Real-Life Experience With Purified Cannabidiol Treatment for Refractory Epilepsy: A Multicenter Retrospective Study.

BACKGROUND: Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population. METHODS: A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel. RESULTS: The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%). CONCLUSION: Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.

Perampanel as precision therapy in rare genetic epilepsies.

OBJECTIVE: Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy. METHODS: This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified. RESULTS: A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity. SIGNIFICANCE: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.

Felbamate for pediatric epilepsy-should we keep on using it as the last resort?

Introduction: Concerns regarding felbamate adverse effects restrict its widespread use in children with drug-resistant epilepsy. We aimed to examine the efficacy and safety of felbamate in those children and identify the ones who may benefit most from its use. Methods: We retrospectively reviewed the medical files of all patients who were treated with felbamate in a tertiary pediatric epilepsy clinic between 2009-2021. Drug efficacy was determined at the first 3 months of treatment and thereafter. Therapeutic response and adverse reactions were monitored throughout the course of treatment. Results: Our study included 75 children (age 8.9 ± 3.7 years), of whom 53 were treated with felbamate for seizures, 16 for electrical status epilepticus during sleep and 6 for both. The median follow-up time was 16 months (range 1-129 months). The most common cause for epilepsy was genetic (29%). The median number of previous anti-seizure medications was six [4-8]. A therapeutic response ≥50% was documented in 37 (51%) patients, and a complete response in 9 (12%). Nineteen patients (25%) sustained adverse reactions, including three cases of elevated liver enzymes and one case of neutropenia with normal bone marrow aspiration. In all cases, treatment could be continued. All children with intractable epilepsy following herpes encephalitis showed a response to felbamate. Conclusion: Felbamate is an efficacious and safe anti-seizure medication in the pediatric population.

Hereditary neuropathy with liability to pressure palsies (HNPP): Intrafamilial phenotypic variability and early childhood refusal to walk as the presenting symptom.

BACKGROUND: Limping and/or refusal to walk is a common complaint in the setting of the pediatric department, with a widely diverse differential diagnosis. An unusual etiology, is that of a hereditary neuropathy. Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy, most commonly caused by a 17p11.2 chromosomal deletion encompassing the PMP22 gene. METHODS: We pursued chromosomal microarray analysis (CMA) in multiple affected individuals of a single extended family, manifesting a range of phenotypic features consistent with HNPP. RESULTS: A 4.5 years-old boy presented for in-patient evaluation due to refusal to walk. Initial investigations including spine MRI and bone scan failed to yield a conclusive diagnosis. Following family history, which implied an autosomal dominant mode of inheritance, CMA was pursued and confirmed a 17p11.2 deletion in the proband consistent with HNPP. Importantly, following this diagnosis, four additional affected family members were demonstrated to harbor the deletion. Their variable phenotypic features, ranging from a prenatal diagnosis of a 6 months-old sibling, to recurrent paresthesias manifesting in the fourth decade of life, are discussed. CONCLUSIONS: Our experience with the family reported herein demonstrates how a thorough anamnesis can lead to a rare genetic etiology with a favorable prognosis and prevent unnecessary investigations, and underscores HNPP as an uncommon diagnostic possibility in the limping child.

Personalized treatment with retigabine for pharmacoresistant epilepsy arising from a pathogenic variant in the KCNQ2 selectivity filter.

Mutations in the KCNQ2 gene, encoding the voltage-gated potassium channel, Kv7.2, cause neonatal epilepsies. The potassium channel opener, retigabine, may improve epilepsy control in cases with loss-of-function mutations, but exacerbate seizures in cases with gain-of-function mutations. Our aim was to describe a patient with a KCNQ2 mutation within the K+-selectivity filter and illustrate how electrophysiological analysis helped us to implement personalized treatment. Medical history of a patient with severe neonatal epileptic encephalopathy was recorded. Diagnosis was reached by whole-exome-sequencing. The pathogenic variant was expressed in Chinese hamster ovary cells, and patch-clamp studies were performed, directing therapy. A seven-year-old male presented with neonatal seizures, progressing to hundreds of seizures/day without developmental milestones. Whole-exome sequencing revealed a pathogenic variant, p.Gly281Arg, in the KCNQ2 gene, located within the ion selectivity filter of the pore, predicted to cause loss-of-function of Kv7.2, not affected by retigabine. Patch-clamp analysis revealed no current with the mutant homomer and reduced current with heterotetramer (KCNQ2WT/KCNQ2G281R/KCNQ3WT) channels, consistent with a dominant-negative effect. Addition of 5 µM retigabine did not produce a current with the mutant homomer, but increased current with the heterotetramer (V50: -30.4 mV vs. -51.3 mV). Following these results, retigabine at 15 mg/kg was administered off-label, prompting a 90% seizure reduction. Drug withdrawal, imposed by revocation of marketing authorisation for retigabine, caused 50% increase in seizure burden. Retigabine may be used for precision therapy in patients with KCNQ2-related epilepsy due to loss-of-function variants. It is imperative to reintroduce safe marketing of retigabine for selected patients as personalized treatment.

