Clustered mutations in the GRIK2 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.

Diffuse Intracerebral Hemorrhage in an Infant With a Novel Homozygous Variant Leading to Severe Protein C Deficiency.

Protein C is a circulating anticoagulant that inhibits factor Va and VIIIa and promotes fibrinolysis. Compound heterozygous or homozygous variants in the Protein C gene (PROC) lead to severe deficiency of protein C and affected neonates typically present shortly after birth with purpura fulminans. We describe an infant who suffered a diffuse intracranial hemorrhage as a neonate and presented with purpura fulminans as an older infant which led to investigations that were consistent with severe protein C deficiency. We demonstrate subacute findings on neuroimaging and suggest this condition should be considered with neonatal presentations of bilateral intraparenchymal hemorrhage.

MITO-FIND: A study in 390 patients to determine a diagnostic strategy for mitochondrial disease.

Mitochondrial diseases, due to nuclear or mitochondrial genome mutations causing mitochondrial dysfunction, have a wide range of clinical features involving neurologic, muscular, cardiac, hepatic, visual, and auditory symptoms. Making a diagnosis of a mitochondrial disease is often challenging since there is no gold standard and traditional testing methods have required tissue biopsy which presents technical challenges and most patients prefer a non-invasive approach. Since a diagnosis invariably involves finding a disease-causing DNA variant, new approaches such as next generation sequencing (NGS) have the potential to make it easier to make a diagnosis. We evaluated the ability of our traditional diagnostic pathway (metabolite analysis, tissue neuropathology and respiratory chain enzyme activity) in 390 patients. The traditional diagnostic pathway provided a diagnosis of mitochondrial disease in 115 patients (29.50%). Analysis of mtDNA, tissue neuropathology, skin electron microscopy, respiratory chain enzyme analysis using inhibitor assays, blue native polyacrylamide gel electrophoresis were all statistically significant in distinguishing patients between a mitochondrial and non-mitochondrial diagnosis. From these 390 patients who underwent traditional analysis, we recruited 116 patients for the NGS part of the study (36 patients who had a mitochondrial diagnosis (MITO) and 80 patients who had no diagnosis (No-Dx)). In the group of 36 MITO patients, nuclear whole exome sequencing (nWES) provided a second diagnosis in 2 cases who already had a pathogenic variant in mtDNA, and a revised diagnosis (GLUL) in one case that had abnormal pathology but no pathogenic mtDNA variant. In the 80 NO-Dx patients, nWES found non-mitochondrial diagnosis in 26 patients and a mitochondrial diagnosis in 1 patient. A genetic diagnosis was obtained in 53/116 (45.70%) cases that were recruited for NGS, but not in 11/116 (9.48%) of cases with abnormal mitochondrial neuropathology. Our results show that a non-invasive, bigenomic sequencing (BGS) approach (using both a nWES and optimized mtDNA analysis to include large deletions) should be the first step in investigating for mitochondrial diseases. There may still be a role for tissue biopsy in unsolved cases or when the diagnosis is still not clear after NGS studies.

Crossed Cerebellar Atrophy in Perinatal Stroke.

Background and Purpose- Perinatal stroke causes most hemiparetic cerebral palsy and lifelong disability. Crossed cerebellar atrophy (CCA) is chronic cerebellar volume loss following contralateral motor pathway injury. We hypothesized that CCA is quantifiable in perinatal stroke and associated with poor motor outcome. Methods- Term-born children with perinatal stroke, magnetic resonance imaging beyond 6 months of age, and no additional neurological disorders were recruited. Blinded scorers measured cerebellar volumes expressed as ratios (contralesional/ipsilesional), with values <1 suggesting CCA. Motor outcomes including perinatal stroke outcome measure (PSOM) motor and cognitive scores (good/poor), Assisting Hand Assessment, and Melbourne Assessment were compared with cerebellar volume measures. Results- Seventy-three children met criteria (53% male). Mean cerebellar ratios were <1.0 (0.975±0.04; range, 0.885-1.079; P<0.001) suggesting occurrence of CCA. Cerebellar ratios did not differ between stroke types or across PSOM motor outcomes. Larger ipsilesional cerebellar volume was associated with poor PSOM cognitive outcome (P=0.042), possibly with poor PSOM motor outcome (P=0.063), and overall PSOM score (P=0.034). Conclusions- CCA occurs in perinatal stroke but is not strongly associated with motor outcome. However, ipsilesional cerebellar volume is associated with poor cognitive and overall outcomes.

