WDR45 encodes WIPI-4, a β-propeller scaffold protein involved in autophagy regulation. Pathogenic variants in WDR45 lead to β-propeller protein-associated neurodegeneration (BPAN), a form of neurodegeneration with brain iron accumulation (NBIA). Through an integration-free reprogramming approach, we generated six hiPSC lines derived from 4 different patients of both genders carrying different mutations. The six cell lines will contribute to a better understanding of the pathology and pave the way for the development of new therapeutic approaches.

Background. Renpenning syndrome (RS) is a rare X-linked disorder caused by mutations in the PQBP1 gene. Patients present with syndromic intellectual disability and developmental microcephaly, but their structural brain phenotype remains largely unspecified. Here, we analysed structural MRI data from a monocentric nine-patients’ series of genotyped RS and 39 age-matched controls. After systematic neuroradiological review, the volumes of the cerebellum, hippocampi, basal ganglia, thalami, brainstem, cerebral hemispheres and ventricles, and the thickness profile of the corpus callosum along its midsagittal section, were automatically measured. Both conventional metric comparisons and normative analyses with allometric-sensitive scaling models were applied to assess region-specific deviations relative to total brain size. Results. We provided a pictorial review of the radiological findings showing no obvious architectural anomalies but indications of region specific undersizing and premature aging. Normative scaling analyses further revealed marked undersizing (excessive size reduction) of the cerebellum, the basal ganglia and the hippocampi relative to total brain size. Conversely, cortical and thalamic volumes, as well as ventricular compartments, were relatively preserved. Corpus callosum profiling revealed mild regionally specific alterations, with a relative thickening of the callosal body compared with normative expectations. Conclusion. The RS brain is characterized by region-specific undersizing rather than uniform microcephaly. This radiological phenotype could prove useful in classifying PQBP1 variants of uncertain significance during the diagnosis of microcephaly. Besides, normative scaling analysis confirmed to be a sensitive framework to detect neuroanatomical discrepancies even in the context of rare diseases of brain development.

Context Hyperphagia, overweight, and obesity are frequent in people with rare neurodevelopmental disorders (NDDs). Prader-Willi syndrome (PWS) is a rare NDD with hyperphagia and hyperghrelinemia. Objectives To measure ghrelin levels, hyperphagia and caregiver burden in rare NDDs patients to understand pathophysiology and improve care. Design A single-visit, noninterventional, national, multicenter, cross-sectional study. Setting Seven French reference centers for rare NDDs participated. Patients A total of 130 patients (43% children) with a rare genetic NDD (27 distinct conditions) were included. Their median age was 19.8 years. Three control groups were used for comparison: "PWS" (n = 153), "Obese" (n = 49), and "Lean" (n = 31) groups. Main outcome measure(s) The primary endpoint was ghrelin level (total, acylated, unacylated). The first secondary endpoint was hyperphagia questionnaire (HQ) scores. Results Median total ghrelin levels were 76.7 (22.2-1110.9) pg/mL; median acylated levels were 33.7 (8.0-754.3) pg/mL; and median unacylated levels were 44.2 (11.5-356.6) pg/mL, which were lower than the PWS group (P < .001) and no different from the Obese group. The mean HQ total score was 26.3 (10-46) for children and 24.0 (11-52) for adults. The HQ total score was statistically higher in children with NDDs and lower in adults compared to PWS. The mean Zarit Burden Interview score was 37.8 (6-74) in children and 37.6 (2-76) in adults, and was positively correlated with the HQ total score. Conclusion Ghrelin levels were normal in our study population. Hyperghrelinemia is a biomarker of PWS. Hyperphagia is more prevalent and severe in children with NDDs compared with PWS.

OBJECTIVES:The diagnosis of shaken baby syndrome (SBS) is difficult; the French High Authority for Health called "Haute Autorité de Santé" (HAS) introduced clinical and radiological criteria in 2017 to classify the diagnosis as "certain" or "probable." The aim of this study is to compare the clinical evolution of children with "certain" and "probable" diagnosis criteria of SBS. METHODS:Records of patients with a diagnosis of SBS according to HAS criteria, aged 1 to 16 months, admitted to a University Hospital between January 1st, 2008, and March 31st, 2018, were retrospectively analysed. Medical follow-up data were collected until December 31st, 2019. The primary endpoint was the Glasgow Outcome Scale (GOS) score at the end of hospitalization: the evolution was "favourable" if the GOS was equal to 5, and "unfavourable" if the GOS was lower than 5. RESULTS:107 children were included. The mortality rate was 10 %. There was no significant difference in the GOS score at the end of hospitalization between children with "certain" diagnosis and those with "probable" diagnosis (p = 0.75). There was no significant difference at last follow-up between these two groups. Among the children with an "unfavourable" outcome, 68 % had psychomotor developmental delay, 57 % had motor sequelae, 38 % had visual impairments and 36 % had epilepsy. Among those with a "favourable" outcome, 31 % had language disorders and 13 % had learning disorders. The GOS score at the end of follow-up was identical to the GOS at the end of hospitalization for 76 % of patients. It had improved for 14 % of the patients and had deteriorated for 10 % of the patients. CONCLUSIONS:The "certain" or "probable" diagnosis of SBS according to HAS criteria does not modify the risk of sequelae during follow-up. Mortality and morbidity remain significant. Multidisciplinary management and specialized medical long-term follow-up are essential in both conditions.