A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.

Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.

Phenotypic variability in patients with unique double homozygous mutations causing variant ataxia telangiectasia.

Ataxia-Telangiectasia (A-T) is a neurodegenerative disease caused by bi-allelic mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene. Complete lack of ATM activity leads to severe A-T and mutations allowing for residual activity cause a milder phenotype, termed variant A-T. There are only sparse data on the variability in phenotypes of variant A-T patients carrying the same mutations. A retrospective study of 15 patients with variant A-T, all double homozygous for the same mutations was conducted. The age of first symptom ranged from 4-180 months, including: truncal ataxia at <18 months of age in 9 patients, ataxia and instability only during fever in one patient, dystonia in one patient and malignancy in 4 patients. Global developmental delay and occulo-motor apraxia were recorded in 4/14 patients. Variant A-T patients with the same mutations in ATM, have variable phenotypes. Environmental, epigenetic, and post translational factors are likely to play a role in creation of the phenotype in variant A-T patients.

Congenital Mirror Movements Associated With Brain Malformations.

BACKGROUND: Congenital mirror movements are involuntary movements of a side of the body imitating intentional movements on the opposite side, appearing in early childhood and persisting beyond 7 years of age. Congenital mirror movements are usually idiopathic but have been reported in association with various brain malformations. METHODS: We describe clinical, genetic, and radiologic features in 9 individuals from 5 families manifesting congenital mirror movements. RESULTS: The brain malformations associated with congenital mirror movements were: dysplastic corpus callosum in father and daughter with a heterozygous p.Met1* mutation in DCC; hypoplastic corpus callosum, dysgyria, and malformed vermis in a mother and son with a heterozygous p.Thr312Met mutation in TUBB3; dysplastic corpus callosum, dysgyria, abnormal vermis, and asymmetric ventricles in a father and 2 daughters with a heterozygous p.Arg121Trp mutation in TUBB; hypoplastic corpus callosum, dysgyria, malformed basal ganglia and abnormal vermis in a patient with a heterozygous p.Glu155Asp mutation in TUBA1A; hydrocephalus, hypoplastic corpus callosum, polymicrogyria, and cerebellar cysts in a patient with a homozygous p.Pro312Leu mutation in POMGNT1. CONCLUSION: DCC, TUBB3, TUBB, TUBA1A, POMGNT1 cause abnormal axonal guidance via different mechanisms and result in congenital mirror movements associated with brain malformations.

Clinical phenotypes of infantile onset CACNA1A-related disorder.

BACKGROUND: CACNA1A-related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients. OBJECTIVE: To describe phenotypes in infantile onset CACNA1A-related disorder and to explore intra-familial variations and genotype-phenotype correlations. MATERIAL AND METHODS: This study was a multicenter international collaboration. A retrospective chart review of CACNA1A patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder. RESULTS: Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two. CONCLUSIONS: Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found.

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.

Four patients with D-bifunctional protein (DBP) deficiency: Expanding the phenotypic spectrum of a highly variable disease.

