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Introduction: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure without an evident cause. Obesity and the female sex have been recognized as risk factors for the development of this syndrome. Until now, Graves’ disease has only been described in the literature as the probable cause of IIH in 7 patients. This report describes the case of a young girl with Graves’ disease presenting with symptoms of intracranial hypertension (IH). Case Presentation: A 21-month-old girl presented with progressive symptoms of poor weight gain and bilateral exophthalmos. She also experienced difficulty sleeping, diarrhea multiple times per day, irritability, and heat intolerance. Laboratory investigation showed elevated free T4, fully suppressed TSH, and elevated anti-TSH antibodies, consistent with a diagnosis of new-onset Graves’ disease. She was successfully treated with monotherapy thiamazole, titrated to the lowest possible dose of 1.25 mg once daily with normalization of thyroid function tests within 3 months of treatment initiation. After 18 months of treatment, her condition unexpectedly deteriorated as papilledema and slight esotropia were found at a routine checkup. An MRI and lumbar puncture showed increased intracranial pressure, but no underlying anatomical cause for the IH was found. Acetazolamide therapy was started, and papilledema in both eyes resolved within weeks. Unfortunately, papilledema has recurred several times over the following 2 years when attempts were made to decrease the acetazolamide dose. Discussion/Conclusion: This case report is the first to describe a very young patient who developed significant IIH in the chronic stage of Graves’ disease. IIH development seemed to be related to the progression of the Graves’ ophthalmopathy, rather than initiation of thiamazole therapy or fluctuations in serum fT4 levels.

Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access) PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Objective: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM.Methods: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5-16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) >= 4) were assessed during a median follow-up of 37 months (IQR 18-75).Results: In total, 14 patients (29%) experienced >= 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02).Conclusion: Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome. (C) 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V.

Intracerebral hemorrhage is rare in term born neonates. Besides several non-genetic risk factors, pathogenic variants in COL4A1 and COL4A2 have been described to play a role in the pathophysiology of neonatal intracerebral hemorrhage. To the best of our knowledge, no intragenic COL4A2 duplications have been reported in humans to date. We report a neonate with intracerebral hemorrhage and a de novo intragenic COL4A2 duplication. Although it is not clear yet whether this genetic factor fully explains the clinical phenotype, it may have contributed at least as a risk factor for cerebral hemorrhage. Screening for intragenic COL4A1 and COL4A2 duplications as part of collagen IV diagnostics should be considered as part of the fetal and neonatal work-up for unexplained cerebral hemorrhages and to collect more evidence of the pathogenicity of this genetic mechanism.

Prenatal exome sequencing (pES) is a promising tool for diagnosing genetic disorders when structural anomalies are detected on prenatal ultrasound. The aim of this study was to investigate the diagnostic yield and clinical impact of pES as an additional modality for fetal neurologists who counsel parents in case of congenital anomalies of the central nervous system (CNS). We assessed 20 pregnancies of 19 couples who were consecutively referred to the fetal neurologist for CNS anomalies. pES had a diagnostic yield of 53% (10/19) with most diagnosed pregnancies having agenesis or hypoplasia of the corpus callosum (7/10). Overall clinical impact was 63% (12/19), of which the pES result aided parental decision making in 55% of cases (6/11), guided perinatal management in 75% of cases (3/4), and was helpful in approving a late termination of pregnancy request in 75% of cases (3/4). Our data suggest that pES had a high diagnostic yield when CNS anomalies are present, although this study is limited by its small sample size. Moreover, pES had substantial clinical impact, which warrants implementation of pES in the routine care of the fetal neurologist in close collaboration with gynecologists and clinical geneticists.

Objective To assess associations between neonatal brain injury assessed by magnetic resonance imaging and cognitive, motor, and behavioral outcomes at 2 and 10 years of age, in a longitudinal cohort of children born very preterm.Study design There were 112 children born at

Background: Preterm born children are at high risk for adverse motor neurodevelopment. The aim of this study was to establish the relationship between motor outcome and advanced magnetic resonance imaging (MRI) and electroencephalography (EEG) measures. Methods: In a prospective cohort study of 64 very preterm born children, the motor outcome was assessed at 9.83 (SD 0.70) years. Volumetric MRI, diffusion tensor imaging (DTI), and EEG were acquired at 10.85 (SD 0.49) years. We investigated associations between motor outcome and brain volumes (white matter, deep gray matter, cerebellum, and ventricles), white matter integrity (fractional anisotropy and mean, axial and radial diffusivity), and brain activity (upper alpha (A2) functional connectivity and relative A2 power). The independence of associations with motor outcome was investigated with a final model. For each technique, the measure with the strongest association was selected to avoid multicollinearity. Results: Ventricular volume, radial diffusivity, mean diffusivity, relative A2 power, and A2 functional connectivity were significantly correlated to motor outcome. The final model showed that ventricular volume and relative A2 power were independently associated with motor outcome (B = −9.42 × 10−5, p = 0.027 and B = 28.9, p = 0.007, respectively). Conclusions: This study suggests that a lasting interplay exists between brain structure and function that might underlie motor outcome at school age. Impact: This is the first study that investigates the relationships between motor outcome and brain volumes, DTI, and brain function in preterm born children at school age.Ventricular volume and relative upper alpha power on EEG have an independent relation with motor outcome in preterm born children at school age.This suggests that there is a lasting interplay between structure and function that underlies adverse motor outcome.