Metachronous Type I pleuropulmonary blastoma and atypical choroid plexus papilloma in a young child.

Pleuropulmonary blastoma (PPB) is a rare childhood tumor, often associated with germline DICER1 mutations and a risk for development of other benign and malignant tumors, a constellation termed DICER1 syndrome. A 1-year-old male was diagnosed with Type I PPB and screened regularly thereafter for detection of intrathoracic and intraabdominal disease. Ten months after diagnosis of PPB, he presented with headaches and vomiting. He was diagnosed with atypical choroid plexus papilloma, a lesion not previously reported with PPB. The presence of central nervous system symptoms in patients with PPB or a phenotype suggestive of DICER1 syndrome should prompt early intracranial imaging.

Magnetic resonance imaging findings of bilateral thalamic involvement in severe paroxysmal sympathetic hyperactivity: a pediatric case series.

PURPOSE: Paroxysmal sympathetic hyperactivity is a complication of brain injury that has mainly been described in the adult brain injury literature. METHODS: We present a case series of three pediatric patients that developed paroxysmal sympathetic hyperactivity of varying severity following hypoxic brain injury. RESULTS: Comparison of brain magnetic resonance imaging revealed bilateral and symmetric global ischemic changes in all three cases. However, the thalamus was not affected in the patient with the mild case of paroxysmal sympathetic hyperactivity. In contrast, bilateral and symmetric damage to the thalamus was observed in the two severe cases. CONCLUSIONS: Our case series suggests that in hypoxic brain injury, evidence of bilateral ischemic injury to the thalamus on magnetic resonance imaging may be an important early predictor of severity and length of paroxysmal sympathetic hyperactivity. While this is an interesting observation, definite proof of our hypothesis requires further research including analysis of larger numbers of patients and comparison of MRI findings in children with hypoxic brain injury that do not develop paroxysmal sympathetic hyperactivity.

Cerebellar atrophy in childhood arterial ischemic stroke: acute diffusion MRI biomarkers.

BACKGROUND AND PURPOSE: Crossed cerebellar atrophy is uncommon in childhood arterial ischemic stroke. Acute corticospinal tract diffusion-weighted imaging (CST-DWI) changes occur in stroke of all ages. Contralateral CST-DWI is unexplained but approximates corticopontocerebellar pathways. We hypothesized that cerebellar atrophy can be quantified on clinical neuroimaging in childhood arterial ischemic stroke and is predicted by contralesional CST-DWI. METHODS: Consecutive children (>28 days-18 years) were included with the following features: (1) acute, unilateral, middle cerebral artery arterial ischemic stroke, (2) DWI <14 days from stroke onset, (3) anatomic T1 MRI >6 months, and (4) Pediatric Stroke Outcome Measure >12 months. Blinded scorers measured cerebellar volumes (left/right/hemisphere/vermis/total) using Osirix software. Cerebellar volumes ratios (nonstroke/stroke) were expressed as asymmetry indices (AI), with chronic/acute ratio <1.0 suggesting crossed atrophy. Acute brain stem and cerebellum (peduncle, hemisphere) DWI ratios were scored. Software measures were compared with visual inspection. Associations between AI, motor outcome (good/poor), and contralesional CST-DWI were sought. Rater reliabilities were assessed. RESULTS: Twenty-three children were studied (median age, 6.3±4.4 years; 62% male). Baseline cerebellar volumes were comparable (right=56.9 cm(3), left=57.1 cm(3)). Cerebellar atrophy was suggested across the sample with overall AI <1.0 (0.973±0.05; P=0.009). Visual atrophy detection was specific (≈100%) but insensitive (54%). Children with poor motor outcome did not have lower AI (0.983±0.027 versus 0.965±0.068; P=0.40); however, children with acute contralesional CST-DWI did (0.928±0.078 versus 986±0.040; P=0.03). Acute cerebellar DWI did not predict atrophy. Rater reliabilities were excellent (>0.92). CONCLUSIONS: Cerebellar atrophy can be demonstrated on MRI in childhood arterial ischemic stroke. Association with acute contralesional pontine DWI signal suggests early degeneration of corticopontocerebellar connections. The clinical significance of cerebellar atrophy in childhood stroke remains to be determined.

