning were performed. Group comparisons and ANCOVA interaction models were used to test the associations between different sleep disturbances and clinical factors that could interfere with sleep., Results: An abnormal sleep score on the SDSC was very common, affecting 79% of children (n = 42) with equal prevalence in all FASD subgroups. Difficulty falling asleep was the most common sleep problem, followed by difficulty staying asleep and waking early. The incidence of epilepsy was 9.4%, with an abnormal EEG seen in 24.5%, and a diagnosis of ADHD in 47.2% of children. The distribution of these conditions was equal in all FASD subgroups. Children with signs of sleep disturbance had poorer working memory, executive function, and adaptive functioning. Children with ADHD had a greater prevalence of sleep disturbance than those without ADHD (OR 1.36; 95% CI 1.03 to 1.79)., Conclusion: Problems with sleep are very common in FASD children and seem independent of FASD subgroup and the presence of epilepsy or a pathological EEG finding, while those with ADHD had more sleep problems. The study underscores the importance of screening for sleep disturbances in all children with FASD as these problems may be treatable., (© 2023 Research Society on Alcohol.)

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.

Background: Pyridoxine-dependent epilepsy (PDE) is a rare seizure disorder usually presenting with neonatal seizures. Most cases are caused by biallelic pathogenic ALDH7A1variants. While anti-seizure medications are ineffective, pyridoxine provides seizure control, and dietary interventions may be of benefit. As the natural history beyond adolescence is insufficiently explored, our study aimed to assess the spectrum of PDE at various ages in Norway., Methods: Patients were ascertained by contacting all Norwegian paediatric, neurological, and neurohabilitation departments and relevant professional societies. Medical records were collected and reviewed., Results: We identified 15 patients treated for PDE; 13 had ALDH7A1 variants (PDE-ALDH7A1), one had PNPO deficiency, and in one, aetiology remained obscure. Of those with PDE-ALDH7A1, 12 were alive at time of study; five were > 18 years old and six were < 4 years. Median age was 10 years (range 2 months-53 years). Estimated minimum prevalence was 6.3/million among children and 1.2/million among adults. Ten had seizure onset on the first day of life. Perinatal complications and neuroradiological abnormalities suggested additional seizure aetiologies in several patients. Pyridoxine had immediate effect in six, while six had delayed (>1 h) or uncertain effect. Median delay from first seizure to continuous treatment was 11 days (range 0-42). Nine experienced breakthrough seizures with intercurrent disease or due to pyridoxine discontinuation. Cognitive outcomes ranged from normal to severe intellectual disability. The condition appeared to remain stable in adult life., Significance: We found a much higher prevalence of PDE-ALDH7A1 in children relative to adults, suggesting previous underdiagnosis and early mortality. Perinatal complications are common and can delay diagnosis and initiation of pyridoxine treatment. Lifelong and continuous treatment with pyridoxine is imperative. Due to better diagnostics and survival, the number of adult patients is expected to rise., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs., (© The Author(s) 2021. Published by Oxford University Press.)

Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel α-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary β-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary β-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: There is an increasing interest in cannabinoid-based products for the treatment of refractory pediatric epilepsy. However, a licensed cannabidiol (CBD) product was first approved for use by the European regulatory authorities in 2019. We aimed to obtain knowledge about clinical experience and attitudes toward cannabinoid use for epilepsy treatment among neuropediatricians in Scandinavia and Germany in the era before a CBD-product was commercially licensed and available. Study design: An internet-based questionnaire (Survey Monkey) was distributed by email to members of neuropediatric societies in Sweden, Germany, Denmark, and Norway between February and April 2018. One reminder email was sent. Results: Eighty-six responded. Only 10 of 86 (12%) respondents had personal experience with off-label prescription of cannabinoid-based products, mainly for severe refractory pediatric epilepsies like Dravet syndrome and Lennox-Gastaut syndrome. However, 49 respondents (57%) had been exposed to relatives of patients that had requested or wanted to discuss cannabinoid therapy, and 32 (37%) respondents knew about cannabinoid self-medication. The knowledge regarding cannabinoid-based therapy among the respondents was overall limited. Main reasons for not prescribing cannabinoid-based therapy were concerns about law regulations and lack of an available product. Conclusion: Off-label cannabinoid-based therapy for pediatric epilepsy was not widely prescribed by neuropediatricians in Scandinavia and Germany in 2018., (Copyright © 2020 Klingenberg, Mouslet, Hjalgrim and Gerstner.)

The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Autosomal dominant congenital mirror movements (CMM) is a neurodevelopmental disorder characterized by early onset involuntary movements of one side of the body that mirror intentional movements on the contralateral side; these persist throughout life in the absence of other neurological symptoms. The main culprit genes responsible for this condition are RAD51 and DCC . This condition has only been reported in a few families, and the molecular mechanisms linking RAD51 mutations and mirror movements (MM) are poorly understood., Methods: We collected demographic, clinical, and genetic data of a new family with CMM due to a truncating mutation of RAD51. We reviewed the literature to identify all reported patients with CMM due to RAD51 mutations., Results: We identified a heterozygous nonsense mutation c.760C>T (p.Arg254*) in eight subjects: four with obvious and disabling MM, and four with a mild phenotype. Including our new family, we identified 32 patients from 6 families with CMM linked to RAD51 variants., Discussion: Our findings further support the involvement of RAD51 in CMM pathogenesis. Possible molecular mechanisms involved in CMM pathogenesis are discussed., Competing Interests: Funding: We thank Merz-pharmaceuticals and the Vestre Viken Hospital Trust (JK) for financial support of this study. Conflict of Interest: The authors report no conflict of interest related to this paper. Ethics statement: Written informed consent was obtained from all included family members in accordance with the ethical agreement 2012/1451 of the Regional Ethical Committee in Norway. This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki. The authors’ institutional ethics committee has approved this study and all patients have provided written informed consent. All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

This paper presents a new initiative in the South-Eastern Health Region of Norway to establish a regional resource center focusing on services for children and adolescents aged 2-18 years with prenatal exposure to alcohol or other drugs. In Norway, the prevalence of fetal alcohol spectrum (FAS) is not known but has been estimated to be between 1 and 2 children per 1000 births, while the prevalence of prenatal exposure to illicit drugs is unknown. The resource center is the first of its kind in Scandinavia and will have three main objectives: (1) provide hospital staff, community health and child welfare personnel, and special educators with information, educational courses, and seminars focused on the identification, diagnosis, and treatment of children with a history of prenatal alcohol/drug exposure; (2) provide specialized health services, such as diagnostic services and intervention planning, for children referred from hospitals in the South-Eastern Health Region of Norway; and (3) initiate multicenter studies focusing on the diagnostic process and evaluation of interventions.