INTRODUCTION: Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures, retinopathy, hearing loss, dysmorphic features, and other complications. The HSD17B4 gene encodes DBP which is essential for oxidation of peroxisomal substrates. We describe 4 patients - 2 unrelated female girls and 2 monozygotic twin sisters - with DBP deficiency and phenotypic diversity. PATIENT REPORTS: Patient 1 presented neonatally with hypotonia and seizures, and later on developed global developmental delay and regression, sensorineural hearing loss, nystagmus and cortical blindness. The brain MRI demonstrated bilateral peri-sylvian polymicrogyria. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.752G>A, p.(Arg251Gln); c.868 + 1delG).Patient 2 presented with hypotonia, motor delay, and sensorineural hearing loss in infancy, considerable developmental regression during her fourth year, nystagmus, and peripheral neuropathy. Brain MRI demonstrated cerebellar atrophy and abnormal basal ganglia and white matter signal, which appeared after the age of two years. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.14 T>G, p.(Leu5Arg); c.752G>A, p.(Arg251Gln)).Patients 3 and 4, two female monozygotic twins, presented with hypotonia, developmental delay, and macrocephaly from birth, and later on also sensorineural hearing loss, infantile spasms and hypsarrhythmia, and adrenal insufficiency. Brain MRI demonstrated delayed myelination, and an assay of peroxisomal beta oxidation suggested DBP deficiency. Sequencing of the HSD17B4 gene revealed the same 2 mutations as in patient 1. DISCUSSION: We describe 4 patients with variable and diverse clinical picture of DBP deficiency and particularly emphasize the clinical, biochemical, and neuroimaging characteristics. Interestingly, the clinical phenotype varied even between patients with the exact two mutations in the HSD17B4 gene. In addition, in two of the three patients in whom levels of VLCFA including phytanic acid were measured, the levels were within normal limits. This is expanding further the clinical spectrum of this disorder, which should be considered in the differential diagnosis of every patient with hypotonia and developmental delay especially if accompanied by polymicrogyria, seizures, sensorineural hearing loss, or adrenal insufficiency regardless of their VLCFA profile.

Functional parameter measurements in children with ataxia telangiectasia.

AIM: To collect preliminary functional data on ataxia telangiectasia and create a disease specific scale: the Ataxia Telangiectasia Functional Scale (ATFS). METHOD: Retrospective information on patients with ataxia telangiectasia referred to the Assistive Technology Unit was included. Functional mobility scales (the Gross Motor Function Classification System [GMFCS] and the Functional Mobility Scale [FMS]-5, FMS-50, FMS-500) and activities of daily living [ADL] parameters were recorded. We created a 51-point ATFS, that consisted of three ambulation items adapted for ataxia telangiectasia in the frame of FMS (home, school, outdoors), five ADL items, and one schooling item. RESULTS: Twenty-seven participants (17 males, 10 females; mean age 10y 8mo [SD 5y 1mo], range 1y 9mo-25y 6mo), were enrolled; 168 measurements were recorded. Patients walked at a mean age of 1 year 4 months (SD 5y 4mo) and lost ambulatory capacity at 8 years 8 months (SD 2y 1mo). GMFCS level and FMS-5, FMS-50, FMS-500 assessments correlated with age (Spearman's correlations r=0.555, -0.617, -0.639, -0.662 respectively, p<0.01 for all), but plateaued after 12 years of age. ATFS mean score was 37.46 (SD 7.88) and increased with age (Spearman's correlation r=0.585, p<0.01). The scale showed three stages of disease progression. INTERPRETATION: In this pilot study we show longitudinal functional data of ambulation and ADL skills in ataxia telangiectasia, and created a framework for a functional scale. This functional scale closely approximated disease course, but further validation is required. WHAT THIS PAPER ADDS: The Gross Motor Function Classification System and the Functional Mobility Scale are ill-suited for ataxia telangiectasia assessments. Three functional mobility scales (home, school, outdoors) suited to ataxia telangiectasia were created. The Ataxia Telangiectasia Functional Scale (ATFS) combines mobility and items of activities of daily living. The ATFS closely approximates the three-stage progression of the disorder.