Normal intracranial periarterial enhancement on pediatric brain MR imaging.

INTRODUCTION: Large/medium vessel vasculitis is an important etiology of childhood stroke. Early research suggests vessel wall enhancement on postcontrast MRI may be a marker of intracranial vasculitis yet no systematic descriptions of normal periarterial enhancement exist in the literature. The aim was to describe normal periarterial enhancement in the pediatric population. METHODS: We included all children who had an MR scan between January 2007 and December 2010, with normal parenchymal imaging, no clinical concern of vasculopathy, and axial and coronal postcontrast fat-saturated T1-weighted images with 3-mm slice thickness. Intensity of periarterial enhancement was graded on a three-point scale by two investigators for all intracranial large and medium arteries. RESULTS: A total of 44 patients aged 4 months to 16 years were included. Inter- and intra-rater reliability in enhancement grading was high (all kappa >0.65). Thin, linear, noncircumferential periarterial enhancement was common and usually symmetrical. It was most commonly prominent in the cavernous and petrous segments of the internal carotid artery and the M1 segment of the middle cerebral artery. Periarterial enhancement was rarely observed at segments surrounded by CSF, including supraclinoid segments of the internal carotid arteries, P1 segments of the posterior cerebral arteries, V4 segments of the vertebral artery, and the basilar arteries. CONCLUSION: Normal periarterial enhancement is common and usually symmetrical along major intracranial arteries but rarely seen around arterial segments bordered by CSF. Knowledge of these findings may be useful for a sensitive and specific interpretation of MR scans of patients with clinical concerns of vasculitis.

Sustained response to weekly vinblastine in 2 children with pilomyxoid astrocytoma associated with diencephalic syndrome.

Diencephalic syndrome (DS) related to hypothalamic/chiasmatic region tumor has mainly been reported with low-grade glioma. We described 2 young children with DS related to pilomyxoid astrocytoma. Despite the recognized more agressive clinical behavior of this histologic subtype, we report successful resolution of DS and sustained tumor response with prolonged use of single-agent vinblastine.

Chronic recurrent multifocal osteomyelitis with a comprehensive approach to differential diagnosis of paediatric skull pain.

A girl in middle childhood was referred to rheumatology with a 1-month history of progressive skull pain, preceded by fleeting musculoskeletal symptoms. Apart from a scaly rash on her scalp, she was well, with moderately elevated inflammatory markers. Skull imaging (radiographs, CT and MRI) revealed osteolytic lesions, soft tissue swelling and pachymeningeal enhancement at frontal and temporal convexities. Langerhans cell histiocytosis, bone infection/inflammation or malignancy was considered. Skin and bone biopsies eventually ruled out mimicking diseases and confirmed the diagnosis of chronic recurrent multifocal osteomyelitis (CRMO). She was treated with intravenous pamidronate (IVPAM) for 9 months, with rapid resolution of pain and gradual resolution of bony abnormalities. She remains in remission at 15-month follow-up. While CRMO can affect any bone, skull involvement is extremely rare, with a broad differential diagnosis. We recommend bone biopsy to confirm skull CRMO. The patient achieved excellent clinical and radiological response to IVPAM.

Reduced ipsilesional cortical volumes in fetal periventricular venous infarction.