Perinatal asphyxia is characterized by oxygen deprivation and lack of perfusion in the perinatal period, leading to hypoxic-ischemic encephalopathy and sequelae such as cerebral palsy, mental retardation, cerebral visual impairment, epilepsy and learning disabilities. On cellular level PA is associated with a decrease in oxygen and glucose leading to ATP depletion and a compromised mitochondrial function. Upon reoxygenation and reperfusion, the renewed availability of oxygen gives rise to not only restoration of cell function, but also to the activation of multiple detrimental biochemical pathways, leading to secondary energy failure and ultimately, cell death. The formation of reactive oxygen species, nitric oxide and peroxynitrite plays a central role in the development of subsequent neurological damage. In this review we give insight into the pathophysiology of perinatal asphyxia, discuss its clinical relevance and summarize current neuroprotective strategies related to therapeutic hypothermia, ischemic postconditioning and pharmacological interventions. The review will also focus on the possible neuroprotective actions and molecular mechanisms of the selective neuronal and inducible nitric oxide synthase inhibitor 2-iminobiotin that may represent a novel therapeutic agent for the treatment of hypoxic-ischemic encephalopathy, both in combination with therapeutic hypothermia in middle- and high-income countries, as well as stand-alone treatment in low-income countries.

Purpose: Exome sequencing (ES) is an efficient tool to diagnose genetic disorders postnatally. Recent studies show that it may have a considerable diagnostic yield in fetuses with structural anomalies on ultrasound. We report on the clinical impact of the implementation of prenatal ES (pES) for ongoing pregnancies in routine care.Methods: We retrospectively analyzed the impact of pES on pregnancy outcome and pre-or perinatal management in the first 22 patients counseled for pES because of one or more structural anomalies on fetal ultrasound.Results: In two cases, a diagnosis was made by chromosomal microarray analysis after ES counseling. The remaining 20 cases were divided in three groups: (1) pES to aid parental decision making (n = 12), (2) pES in the context of late pregnancy termination requests (n = 5), and (3) pES to guide pre-or perinatal management (n = 3). pES had a clinical impact in 75% (9/12), 40% (2/5), and 100% (3/3) respectively, showing an overall clinical impact of pES of 70% (14/20).Conclusion: We show that clinical implementation of pES is feasible and affects parental decision making or pre- and perinatal management supporting further implementation of ES in the prenatal setting.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Purpose: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. Methods: We retrospectively evaluated all genetic NICU consultations in a 2-year period. Results: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. Conclusions: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Timely detection of severe infratentorial hemorrhage in neonates is crucial, especially in case of life-threatening brain stem compression and/or acute obstructive hydrocephalus, which need lifesaving neurosurgical intervention. Although the detection of infratentorial hemorrhage by ultrasound scanning is often considered as difficult, the use of additional acoustic windows and recognition of characteristic ultrasound features facilitate early diagnosis. In this case series, we report on newborns with severe, symptomatic infratentorial hemorrhage detected primarily by cranial ultrasound. We demonstrate the characteristic ultrasound features present in all cases and discuss how ultrasound diagnosis contributed to early diagnosis and treatment.

Background: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia. Objective: The present first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without Captisol® as a solubilizing agent. Methods: This randomized, double-blind, placebo-controlled, dose-escalation study was executed in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or placebo were infused every 4 h for 6 administrations in total. Results: Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol® were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not to be affected by the presence of Captisol®. Conclusion: Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile with a small volume of distribution, with time-independent PK. Preliminary PD characterization of repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in the currently pursued indication of cerebral hypoxia-ischemia.

Objective: To determine classroom-evaluated school performance nine years after preterm birth, predicted by perinatal risk factors and neonatal brain abnormalities.Study design: Children were recruited from a consecutive cohort of 113 preterm infants (Results: Information on school enrollment was available for 87 children (77%), of whom 7 (8%) were in special primary education and 19 (22%) repeated a grade. This was significantly higher compared to national rates (p ≤ .05). Results on school performance were available for 74 children (65%) and showed clearly below average scores in reading comprehension (p = .006), spelling (p = .014) and mathematics (p Conclusion: Preterm born children more often need special primary education and have higher grade repeat rates. They perform poorer on reading comprehension, spelling and mathematics. Regular follow-up remains important for preterm born children during school age.

