New insights into CC2D2A-related Joubert syndrome.

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Paediatric intracranial dural arteriovenous shunts: types, clinical presentation and therapeutic management.

Paediatric intracranial dural arteriovenous shunts have clinical presentations and evolutions, with angiographic characteristics that differ from those described in adults. We report our experience concerning their therapeutic management, emphasizing the relevance of early diagnosis and appropriate treatment for satisfactory neurocognitive development. Using a prospective database, we reviewed the clinical and radiological data of all children with dural arteriovenous shunts managed between 2002 and 2020. Dural shunts were categorized into three types: dural sinus malformations with arteriovenous shunts; infantile dural arteriovenous shunts; and adult-type dural arteriovenous shunts. Therapeutic strategies and outcomes were analysed depending on lesional subtypes. Modified Rankin Scale for the paediatric population was assessed pre-treatment and at last follow-up. Twenty-eight patients [16 girls (57.1%); 12 boys (42.9%)] were included: 17 dural sinus malformation [10 boys (58.8%); seven girls (41.2%)], three infantile shunts [three girls (100%)], eight adult-type shunts [four girls (50%)]; four boys (50%)], with a mean age of 19.2 ± 36.6 months at presentation. Twelve (42.9%) had a modified Rankin Scale score of 0-2, four (14.3%) had a score of 3, three (10.7%) had a score of 4 and eight (28.6%) had a score of 5. Embolization was performed in 22 children [78.6%; 12 girls (54.5%); 10 boys (45.5%)]. Fifteen patients could be cured (68.2%): 11 dural sinus malformations (73.3%), four adult-type lesions (100%) but no infantile shunt. Mean post-treatment follow-up was 39.5 months (max. 139 months): 14 patients (63.6%) presented a modified Rankin Scale score of 0-2 and eight (36.4%) had a score ≥3. In the dural sinus malformation group, the modified Rankin Scale score was improved in 11 patients (73.3%) and unchanged in three (20%). Only one patient with infantile subtype (33.3%) improved clinically. In the adult-subtype group, all children (100%) improved. Of six untreated patients [four girls (66.7%); two boys (33.3%)], four with adult-subtype shunts showed uneventful evolutions, one with dural sinus malformation died, and therapeutic abortion was conducted in an antenatally diagnosed dural sinus malformation. Paediatric dural fistulas comprise different subtypes with variable clinical courses. Proper diagnosis is mandatory for optimal therapeutic strategies within appropriate therapeutic windows.

Psychomotor development in infants and young children with Down syndrome-A prospective, repeated measure, post-hoc analysis.

Children with Down syndrome (DS) show delayed acquisition of cognitive and functional skills compared to typically developing children. The objective of this study was to accurately describe early development of infants and young children (children hereafter) with DS based on a large recent sample. We carried out repeated measure analysis of the global development quotient (GDQ) and developmental age using data from the Assessment of Systematic Treatment with Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) study (NCT01576705). Because there was no statistically significant difference in the primary endpoint between active treatment and placebo, data from all treatment groups were pooled for post-hoc analysis. Data of 141 children with DS aged 6-18 months at inclusion were analyzed. Mean GDQ decreased over the study period, especially in the youngest age classes ([6-9] and [9-12] months), indicating that acquisition of skills occurred at a slower pace compared to typically developing children. Strongest deficits were observed for motor and hearing and language skills. Only GDQ at baseline correlated significantly with evolution of GDQ. Future studies should aim at elucidating the mechanisms underlying motor and language development. Early pharmacological interventions together with early childhood therapies might be necessary to improve the developmental trajectory of children with DS.

Tremor-like subcortical myoclonus in STXBP1 encephalopathy.

The phenotypic spectrum of STXBP1-related encephalopathy ranges from infantile epileptic encephalopathy to intellectual disability with nonsyndromic or absent epilepsy. Although being frequently reported, the tremor associated with STXBP1 has not been fully characterized to date. The aim of our study was to describe it. We recruited patients with intellectual disability due to STXBP1 variants, regardless of their epileptic phenotype, who had tremor at examination and who underwent neurophysiological testing including polymyographic registration of upper limbs muscles activity at rest, during posture maintenance and action. Six patients met the inclusion criteria over four years. Clinically, all had a postural and action distal tremor increased by emotions. Neurophysiological recordings showed a specific myoclonus pattern and were highly suggestive of a subcortical generator. The tremor-like observed in STXBP1 encephalopathy is due to a subcortical pseudo-rhythmic myoclonus.

Reading Comprehension Impairment in Children With Neurofibromatosis Type 1 (NF1): The Need of Multimodal Assessment of Attention.