MEDICIONES DE PARÁMETROS FUNCIONALES EN NIÑOS CON ATAXIA TELANGIECTASIA: OBJETIVO: Recopilar datos funcionales preliminares sobre la ataxia telangiectasia y crear una escala específica de la enfermedad: la escala funcional de la ataxia telangiectasia (ATFS). MÉTODO: Se incluyó información retrospectiva sobre pacientes con ataxia telangiectasia remitidos a la Unidad de Tecnología Asistiva. Se registraron las escalas de movilidad funcional (el sistema de clasificación de la función motora gruesa [GMFCS] y la escala de movilidad funcional [FMS-5, FMS-50, FMS-500]) y los parámetros de las actividades de la vida diaria [ADL]. Creamos un ATFS de 51 puntos, que constaba de tres elementos de asistencia a la deambulación adaptados para la ataxia telangiectasia según los requerimientos de FMS (hogar, escuela, exteriores), cinco elementos de ADL y un elemento de escolarización. RESULTADOS: Se reclutaron 27 participantes (17 varones, 10 mujeres; edad media 10a 8m[DE 5a 1m], rango 1a 9m- 25a 6m); se registraron 168 mediciones. Los pacientes caminaron a una edad promedio de 1 año y 4 meses (DE 5 y 4 meses) y perdieron la capacidad ambulatoria a los 8 años y 8 meses (DE 2 y 1 meses). Las evaluaciones GMFCS y FMS-5, FMS-50, FMS-500 se correlacionaron con la edad (correlaciones de Spearman r = 0,555, -0,617, -0,639, -0,662 respectivamente, p <0,01 para todos), pero se estancaron después de los 12 años de edad. La puntuación media de ATFS fue 37,46 (SD 7,88) y aumentó con la edad (correlación de Spearman r = 0,585, p <0,01). La escala mostró tres etapas de progresión de la enfermedad. INTERPRETACIÓN: En este estudio piloto, mostramos datos funcionales longitudinales de ambulación y habilidades de ADL en la ataxia telangiectasia, y creamos un marco para una escala funcional. Esta escala funcional se aproximó mucho al curso de la enfermedad, pero se requiere validación adicional.

MEDIDAS DE PARÂMETROS FUNCIONAIS EM CRIANÇAS COM ATAXIA TELANGIECTASIA: OBJETIVO: Coletar dados funcionais prelimiares sobre ataxia telangiectasia e criar uma escala específica para a doença: a Escala Funcional de Ataxia Telangiectasia (EFAT). MÉTODO: Informações retrospectivas sobre pacientes com ataxia telangiectasia encaminhados para a Unidade de Tecnologia Assistiva foram incluídas. Escalas de mobilidade funcional (o Sistema de Classificação da Função Motora grossa [GMFCS] e a Escala de Mobilidade Funcional [FMS]-5, FMS-50, FMS-500) e parâmetros de atividades da vida diária [AVD] foram registrados. Uma EFAT de 51 pontos foi criada, consistindo de três itens de deambulação adaptados para ataxia telangiectasia na estrutura da FMF (casa, escola, comunidade), cinco itens de AVDs, e um item sobre escolaridade. RESULTADOS: Vinte e sete participantes (17 do sexo masculino, 10 nomes do sexo feminino; média de idade 10a 8m [DP 5a 1m], variação 1a 9m-25a 6m), foram recrutados; 168 medidas foram registradas. Os pacientes deambularam com uma média de (DP 5a 4m) e perderam a capacidade deambulatória com 8a 8m (DP 2a 1m). As avaliações de GMFCS e FMS-5, FMS-50, FMS-500 se correlacionara mcom a idade (correlações de r=0,555, -0,617, -0,639, -0,662 respectivamen, p<0,01 para todos), mas atingiram platô após a idade de 12 anos. O escore médio da EFAT foi 37,46 (DP 7,88) e houve aumento com a idade (correlação de Spearman r=0,585, p<0,01). A escala mostrou três estágios de progressão da doença. INTERPRETAÇÃO: Neste estudo piloto, mostramos dados funcionais longitudinais sobre a deambulação e AVDs em ataxia telangiectasia, e criamos uma estrutura para uma escala fncional. Esta escala funcional se assemelhou com o curso da doença, porém maiores estudos para validação são necessaries.

Netrin-G2 dysfunction causes a Rett-like phenotype with areflexia.

