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The French Society of Pediatric Neurology and the FILNEMUS network created a working group on corticosteroid therapy in children with Duchenne muscular dystrophy in order to analyze the literature review and current French practices. The aim of this work was to produce guidelines regarding treatment initiation, pre-therapeutic interventions, choice between available compounds, and treatment monitoring (dosage, duration, and discontinuation). The treatment side effects and their management are also detailed: osteoporosis, endocrinological anomaly (growth delay, weight gain, pubertal delay), cataract, arterial hypertension, behavioral disorders, management of immunosuppression and vaccines, and management of gastrointestinal and metabolic complications., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Société française de pédiatrie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number., Results: We found that 93% of the patients gained new motor skills during the 3 years-standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies., Conclusion: Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies., Competing Interests: Declaration of Competing Interest JD, CV, MGGB, and UWL received funding as scientific advisory boards member from Biogen. VL, FA, JD, AI, MCN, JBD, CET, MGGB, and UWL received funding as scientific advisory boards member from Novartis. JD, CC, MGGB, and ID received funding as scientific advisory boards member from Roche. ID received funding as scientific advisory boards member from PTC therapeutics. CC, CET, and UWL received funding as scientific advisory boards member from Pfizer. VL, FA, CB, AI, JBD, CS, and ID received compensations for presentation from Novartis. FA, CB, JBD, CV, and CET received compensations for presentation from Biogen. CC received compensations for presentation from Roche. CS received compensations for presentation from PTC therapeutics and Sanofi Adventis. CC and ID received compensations for presentation from Pfizer. JBD is investigator for ongoing Roche clinical trials. MGGB is sub-investigator in SMA studies for Biogen, Novartis, and Roche. SMD, MC, and MB, declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Masson SAS.)

Purpose: Electronic health records are gaining popularity to detect and propose interdisciplinary treatments for patients with similar medical histories, diagnoses, and outcomes. These files are compiled by different nonexperts and expert clinicians. Data mining in these unstructured data is a transposable and sustainable methodology to search for patients presenting a high similitude of clinical features., Methods: Exome and targeted next-generation sequencing bioinformatics analyses were performed at the Imagine Institute. Similarity Index (SI), an algorithm based on a vector space model (VSM) that exploits concepts extracted from clinical narrative reports was used to identify patients with highly similar clinical features., Results: Here we describe a case of "automated diagnosis" indicated by Dr. Warehouse, a biomedical data warehouse oriented toward clinical narrative reports, developed at Necker Children's Hospital using around 500,000 patients' records. Through the use of this warehouse, we were able to match and identify two patients sharing very specific clinical neonatal and childhood features harboring the same de novo variant in KCNA2., Conclusion: This innovative application of database clustering clinical features could advance identification of patients with rare and common genetic conditions and detect with high accuracy the natural history of patients harboring similar genetic pathogenic variants.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTN and NEB variants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit and Nextera Rapid Capture Custom Enrichment kit) and of two whole-exome sequencing kits (SureSelect V5 and TruSeq RapidExome capture) revealed best coverage with the SeqCap EZ Choice protocol. A marked decrease in coverage was observed with the other kits, affecting mostly the first exons of genes and the repeated regions of TTN and NEB. Bioinformatics analysis strategy was fine-tuned to achieve optimal detection of variants, including small insertions/deletions (INDELs) and copy number variants (CNVs). Analysis of a cohort of 128 patients allowed the detection of 52 substitutions, 13 INDELs (including a trinucleotide repeat expansion), and 3 CNVs. Two INDELs were localized in the repeated regions of NEB, suggesting that these mutations may be frequent but underestimated. A large deletion was also identified in TTN that is, to our knowledge, the first published CNV in this gene., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Arthrogryposis is a descriptive term defining a sign. It describes a set of joint contractures, sometimes identifiable in utero, present from birth and nonprogressive. This term includes a heterogeneous group of diseases, of neurological, neuromuscular, genetic or mechanical origin. The common physiopathological mechanism is fetal immobility syndrome. Two types of classification have been developed: a clinical one (types I, II and III) and an etiological one. The main aim of this study was to define a standardized protocol for etiological investigation based on a descriptive analysis of the various etiologies identified in a population of children followed up for arthrogryposis. Its secondary aim was to assess first the comprehensiveness and relevance of the complementary assessment and second the way in which the classifications proposed by Professor Judith Goslin Hall are applied., Material and Methods: Retrospective multicenter observational study. We enrolled pediatric patients with arthrogryposis being treated at a reference center for neuromuscular diseases, i.e., in three university hospital pediatric neurology units, between February 1997 and January 2017., Results: Forty-two patients (25 boys and 17 girls) were enrolled. According to the clinical classification (Hall et al.), this population consisted of eight cases of type 1 arthrogryposis (19.1%), 14 type II (33.3%) and 20 type III (47.6%). The main etiology was neurological (19.1%), predominantly involving problems with gyration of a polymicrogyria type. Myopathic origin accounted for 9.5% of the population, predominantly involving genotyped distal arthrogryposis (ECEL1 gene). Additional tests produced a diagnosis of 25% type I, 43% type II and 75% type III., Conclusion: Arthrogryposis is a sign suggesting multiple etiologies. The main ones are neurological. Several genes have recently been identified, explaining the physiopathological mechanisms. The diagnostic process must be rigorous and coordinated within a multidisciplinary team, following a shared protocol for analysis., (Copyright © 2018. Published by Elsevier Masson SAS.)