Attention span, which has been shown to have an impact on reading quality in many other conditions, is one of the main cognitive disorders of neurofibromatosis type 1 (NF1). The aim of this work is to observe the impact of attention on reading comprehension, in NF1 and non-NF1 children. A multicenter, cross-sectional study was conducted on 150 children (8-12 years old) with or without NF1 (75 NF1 vs 75 non-NF1; 72 female, 78 male), matched for age, sex, handedness, and reading level, thus forming a continuum from good to poor readers in both NF1 and non-NF1 groups. Children with intellectual deficiency or neurologic or psychiatric disorder were excluded. Attentional skills were assessed by combining a parent questionnaire (Child Behavior CheckList) and a performance-based assessment (Conner's Continuous Performance Test-Second Edition). Reading comprehension was assessed through a standardized reading comprehension test (ORLEC Lobrot). The performance-based attention scores were associated with text and sentence comprehension ability (P = .0235 and P = .0164, respectively), while indirect questionnaire attention scores were only associated with sentence comprehension (P = .0263). For both groups, the correlations between questionnaire and performance-based measures were low. We have shown that reading comprehension is greatly influenced by attention in NF1 and non-NF1, even if predictors of good reading comprehension also include IQ score and reading accuracy. Indirect observer-rated questionnaires and direct performance-based measures of attention do not assess the same variables, are linked to different components of reading skills, and are not interchangeable assessments of attention difficulties. Both assessments are complementary and must be used simultaneously, leading to recommendations that support multimodal assessment of attention.

Focal polymicrogyria in children: Contribution of invasive explorations and epileptogenicity mapping in the surgical decision.

OBJECTIVE: Report of the contribution of invasive EEG (iEEG) and epileptogenicity mappings (EM) in a pediatric cohort of patients with epilepsy associated with focal polymicrogyria (PMG) and candidates for resective surgery. METHOD: Retrospective pediatric case series of patients presenting focal PMG-related refractory epilepsy undergoing an invasive exploration (iEEG) at Fondation Rothschild Hospital. We reviewed clinical data, structural MRI, and visual analysis of iEEG recordings. Moreover, time-frequency analysis of SEEG signals with a neuroimaging approach (epileptogenicity maps) was used to support visual analysis. RESULTS: Between 2012 and 2019, eight patients were selected. Five patients were explored with stereoelectroencephalography (SEEG) only, one patient with subdural exploration (SDE) only and two patients first underwent SEEG and then SDE. The mean age at seizure onset was 40.3 months (range 3-120), and the mean age for the iEEG 10.8 years (range 7-15). The epileptogenic zone (EZ) appeared concordant to the PMG lesion in only one case, was larger in three cases, smaller in two cases and different in one case. Four cases were selected for tailored resective surgery and one for total callosotomy. Two patients remained seizure-free at their last follow-up (mean 32.6 months, range 7-98). Epileptogenicity mapping (EM) refined the qualitative analysis, showing in four patients an EZ larger than visually defined. CONCLUSION: This study is the first pediatric study to analyze the value of iEEG and EM as well as operability in focal PMG-related refractory epilepsy. The results illustrate the complexity of this pathology with variable concordance between the EZ and the lesion and mixed response to surgery.

Endovascular management of torcular dural sinus malformations in children: the role of straight sinus occlusion.

BACKGROUND: Torcular dural sinus malformations (tDSMs) with arteriovenous shunts are rare congenital intracranial vascular malformations that carry a high rate of neurologic impairment and death in the neonatal, infant and young pediatric population. Their impact on brain venous drainage, especially the deep venous system, is one of the key factors in the clinical prognosis and natural history of the disease. We describe our therapeutic strategy for tDSMs, disconnecting the reflux into the deep venous system by performing an endovascular straight sinus occlusion. METHODS: Among all children with dural sinus malformations seen between 2002 and 2020, we retrospectively reviewed those with tDSM in whom straight sinus occlusion had been performed. RESULTS: Our databank included nine patients with tDSM that were embolized. Mean age at the clinical onset was 8.9±9.6 months (min-max=0-31). Five patients presented a significant reflux in the straight sinus on digital subtraction angiography. Those patients were initially clinically worse (mean modified Rankin Scale (mRS) 3.8) than those who did not present with reflux (mean mRS 2.25), this reflux being responsible for intraventricular hemorrhage in three patients. The reflux was suppressed by transarterial embolization in one patient and by transvenous straight sinus occlusion in four patients. Staged endovascular treatment resulted in a complete cure in six patients without complications, and clinical improvement in all patients. CONCLUSION: Straight sinus occlusion is a feasible technique that needs to be considered in the treatment strategy for tDSM with deep venous reflux in order to avoid or minimize brain damage.

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Mitochondrial dysfunction caused by novel ATAD3A mutations.