We describe the underlying genetic cause of a novel Rett-like phenotype accompanied by areflexia in three methyl-CpG-binding protein 2-negative individuals from two unrelated families. Discovery analysis was performed using whole-exome sequencing followed by Sanger sequencing for validation and segregation. Functional studies using short-hairpin RNA for targeted gene knockdown were implemented by the transfection of mouse cultured primary hippocampal neurons and in vivo by in utero electroporation. All patients shared a common homozygous frameshift mutation (chr9:135073515, c.376dupT, p.(Ser126PhefsTer241)) in netrin-G2 (NTNG2, NM_032536.3) with predicted nonsense-mediated decay. The mutation fully segregated with the disease in both families. The knockdown of either NTNG2 or the related netrin-G family member NTNG1 resulted in severe neurodevelopmental defects of neuronal morphology and migration. While NTNG1 has previously been linked to a Rett syndrome (RTT)-like phenotype, this is the first description of a RTT-like phenotype caused by NTNG2 mutation. Netrin-G proteins have been shown to be required for proper axonal guidance during early brain development and involved in N-methyl- d-aspartate-mediated synaptic transmission. Our results demonstrating that knockdown of murine NTNG2 causes severe impairments of neuronal morphology and cortical migration are consistent with those of RTT animal models and the shared neurodevelopmental phenotypes between the individuals described here and typical RTT patients.

Treatment with brivaracetam in children - The experience of a pediatric epilepsy center.

INTRODUCTION: The new anticonvulsant brivaracetam is a levetiracetam analog which binds to the synaptic vesicle protein 2A, and inhibits excitatory neurotransmitters' release. Brivaracetam was Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved in 2016 as adjunctive treatment for focal onset seizures in patients over 16 years of age, and in 2018 for children over four years of age. Our aim was to describe effectiveness and tolerability in real-life pediatric epilepsy clinic. METHODS: Cross-sectional retrospective chart review of patients under 20 years of age, treated with brivaracetam. Positive response to treatment was considered when 50% decrease in seizure frequency was noted. In responders to levetiracetam, positive effect was regarded if switching to brivaracetam maintained at least the same seizure control. RESULTS: Thirty-one patients (67.7% males), aged 13.8 ±â€¯4.07 (6.9-20 years), were treated with brivaracetam 3.8 mg/kg ±â€¯1.8. Age of onset of epilepsy was 5.7 ±â€¯3.7 years; 20 patients had focal epilepsies; and 11 had epileptic syndromes (5 - Lennox-Gastaut, 3 - myoclonic absence, 3 - myoclonic-atonic). Responder rate was 45.2%, with no statistical difference under and over 16 years of age (40% vs. 54.5%, Fisher's exact test). Eight patients had better response to seizures compared to levetiracetam. Gender, duration of epilepsy, and dosage did not affect epilepsy control. Six patients had seizure aggravation. Adverse effects were rare: mild somnolence (6.4%), psychosis (3.2%), and nausea (3.2%). CONCLUSION: Brivaracetam is an effective add-on treatment in focal, as well as generalized seizures in children, with negligible side effects, including children who failed previously on levetiracetam. Seizure exacerbation may occur, but it's reason is unclear.

Analysis of the Phenotypes in the Rett Networked Database.

Rett spectrum disorder is a progressive neurological disease and the most common genetic cause of intellectual disability in females. MECP2 is the major causative gene. In addition, CDKL5 and FOXG1 mutations have been reported in Rett patients, especially with the atypical presentation. Each gene and different mutations within each gene contribute to variability in clinical presentation, and several groups worldwide performed genotype-phenotype correlation studies using cohorts of patients with classic and atypical forms of Rett spectrum disorder. The Rett Networked Database is a unified registry of clinical and molecular data of Rett patients, and it is currently one of the largest Rett registries worldwide with several hundred records provided by Rett expert clinicians from 13 countries. Collected data revealed that the majority of MECP2-mutated patients present with the classic form, the majority of CDKL5-mutated patients with the early-onset seizure variant, and the majority of FOXG1-mutated patients with the congenital form. A computation of severity scores further revealed significant differences between groups of patients and correlation with mutation types. The highly detailed phenotypic information contained in the Rett Networked Database allows the grouping of patients presenting specific clinical and genetic characteristics for studies by the Rett community and beyond. These data will also serve for the development of clinical trials involving homogeneous groups of patients.

In vivo, in vitro and in silico correlations of four de novo SCN1A missense mutations.