BACKGROUND AND PURPOSE: Perinatal stroke causes most term-born hemiplegic cerebral palsy. Many suffer additional sequelae. Periventricular venous infarction (PVI) is a common fetal stroke in which isolated subcortical injury may cause only motor deficits. However, cognitive, language, and behavioral deficits also occur. We hypothesized that ipsilesional cortical gray matter volumes are reduced in PVI. METHODS: Children (12 months to 18 years) with MRI-confirmed PVI were identified through the Alberta Perinatal Stroke Project. We developed an MRI method to quantify sectional gray (GM) and white matter (WM) volumes from lesioned and unlesioned (control) hemispheres (OsiriX software). Differences in cortical GM and WM volumes were compared between hemispheres in preselected regions "above" the lesion (middle) and anterior and posterior to this. Outcomes dichotomized for "cortical dysfunction" (cognitive, behavioral, language) and motor deficit severity (Pediatric Stroke Outcome Measure) were compared with GM volumes. RESULTS: Twenty-two children (81% boys; median age, 8 years) were included. Methods demonstrated high intrarater and inter-rater reliabilities (ρ=0.988, ρ=0.943) and minimal observer bias. Ipsilesional GM volume was significantly reduced in the middle (P=0.007) and posterior (P=0.03) regions. Middle ipsilesional WM volumes were reduced (P<0.001). The degree of GM reduction was not associated with cortical dysfunction or severity of motor deficit. CONCLUSIONS: Ipsilesional GM volume is diminished in PVI. Speculative mechanisms include retrograde neuronal degeneration and disrupted migration. Neuropsychological testing of larger samples is required to determine clinical significance.

A rare case of cardiac rhabdomyomas in a dizygotic twin pair.

Cardiac rhabdomyoma (CR) is the cardiac tumour most commonly diagnosed in utero. Eighty percent of CRs are associated with tuberous sclerosis (TS). TS is a rare multi-system disease, with autosomal dominant genetic transmission. If the parents of an affected child do not have features of TS, then either one parent is mosaic for the TS gene mutation or the affected child is the result of a de novo germline mutation. We present a case of a dizygotic twin pregnancy complicated by CRs in both fetuses at 24 weeks. Twin A died in utero at 28 weeks. Preterm labour and delivery of twin B occurred at 33 weeks. Twin B had multiple small CRs and a large apical CR. At six weeks after delivery, the CRs had disappeared or reduced in size. Regression in the third trimester or postnatally is the natural course of CRs. Molecular testing for TS identified two variants in the TSC2 gene. The parents were clinically unaffected; however, the father was subsequently found on an MRI of the head to have cortical tubers, and he was found to carry the pathogenic TSC2 mutation. Since dizygotic twin pregnancy is akin to two consecutive pregnancies, the etiology in our case is due to one parent having subclinical TS. To the best of our knowledge, this is the first such case to be reported.

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates.

The development of the cerebral cortex requires balanced expansion and differentiation of neural stem/progenitor cells (NPCs), which rely on precise regulation of gene expression. Because NPCs often exhibit transcriptional priming of cell-fate-determination genes, the ultimate output of these genes for fate decisions must be carefully controlled in a timely fashion at the post-transcriptional level, but how that is achieved is poorly understood. Here, we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb NPC fate decisions in mice by disrupting CELF2 nucleocytoplasmic transport. In self-renewing NPCs, CELF2 resides in the cytoplasm, where it represses mRNAs encoding cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNA for translation and thereby triggers NPC differentiation. Our results reveal that CELF2 translocation between subcellular compartments orchestrates mRNA at the translational level to instruct cell fates in cortical development.

Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging.

We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D-bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal.

Electrical detection of plasmonic waves using an ultra-compact structure via a nanocavity.

A novel structure is proposed to electrically detect the plasmonic waves from a subwavelength plasmonic waveguide. By locating two L-shaped metallic nanorods in close proximity of each other at the end of the plasmonic waveguide, a metal-semiconductor-metal plasmonic detector is constructed. The L-shaped nanorods also form a dipole nanoantenna and a nanocavity to focus the photonic power into the active volume of the detector. The dimensions and locations of the L-shaped nanorods are studied to maximize the transmission efficiency of the photonic power from the plasmonic waveguide to the detector. Impedance matching with a sub is investigated to further improve the power transmission. Possible leads of the detector are discussed and their effects are investigated. Proposed detector has an ultra-compact and easy-to-fabricate planar structure, and a potentially THz speed, high responsivity as well as low power dissipation.

Aphonogelia After Recovery From Severe Traumatic Brain Injury: A Case Report.

During rehabilitation from a severe traumatic brain injury, a 16-year-old girl became aware that she had lost the ability to laugh out loud. This rare phenomenon previously has been described as "aphonogelia." A discussion of therapeutic avenues that were explored with this patient is presented in the first case, to our knowledge, of aphonogelia after a traumatic brain injury. LEVEL OF EVIDENCE: V.