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes. ispartof: American Journal Of Human Genetics vol:104 issue:1 pages:139-156 ispartof: location:United States status: published

Congenital heart defects (CHDs) are associated with neurodevelopmental (ND) delay. This study aims to assess evidence for impaired prenatal brain development, in fetuses with CHD. A systematical search was performed, and 34 studies evaluating the fetal brain [magnetic resonance imaging (MRI) or ultrasound] in isolated CHD were included (1990-2015). Data regarding cerebral abnormalities, head circumference growth and middle cerebral artery flow were extracted. Prenatal MRI was studied in ten articles (445 fetuses), resulting in a pooled prevalence of 18% (95%CI -6%; 42%) for combined structural and acquired cerebral abnormalities. Prenatal head circumference was studied in 13 articles (753 fetuses), resulting in a pooled z-score of -0.51 (95%CI -0.84; -0.18). Doppler was studied in 21 articles (1412 fetuses), resulting in a lower middle cerebral artery pulsatility index (z-score -0.70 95%CI -0.99; -0.41) in left-sided CHD only. We conclude that prenatal MRI and ultrasound demonstrate brain abnormalities, delay in head growth and brainsparing in subgroups of CHD. However, large MRI studies are scarce, and ultrasound data are biased towards severe and left-sided CHD. Long-term follow-up studies correlating prenatal findings with postnatal ND outcome are limited, and data are lacking to support counseling families regarding ND outcome based on prenatal findings suggestive of altered brain development. © 2016 John Wiley & Sons, Ltd.

Prematurely born children are at higher risk for long-term adverse motor and cognitive outcomes. The aim of this paper was to compare quantitative measures derived from electroencephalography (EEG) between extremely (EP) and very prematurely (VP) born children at 9–10 years of age. Fifty-five children born

Introduction: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. Methods: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. Results: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28–84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). Conclusion: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10–14 years). Electronic supplementary material The online version of this article (doi:10.1007/s10048-017-0517-5) contains supplementary material, which is available to authorized users.

Several animal models have been used to simulate cerebral hypoxia-ischemia and suggested neuroprotective effects of the biotin analogue 2-iminobiotin (2-IB). The aims of this study were to employ a human in-vitro hypoxia model to confirm protective effects of 2-IB on neuronal cells, determine the optimal neuroprotective concentrations of 2-IB and scrutinize underlying cellular effects of 2-IB. Neuronal IMR-32 cells were exposed to hypoxia employing an enzymatic hypoxia system and were thereafter incubated with various concentrations of 2-IB (10 to 300ng/ml). Cell damage, metabolic activity and generation of reactive oxygen species were quantified using colorimetric/fluorometric lactate dehydrogenase (LDH), tetrazolium-based (MTS) and reactive oxygen species assays. Proteome profiling arrays were performed to evaluate the regulation of cell stress protein expression by hypoxia and 2-IB. Seven hours of hypoxia led to morphological changes in IMR-32 cultures, increased neuronal cell damage (P

Chudley-McCullough syndrome (CMS) is characterized by profound sensorineural hearing loss and brain anomalies. Variants in GPSM2 have recently been reported as a cause of CMS by Doherty et al. In this study we have performed exome sequencing of three CMS patients from two unrelated families from the same Dutch village. We identified one homozygous frameshift GPSM2 variants c.1473delG in all patients. We show that this variant arises from a shared, rare haplotype. Since the c.1473delG variant was found in Mennonite settlers, it likely originated in Europe. To support DNA diagnostics, we established an LOVD database for GPSM2 containing all variants thus far described.

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.European Journal of Human Genetics advance online publication, 13 January 2016; doi:10.1038/ejhg.2015.282. ispartof: European Journal of Human Genetics vol:24 issue:8 pages:1145-1153 ispartof: location:England status: published

Case presentationA pregnant woman (36 weeks gestation) underwent cesareansection and laparotomy because of fever and peritoneal signs. Anormal appendix and no signs of intra-abdominal infection wereseen. A girl was born in good condition.On the fourth day of life, the neonate became lethargic withcyanotic spells, requiring admission to the neonatal intensive careunit and antibiotic therapy was started. Cerebrospinal fluid (CSF)cell count, protein and glucose level and urine microscopy werenormal.Five days after birth, respiratory and circulatory failuredeveloped. CSF showed 26×10

