Increased concentrations of both NMDA receptor co-agonists D-serine and glycine in global ischemia:A potential novel treatment target for perinatal asphyxia

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

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in <i>SCN2A </i>and <i>KCNQ3</i>-related epilepsy in neonates

Purpose: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. Methods: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. Results: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. Discussion: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.</p

Endovascular treatment of patients with stroke caused by anterior cerebral artery occlusions

Background: Occlusion of the anterior cerebral artery (ACA) is uncommon but may lead to significant disability. The benefit of endovascular treatment (EVT) for ACA occlusions remains uncertain. Methods: We included patients treated with EVT and compared patients with ACA occlusions with patients who had internal carotid artery (ICA) or proximal (M1/M2) middle cerebral artery (MCA) occlusions from the MR CLEAN Registry. Primary outcome was the modified Rankin Scale score (mRS). Secondary outcomes were functional independence (mRS 0–2), National Institutes of Health Stroke Scale (NIHSS) score, delta-NIHSS (baseline minus NIHSS score at 24–48 h), and successful recanalization (expanded thrombolysis in cerebral infarction (eTICI) score 2b-3). Safety outcomes were symptomatic intracranial hemorrhage (sICH), periprocedural complications, and mortality. Results: Of 5193 patients, 11 (0.2%) had primary ACA occlusions. Median NIHSS at baseline was lower in patients with ACA versus ICA/MCA occlusions (11, IQR 9–14; versus 15, IQR 11–19). Functional outcome did not differ from patients with ICA/MCA occlusions. Functional independence was 4/11 (36%) in patients with ACA versus 1949/4815 (41%) in ICA/MCA occlusions; median delta-NIHSS was − 1 (IQR − 7 to 2) and − 4 (IQR − 9 to 0), respectively. Successful recanalization was 4/9 (44%), versus 3083/4787 (64%) in ICA/MCA occlusions. Mortality was 3/11 (27%) versus 1263/4815 (26%). One patient with ACA occlusion had sICH; no other complications occurred. Conclusion: In this cohort ACA occlusions were uncommon. Functional outcome did not differ between patients with ACA occlusions and ICA/MCA occlusions. Prospective research is needed to determine feasibility, safety, and outcomes of EVT for ACA occlusions.</p

Longitudinal Follow-Up of Children Born Preterm: Neurodevelopment From 2 to 10 Years of Age

Objective: To investigate the rate and stability of impairments in children born preterm by assessing (1) early and school-age outcome in four developmental domains and (2) individual changes in outcome at both timepoints.Design: Prospective, longitudinal cohort study in children born in 2006–2007, &lt;32 weeks' gestation. Follow-up at 2 and 10 years of age included standardized neurological, motor, cognitive and behavioral assessments. Children were categorized as having no, mild or moderate-severe impairment in these four domains. A composite impairment score was composed and the number of domains with impairments counted. For each child, individual outcomes at both timepoints were compared.Results: Follow-up at both time-points was available in 71/113(63%) children. At group level, there were no significant changes in the severity of impairments per domain. However, at individual level, there were less children with a mild abnormal composite score at 10 years of age (44 vs. 20%; p = 0.006), and more with a moderate-severe abnormal composite score (12 vs. 35%; p = 0.001). Especially children with normal/mild outcome at 2 years were likely to shift to other outcome categories over time.Conclusions: Children with early severe impairment are likely experiencing impairments later on, but early normal/mild abnormal outcomes should be interpreted with care, considering the large individual shifts over time. Long-term follow-up in all children born very preterm should therefore be continued to at least school-age

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study

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

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

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

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Van der Knoop et al. describe the clinical features of 21 individuals with biallelic pathogenic variants in ADAM22 and confirm the deleteriousness of the variants with functional studies. Clinical hallmarks of this rare disorder comprise progressive encephalopathy and infantile-onset refractory epilepsy.Peer reviewe