BACKGROUND:Epileptic disorders are a heterogeneous group of neurological conditions, with many cases linked to monogenic causes, particularly in developmental and epileptic encephalopathies (DEE). Identifying pathogenic variants aids treatment, prognosis, and family planning. In France, genetic testing is coordinated through the EpiGene network. METHODS:We analyzed clinical and genetic data from 2563 epilepsy patients referred to four diagnostic labs (2016-2023). Epilepsy syndromes were classified via pre-test questionnaires, and genotyping used various gene panels, including a 68-gene core panel. Multivariate logistic regression assessed diagnostic rates and genotype-phenotype correlations. RESULTS:Overall, 27.0% of patients had pathogenic/likely pathogenic variants, mainly within the core panel (24%). SCN1A and KCNQ2 were the most frequently mutated genes. Diagnostic yield varied by syndrome, with Dravet Syndrome Spectrum (DSS) and early-infantile DEE (EIDEE) showing the highest rates (41% and 34%, respectively). Genetic heterogeneity differed across syndromes, from DSS (predominantly SCN1A) to Infantile Epileptic Spasms Syndrome (IESS, 12%), involving ≥ 26 genes. Outside DEE, self-limited neonatal epilepsy (SeLNE) had the highest yield (50%). Earlier seizure onset was associated with a higher likelihood of a positive molecular diagnosis, whereas intellectual disability severity and drug resistance were not independently predictive of diagnostic outcome. Genotype-phenotype correlations highlighted that objective clinical data (e.g., age of onset) can outperform syndrome labels (e.g., EIDEE) in predicting diagnosis. CONCLUSION:This large cohort study refines the genetic landscape of epilepsy, informs classification challenges, and enhances genetic testing strategies, ultimately improving patient care and future research directions.

BACKGROUND:Although initial clinical presentation of hyperekplexia/startle disease is well known, data regarding long-term clinical outcomes is lacking. OBJECTIVES:We provide a long-term evaluation from clinical and pharmacological perspectives, focusing on neurodevelopmental trajectory. METHODS:Twenty-eight patients from nine French hospitals were included based on clinical diagnosis criteria. Adaptive abilities were assessed using VABS-II. RESULTS:VABS-II showed preserved adaptive abilities, except in motor skills. Early development was marked by neurodevelopmental delay in 53% of patients, with 57% developing neurodevelopmental disorders, primarily specific learning disorders. Intellectual disability and/or autism spectrum disorder were present in five patients. Symptoms were most frequent during the first 3 years of life, with persistence of exaggerated startle reflex and falls. One-quarter of the patients discontinued clonazepam. A genetic variant was found in 85% of patients, involving one of the three main genes GLRA1, SLC6A5, or GLRB. CONCLUSIONS:Our findings highlight preserved adaptive abilities, frequent neurodevelopmental disorders and long-term pharmacodependence.

BACKGROUND:Creatine transporter deficiency (CTD) is a rare X-linked disease caused by SLC6A8 variants, which impair ATP-dependent energy metabolism in neurons and myocytes. Although the neurologic and muscular manifestations are well characterized, the cardiac phenotype remains poorly understood. Early clinical reports and a transgenic mouse model have raised concerns about possible associations with corrected QT (QTc) interval prolongation and dilated cardiomyopathy. OBJECTIVE:This study aimed to characterize the cardiac phenotype of male patients with CTD. METHODS:This cross-sectional study prospectively included male patients with CTD with confirmed SLC6A8 pathogenic variants. A systematic cardiological evaluation was performed, including 12-lead resting electrocardiogram (ECG), ambulatory ECG (Holter monitoring), transthoracic echocardiography, and biological analysis. RESULTS:23 male patients with CTD (median [interquartile range] age 17.1 years [13.5-20.5]) with 20 distinct SLC6A8 variants were included. Prominent U-waves were observed in 82.6% of resting ECGs and 95% of ambulatory ECGs, and biphasic T-waves in 30.4% and 90%, respectively. No patient had a prolonged QTc interval (median [interquartile range] QTc interval 431 ms [411-443]) when the U-waves were excluded. Repolarization abnormalities were not secondary to electrolyte disorders. No sustained arrhythmias or conduction disorders were observed. No patient reported syncope or cardiac arrest. Transthoracic echocardiography revealed no cardiomyopathy or congenital heart defects. 2 patients had mildly elevated N-terminal pro-brain natriuretic peptide with no clinical or imaging abnormalities. CONCLUSION:This study highlighted an atypical ventricular repolarization pattern in patients with CTD (prominent U-waves and biphasic T-waves) without QTc interval prolongation. Long-term follow-up data are needed to establish its prognosis, but it must be distinguished from long-QT syndrome. No patient met diagnostic criteria for cardiomyopathy or congenital heart defect.