Mitochondrial respiratory chain integrity depends on a number of proteins encoded by nuclear and mitochondrial genomes. Mutations of such factors can result in isolated or combined respiratory chain deficits, some of which can induce abnormal morphology of the mitochondrial network or accumulation of intermediary metabolites. Consequently, affected patients are clinically heterogeneous, presenting with central nervous system, muscular, or neurodegenerative disorders. ATAD3A is a nuclear-encoded ATPase protein of the AAA+ family and has been localized to the inner mitochondrial membrane. Recently reported mutations or large deletions in the ATDA3A gene in patients have been shown to induce altered mitochondrial structure and function and abnormal cholesterol metabolism in a recessive or dominant manner. Here, we report two siblings presenting axonal sensory-motor neuropathy associated with neonatal cataract. Genetic analyses identified two novel mutations in ATAD3A; a point mutation and an intronic 15 bp deletion affecting splicing and leading to exon skipping. Biochemical analysis in patient cells and tissues showed abnormal function of the mitochondrial respiratory chain in muscle and abnormal mitochondrial cristae structure. These new cases underline the large spectrum of biochemical and clinical presentations of ATAD3A deficiency and the different modes of inheritance, making it an atypical mitochondrial disorder.

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature.

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.

Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial.

PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.

Invasive evaluation in children (SEEG vs subdural grids).

Designed from the 60s to the 80s for adults, and despite the development of many new techniques, invasive explorations still have indications in children with focal drug-resistant epilepsy. The main types are stereoelectroencephalography (SEEG) and subdural explorations (SDE). They provide precise information on the localization of the epileptogenic zone (EZ), its relationships with eloquent cortex, and the feasibility of performing a tailored surgical resection. Thermocoagulations, which are a diagnostic and therapeutic tool, can be performed using SEEG electrodes. Both techniques are feasible in children, with an age limitation for SEEG (which requires a bone thickness above 2 mm). The complication rate is higher with SDE. Opposed for a long time and never compared in a systematic study, they should presently be considered complementary. The indications cannot be directly inferred from those for adults, as there are pediatric particularities in the seizures' semiology, functional areas, imaging and urgent situations. We successively discuss the choice in individual cases of SEEG or SDE respectively, the specific problematic in infancy and early childhood, the schema in SEEG for cryptogenic epilepsies (in particular insular), the particularities of polymicrogyria and deeply located lesions, and finally, SEEG designed for thermocoagulations. Future improvements should include more accurate implantation schemas thanks to advanced non-invasive explorations and possibilities to perform SEEG in infants.

Seizure outcome and prognostic factors for surgical management of hypothalamic hamartomas in children.

PURPOSE: Hypothalamic hamartomas (HH) are rare benign lesions frequently associated with gelastic seizures early in life. Epilepsy can progress to multiple seizure types with cognitive impairment and behavioural disturbance, leading in some cases to epileptic encephalopathy. METHODS: We reviewed a retrospective series of 112 children treated in a single center, between 1998 and 2017. RESULTS: According to Delalande's HH classification, type1 was found in 2 patients, type 2 in 67, type 3 in 31, and type 4 in 12 patients. Stereotactic endoscopic disconnection was performed in 92 % of the procedures. Median age at diagnosis was 40 months and 7.6 years at surgery. Median time between diagnosis and surgery was 31 months and median follow up 4.1 years. For all HH types, 77.6 % of the patients had a favourable outcome (Engel I + II outcome score) with 57.1 % seizure-free (Engel I). The best outcome was obtained in patients with type 2 HH, (68.7 % Engel I and 85.1 % Engel I + II). The overall complication rate was 8.3 %, which is in line with previous series. Patients with isolated gelastic seizures had a better outcome (Engel I + II in 90 %), as compared to those with other seizure types (p = 0.07). A short delay between hamartoma diagnosis and surgery was a statistically significant factor for a good outcome (p = 0.03). CONCLUSION: Patients with HH and drug-resistant epilepsy should be early identified in order to propose surgical treatment without delay. Endoscopic disconnection is a safe and efficacious surgical option with good seizure outcome and immediate treatment results.

Parasagittal hemispherotomy in hemispheric polymicrogyria with electrical status epilepticus during slow sleep: Indications, results and follow-up.