Worldwide, perinatal asphyxia is an important cause of morbidity and mortality among term-born children. Overactivation of the N-methyl-D-aspartate receptor (NMDAr) plays a central role in the pathogenesis of cerebral hypoxia-ischemia, but the role of both endogenous NMDAr co-agonists D-serine and glycine remains largely elusive. We investigated D-serine and glycine concentration changes in rat glioma cells, subjected to oxygen and glucose deprivation (OGD) and CSF from piglets exposed to hypoxia-ischemia by occlusion of both carotid arteries and hypoxia. We illustrated these findings with analyses of cerebrospinal fluid (CSF) from human newborns affected by perinatal asphyxia. Extracellular concentrations of glycine and D-serine were markedly increased in rat glioma cells exposed to OGD, presumably through increased synthesis from L-serine. Upon reperfusion glycine concentrations normalized and D-serine concentrations were significantly lowered. The in vivo studies corroborated the finding of initially elevated and then normalizing concentrations of glycine and decreased D-serine concentrations upon reperfusion These significant increases of both endogenous NMDAr co-agonists in combination with elevated glutamate concentrations, as induced by global cerebral ischemia, are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently poorly treatable condition.

Item does not contain fulltext Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (

Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP-array and confirmed by fluorescence in situ hybridization. Mate-pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.

Perinatale hypoxie-ischemie is een belangrijke oorzaak van neonatale mortaliteit en morbiditeit (spasticiteit en mentale retardatie). Een groot deel van de hierbij opgelopen hersenschade ontstaat gedurende en na reperfusie en reoxygenatie door de productie van exciterende neurotransmitters en vrije radicalen door overmatige stikstofmonoxideproductie, het vrijkomen van cytokinen en een afname in de endogene groeifactorenproductie. Het bestaan van een kritische tussenfase tussen het moment van hypoxie-ischemie en het optreden van celdood creeert mogelijkheden om zowel medicamenteus als niet-medicamenteus te intervenieren. Dit artikel geeft informatie over de mechanismen die leiden tot hersenschade na perinatale hypoxie-ischemie. Vervolgens wordt beknopt ingegaan op mogelijke medicamenteuze interventiestrategieen om de post-hypoxisch-ischemische reperfusieschade aan de hersenen te voorkomen of te reduceren. Ten slotte worden enkele niet-medicamenteuze interventies besproken, te weten hypothermie en het gebruik van hyperbare zuurstoftherapie. Een combinatie van medicamenteuze en niet-medicamenteuze interventies is het meest veelbelovend om neuroprotectie te kunnen bewerkstelligen na perinatale hypoxie-ischemie.

Recently, Desai et al. described six subjects with deletions in the ATAD3 gene cluster ( Desai et al. 2017 ). Most of these patients died within their first week of life and one died after 7 months, but one was still alive at 30 years of age. Harel et al. (2016) described three patients with biallellic variations in ATAD3A, one of whom died in the second week of life but the other two were alive at 24 and 26 years, respectively. For pre- and postnatal management it is important to understand why some patients die very early, whereas others seem to have a much milder clinical affect.

Arterial ischaemic stroke is an important cause of morbidity in children. Timely diagnosis is necessary for acute stroke treatment but can be challenging in clinical practice. Due to a paucity of data there are no specific recommendations regarding the use of mechanical thrombectomy devices in current paediatric stroke guidelines. A 14-year-old boy presented with a severe acute left hemisphere stroke due to a proximal middle cerebral artery occlusion caused by emboli from an atrial myxoma. No clinical improvement was seen after administration of intravenous thrombolysis. Subsequent mechanical thrombectomy with a second-generation stent-based thrombectomy device resulted in successful recanalization and clinical improvement. To our knowledge, this is the first report of mechanical thrombectomy in a child with acute embolic stroke caused by atrial myxoma.

Background The cerebellum is an extremely rapidly developing brain structure during late gestation. The extensive germinal matrix layer of the foetal cerebellum is fragile and susceptible to injury. When injury occurs it may subsequently impair further cerebellar development. Cerebellar haemorrhage (CBH) is increasingly being recognized as a relatively common complication of preterm birth and is associated with a broad spectrum of neurologic disabilities. However, CBH seems a rare prenatal event. Recent advances in prenatal neuroimaging have led to an increased recognition of cerebellar lesions in the high risk foetus. Information about its pathogenesis and prognostic consequences is limited. Objective To describe the pathogenesis and neurodevelopmental outcome in foetuses with isolated CBH. Methods The Leiden University Medical Centre is a tertiary referral centre for multidisciplinary antenatal diagnosis and treatment of foetal disorders. In the past four years we have encountered four cases of isolated foetal CBH at our centre. In order to identify factors involved in the pathogenesis of isolated foetal CBH and its prognosis, we will describe the characteristics of these cases as well as their neurodevelopmental outcome. Results and conclusion These cases suggest that isolated foetal CBH may have a favourable prognosis. However, given recent reports on the role of cerebellum in cognitive, learning and behavioural functions, longer follow-up data in larger groups of patients are necessary to detect potential neurological defects in the long term.

Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2 days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated. peerReviewed