Anomalies of the corpus callosum (AnCC) are congenital malformations associated with highly variable neurodevelopmental outcomes. We performed prenatal exome sequencing (pES) on a cohort of 352 fetuses diagnosed with AnCC, analysing the diagnostic yield, the implicated genes based on the type of anomaly (partial or complete agenesis, short corpus callosum, or callosal dysgenesis) and assessing the impact on pregnancy outcomes. The overall diagnostic yield of pES was 23%, with pathogenic or likely pathogenic variants identified in 49 different genes, most of which linked to intellectual developmental disorders. The highest diagnostic yield (46%) was observed in fetuses with callosal dysgenesis. Notably, in cases of corpus callosum agenesis, variants in the DCC gene were the most frequently identified aetiology (3.2%, n = 9), associated with a favourable neurodevelopmental outcome. All couples with a fetal DCC variant decided to continue the pregnancy to term. In contrast, 73% of couples with other genetic diagnoses chose pregnancy termination, compared to 17% in cases without a genetic diagnosis. Prenatal decision-making and care are supported by essential prognosis information provided by pES. The identification of genes associated with favourable outcomes, along with the integration of pES into prenatal diagnosis, enhances informed decision-making for parents and improves the clinical management of AnCC.

Over the last 15 years, significant progress has been made for Creatine Transporter Deficiency (CTD) patients, with increased awareness and visibility, better diagnosis, and improved care. Research projects have paved the way for clinical trials on the horizon. However, girls with CTD have been overlooked. Because they are considered a negligible cohort with less serious symptoms compared to males, girls with rare X-linked disorders have never been a priority for diagnosis and research. This results in underdiagnosis, systematic exclusion from clinical studies, and a considerable impact on the development of female patients. As a patient association, Xtraordinaire aims to counter these beliefs and to show that females deserve as much attention as males. Our first initiative identified girls with CTD within our community and led to the development of an international questionnaire to collect more specific data in this population. Of the 22 families who completed the questionnaire, the delay between symptom onset (mean age 1.8 years) and diagnosis (mean age 11.8 years) highlighted the difficulty of diagnosis for girls, often given several wavering diagnoses before reaching a CTD diagnosis. Almost half of families (47%) had difficulties securing a specialist appointment. Our questionnaire emphasized that girls with CTD have identical symptoms to males and similar delays in development milestones. These data have generated interest, and researchers have started to include girls in their studies. We strongly believe that upcoming studies on females will enrich our knowledge, further our understanding of CTD, help better diagnose girls, and develop adapted treatments.

Background and ObjectivesCreatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials. MethodsAs part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software. ResultsThirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence. DiscussionIn addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials. Trial Registration InformationANSM Registration Number 2010-A00327-32.

The Aristaless-related homeobox (ARX) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX-related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in ARX families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo ARX pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic ARX variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying ARX pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.