Mutations in the SCN1A gene, which encodes for the voltage-gated sodium channel NaV1.1, cause Dravet syndrome, a severe developmental and epileptic encephalopathy. Genetic testing of this gene is recommended early in life. However, predicting the outcome of de novo missense SCN1A mutations is difficult, since milder epileptic syndromes may also be associated. In this study, we correlated clinical severity with functional in vitro electrophysiological testing of channel activity and bioinformatics prediction of damaging mutational effects. Three patients, bearing the mutations p.Gly177Ala, p.Ser259Arg and p.Glu1923Arg, showed frequent intractable seizures that had started early in life, with cognitive and behavioral deterioration, consistent with classical Dravet phenotypes. These mutations failed to produce measurable sodium currents in a mammalian expression system, indicating complete loss of channel function. A fourth patient, who harbored the mutation p.Met1267Ile, though presenting with seizures early in life, showed lower seizure burden and higher cognitive function, matching borderland Dravet phenotypes. In correlation with this, functional analysis demonstrated the presence of sodium currents, but with partial loss of function. In contrast, six bioinformatics tools for predicting mutational pathogenicity suggested similar impact for all mutations. Likewise, homology modeling of the secondary and tertiary structures failed to reveal misfolding. In conclusion, functional studies using patch clamp are suggested as a prognostic tool, whereby detectable currents imply milder phenotypes and absence of currents indicate an unfavorable prognosis. Future development of automated patch clamp systems will facilitate the inclusion of such functional testing as part of personalized patient diagnostic schemes.

Secondary enuresis and urological manifestations in children with ataxia telangiectasia.

BACKGROUND: Ataxia telangiectasia (AT) is a neurodegenerative cerebellar disorder, caused by mutations in the ATM gene, involved in DNA repair. Radiosensitivity, progressive ataxia, immune deficiency and malignancies, are well known symptoms, but urological manifestations are scarcely described. OBJECTIVE: To characterize urologic manifestations in a large cohort of AT patients. METHODS: Retrospective cross-sectional chart study comprising 52 AT patients followed at a National AT Center. RESULTS: 25% of the cohort (13 patients/8 males) had urologic symptoms, which presented at 11 ± 4.3 years. The most common symptom was secondary enuresis affecting 15% of the patients (8 children/4 males). Incontinence appeared at 8 ± 6.2 years of age, and resolved spontaneously within 15 ± 8.3 months in 6 patients. It preceded loss of ambulatory capacity by 1-2 years in 7 patients. Lumbosacral MRI were normal (4 children) and urine cultures (all) were negative. Urodynamic evaluation that was performed in only one patient revealed overactive bladder. Additional manifestations were macroscopic hematuria due to bladder telangiectasia in a 12-year-old, and renal cell carcinoma in a 22-year-old. Other manifestations unrelated to AT were neprolithiasis, vesico-ureteral reflux and scrotal pain, each in 1 patient. DISCUSSION: Transient secondary enuresis is a frequent finding in AT patients, heralding loss of ambulatory capacity, tough it's pathophysiological mechanism is largely no understood.

Long-term nutritional and gastrointestinal aspects in patients with ataxia telangiectasia.

OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic disease involving multiple organs, but, to our knowledge, data on long-term gastrointestinal and nutritional involvement are scarce. The aim of this study was to longitudinally review the nutritional and gastrointestinal aspects of A-T. METHODS: This was a retrospective chart review of patients followed from 1986 to 2015 at one center. Demographic, laboratory, and nutritional data were retrieved. Body mass index (BMI) values were converted to BMI Z-score (BMI-Z). Caloric intake was estimated by food diaries and compared with estimated energy requirements for sex and age with a physical activity level factor for light physical activity. RESULTS: The study included 53 patients (28 males [53%], ages 14.6 ± 5.2 y). BMI-Z was inversely correlated with age (r = 0.48; P < 0.004). A decline below minimal BMI percentiles was observed after the age of 4 y in boys and 7 y in girls. The relative percentage of caloric intake decreased with age (r = -0.5; P < 0.002), and was positively correlated with BMI-Z (r = 0.35; P < 0.05). Presence of cough during meals was associated with recurrent lower respiratory tract infections (Fisher exact test, P < 0.01). Gastrostomy tubes were inserted in 12 patients, leading to improvement in BMI-Z from -5.1 ± 2.4 to -4 ± 2.9 (P < 0.05). CONCLUSIONS: There is a progressive growth failure and low nutritional intake with age in patients with A-T, starting in early childhood in males, and more prominent in patients with cough and choking during meals. A proactive approach and insertion of a percutaneous gastrostomy tube as soon as the BMI-Z starts to decrease should be considered.