PURPOSE: Polymicrogyria (PMG), although the most common brain malformation, represents a low percentage among patients operated on for epilepsy. In cases of hemispheric PMG, electrical status epilepticus during slow sleep (ESESS) may occur leading to an aggravation of the neurological condition and a risk of drug resistance. In such cases, surgical treatment can be offered. METHODS: From a population of 230 children who underwent hemispherotomy for epilepsy, we retrospectively reviewed the patients with unilateral PMG and drug-resistant ESESS focusing on clinical charts, electrophysiological data and post-surgical outcome. RESULTS: Eighteen patients were operated on at a mean age of 7.2 years. The average age was 2 years at seizure onset and 4.4 years at diagnosis of ESESS. All the patients preoperatively had some degree of developmental delay associated with a hemiparesis. During ESESS all of them evidenced a cognitive decline and eight experienced a worsening of the hemiparesis; ESESS was resistant to at least three antiepileptic drugs. The outcome of epilepsy, with a mean follow-up of 12.8 years showed that ESESS disappeared in all patients while 16 of 18 became seizure-free. An improvement of behavior and cognitive condition was observed in all. CONCLUSION: Hemispherotomy can be helpful in patients with drug-resistant ESESS and hemispheric PMG while keeping in mind that more often an accurate medical treatment can be sufficient. The main benefit of surgery is to definitively stop the seizures and to withdraw the medical treatment while keeping in mind the risk of motor aggravation.

Dissecting the genetic basis of focal cortical dysplasia: a large cohort study.

Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population.

SEEG-guided radiofrequency thermocoagulation of epileptic foci in the paediatric population: Feasibility, safety and efficacy.

PURPOSE: Focal epilepsy in children may be refractory to pharmacological treatment and surgical resection may be an appropriate option. When invasive electroencephalogram is required in the presurgical evaluation, depth electrodes can be used to create focal lesions in the epileptogenic zone using radiofrequency thermocoagulation (RFTC), to disrupt the epileptogenic zone. METHODS: This study aimed to assess the efficacy and safety of RFTC in a paediatric population of 46 patients. RESULTS: The mean age of onset was 3.3 years and the mean age at SEEG was 8.2 years. MRI lesions were identified in 71.7% of the series, among them 60% of malformation of cortical development. 43.5% of the patients were seizure free at 1 month, 26.1% were responders. The mean duration of improvement was 6.8 months. 8 children were seizure free for >8 months and among them, 6 are currently seizure free for 8-24 months. 5 patients had functional deficits post-procedures, transient in 4 patients and prolonged in one of whom. 3/5 were anticipated following the results of cortical stimulation. Multivariate analysis found 3 independent criteria linked to RFTC efficiency one month after RFTC: frequency of the seizures before RFTC, age and number of contacts used. CONCLUSION: RFTC is a safe method for the paediatric population providing important predictive information for surgical resection. An improvement in seizure frequency, often transient, is seen in 2/3 of our patients. RTFC could be useful as a palliative technique for children with an epileptogenic zone overlapping with eloquent areas, with minimal risk of sequelae.

Investigation of paediatric occipital epilepsy using stereo-EEG reveals a better surgical outcome than in adults, especially when the supracalcarine area is affected.

Occipital epilepsy is the least common among surgical series because: (1) the location makes it hard to asses by EEG; (2) the seizure semiology often reflects propagation; and (3) surgery entails a high risk of neurological deficits. In children, subjective symptoms are harder to assess, adding to the difficulty of a proper diagnosis. We aimed to determine electroclinical characteristics of occipital lobe epilepsy in a paediatric population by reviewing 20 children between one and 16 years, who had undergone intracranial recordings with depth electrodes. Eight patients had pure occipital epilepsies and 12 had "occipital plus" epilepsies. We identified four different seizure spreading patterns: (1) pure occipital (40%) with oculomotor symptoms; (2) temporal (30%) with hypomotor behaviour and automatisms; (3) frontal (20%) with movements of the limbs; and (4) spasms (10%). Two thirds of the children above 11 years reported visual aura, but this was probably underestimated in younger children as some seizures began with non-specific motion arrest. Automatisms were only observed when the lateral temporal lobe was involved. Patients with a pure occipital form had a seizure onset zone strictly in the occipital lobe. Lingual and cuneus gyri were the most epileptogenic structures. Scalp EEG showed diffuse EEG abnormalities in two thirds of the patients and 25% of these led to false lateralization of the SOZ. Although MRI lesions were always visible, imaging and scalp EEG could be misleading and often not sufficient to guide surgery. After surgery, 68% of the patients were classified as Engel Class I, and surgical outcome was even better for patients in whom the supracalcarine area was affected, with 87.5% reaching seizure freedom. Seizure spread patterns in occipital epilepsy are similar in paediatric and adult populations, even though it is often impossible to obtain subjective symptoms in children. Postsurgical outcome is better than in adults, especially in patients in whom the supracalcarine area is affected.

Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

Deep brain stimulation is effective in pediatric patients with GNAO1 associated severe hyperkinesia.

BACKGROUND: Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication. OBJECTIVE: The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations. METHODS: We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS. RESULTS: The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723+1G>T) in patient 1, a new missense mutation (c.610G>C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625>T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G>A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation. CONCLUSION: In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.