Le TDA/H est le plus fréquent des troubles du neuro-développement, dont les critères sont définis dans le manuel DSMV associant 3 symptômes principaux que sont le déficit attentionnel, l’impulsivité et l’hyperactivité à des degrés divers. Sa prévalence est estimée entre 3 et 7 % des enfants d’âge scolaire, préférentiellement des garçons ; de ce fait, les pédiatres sont très souvent amenés à voir ces enfants en consultations et doivent être familiarisés avec les outils de repérage précoce et les modalités de suivi de ces enfants. Le TDA/H est un trouble aux étiologies multiples. La combinaison de facteurs génétiques, neurologiques et environnementaux contribue à sa pathogenèse et à son phénotype hétérogène. Son diagnostic repose sur un faisceau d’arguments cliniques basé sur l’anamnèse et l’observation de l’enfant, mais nécessitera la réalisation de questionnaires et de tests neuropsychologiques afin de le confirmer et d’éliminer les diagnostics différentiels. Ce diagnostic sera à intégrer dans le cadre du fonctionnement cognitif et psychoaffectif global de l’enfant. En effet, le TDA/H s’accompagne de façon assez fréquente de comorbidités (troubles d’apprentissages, troubles anxieux, TOP…), nécessitant aussi un dépistage précoce. Les symptômes du TDA/H entraînent une altération du fonctionnement global de l’enfant avec des répercussions sociales, scolaires et familiales et sur la qualité de vie. Une prise en charge adaptée doit être proposée dès le diagnostic et repose en premier lieu sur des mesures non médicamenteuses : aménagements pédagogiques, prises en charge psycho-éducatives de l’enfant et de sa famille. Le traitement par psychostimulant sera proposé chez les enfants de plus de 6 ans en cas d’insuffisance de ces premières mesures et s’intègre dans la prise en charge globale du patient.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na +/ K + ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3 -negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 ( n = 3), ATP1A2 ( n = 3), ANK3 ( n = 1), SCN2A ( n = 1), and CHD2 ( n = 1). In follow-up investigations, two additional ATP1A3 -negative individuals were found to have rare missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A , lead to AHC or AHC-like presentation. Still, the majority of ATP1A3 -negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder due to a mutation in NF1 gene, resulting in phenotypically heterogeneous systemic manifestations. Patients with NF1 are prone to develop neoplasms of the central nervous system (CNS) and are particularly at risk for optic pathway gliomas (OPG). Epilepsy is another recognized neurologic complication in patients with NF1, with a prevalence estimated between 4% and 14%. Several case reports and early phase clinical trials have demonstrated that the mitogen-activated protein kinase inhibitors (MEKi) are effective in NF1-low-grade gliomas (LGGs), but their influence on seizure activity in humans has not been established.Case study: Here, we report a patient with NF1 and developmental and epileptic encephalopathy (DEE) harboring pharmacoresistant tonic seizures, and progressive optic pathway glioma (OPG). By using a MEKi therapy for her OPG, we observed an end to epileptic seizures as well as a significant improvement of interictal EEG abnormalities, despite a lack of tumor reduction.Conclusion: MEK inhibitor therapy should be considered for patients with NF1 and refractory epilepsy.

Les maladies associées aux anticorps anti-MOG sont fréquentes en pédiatrie. La récupération somatique au décours est souvent bonne, mais les séquelles cognitives sont mal décrites et imparfaitement évaluées. L'objectif de notre étude était de décrire, dans une cohorte de patients MOGAD pédiatriques, l'impact de la maladie sur les capacités cognitives et le cursus scolaire. Il s'agissait d'une étude observationnelle, rétrospective, monocentrique, sur une cohorte de patients MOGAD à début pédiatrique. Les caractéristiques démographiques (dont pré et néonatales, et sur le développement psychomoteur), cliniques, biologiques, d'imagerie, scolaires, ainsi que les évaluations cognitives par l'échelle du WISC-V étaient recueillis. Cinquante et un patients ont été inclus, avec un âge médian de 8 ans au diagnostic. L'encéphalomyélite aiguë disséminée était la présentation la plus fréquente (54,6 %), suivie de la névrite optique (35 %). Le taux de récidive était de 27,4 %. Au cours du suivi, une augmentation significative des adaptations scolaires et de la nécessité d'une auxiliaire de vie scolaire était notée. Les évaluations par WISC-V (10 patients), montraient des résultats hétérogènes, dans la moyenne basse. Parmi les patients ayant une scolarité adaptée, 75 % avaient un phénotype initial d'ADEM, 25 % de névrite optique. Ceci suggère une association entre phénotype initial, topographie des lésions, et difficultés cognitives. Aucun facteur de risque pré ou néonatal de difficulté cognitive n'a été mis en évidence. Les atteintes cognitives sont fréquentes au décours des MOGAD pédiatriques. Elles se traduisent par des difficultés scolaires et des résultats faibles au WISC-V, suggérant l'intérêt d'un dépistage systématique.

DéfiGame, serious game de la filière de santé maladies rares DéfiScience, est un outil de formation conçu avec des médecins et des parents experts. De façon interactive et grâce à des mises en situation, il permet de s’approprier les recommandations de bonnes pratiques concernant le repérage, la démarche diagnostique et la coordination d’un parcours pertinent de prescription, de soins et d’accompagnement de personnes ayant un trouble du neurodéveloppement ( tnd ) et de leur famille.