Fragile X syndrome is the most usual cause of hereditary intellectual deficiency. Typical symptoms combine intellectual deficiency, social anxiety, intense emotional vigilance, and a characteristic facial dysmorphy. This is subsequent to a complete mutation of the FMR1 gene, considering a semidominant transmission linked to the unstable X. The expansion of the CGG triplet greater than 200 units combined with a high methylation pattern lead to a transcriptional silence of the FMR1 gene, and the protein product, the FMRP, is not synthesized. This protein is involved in synaptic plasticity. Brain MRI can show an increased volume of the caudate nucleus and hippocampus, combined with hypoplasia of the cerebellar vermis. Fragile X Associated Tremor Ataxia Syndrome (FXTAS) syndrome is a neurodegenerative disorder occurring in carriers of the premutation in FMR1. Brain MRI shows an increased T2 signal in the middle cerebellar peduncles. This syndrome is linked to a premutation in the FMR1 gene. We report here the case of two brothers presenting a typical fragile X symptomatology. Brain MRI showed hyperintensities of the middle cerebellar peduncles. Such MRI findings support the assumption of a genetic mosaicism., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Unlabelled: Apart from spinal muscular atrophy (SMA) and myotonic dystrophy type 1 (DM1), congenital neuromuscular diseases with early neonatal symptoms mean diagnostic and prognostic challenges mainly when infants require ventilatory support., Objectives: Consider a standardized strategy for infants suspected of congenital neuromuscular disease from analysis of the literature and retrospective experience with floppy and ventilatory support-dependent infants, after exclusion of well-known diseases (DM1, SMA)., Patients and Methods: Floppy infants requiring ventilatory support in their 1st month of life, but showing no evidence of DM1, SMA, Prader-Willi syndrome, or encephalopathy. The retrospective multicenter study was based on the response of regional referent neuropediatricians in the Reference Centre for Neuromuscular Diseases of Greater Southwest France to an inquiry about prenatal and perinatal history, investigations, diagnosis, and outcome of the child and family. It was conducted between 2007 and 2012., Results: Among the 19 newborns studied, all had severe hypotonia. Prenatal and perinatal features were similar. Their outcome was generally severe: the median survival as measured by the Kaplan-Meier method was 6.9 months. Thirteen children died at a median age of 61 days; ten of them were treated with a palliative procedure. Five children had achieved respiratory independence but suffered from a small delay in motor development. Among the three children who continuously required ventilatory support, only one survived (follow-up period: 23 months); he was the only one undergoing tracheostomy in the cohort. Diagnostic processes were different, leading to pathological and genetic diagnosis for only six infants. There was only histological orientation for seven and no specific diagnostic orientation for the last six. These difficulties have led us to propose an exploration process based on the literature., Conclusion: This study highlights difficulties in obtaining a diagnosis and a precise prognosis for floppy ventilated infants. An exploration-standardized process for infants suspected of congenital neuromuscular diseases was made in order to standardize procedures. It could be used as a tool for all professionals involved., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia). The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort., Methods: 265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings., Results: 53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood., Conclusions: Our data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype-phenotype correlations., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Proteus syndrome (PS) is a sporadic and rare congenital disorder characterized by a patchy or mosaic postnatal overgrowth, sometimes involving the face. The onset of overgrowth typically occurs in infancy and can commonly involve skin, connective tissue, central nervous system, eyes and viscera. The progressive overgrowth causes severe complications, such as skeletal deformities, cystic lung disease, invasive lipomas, connective tissue hyperplasia, benign and malignant tumours and deep venous thrombosis with pulmonary embolism, which can cause premature death. This disorder is caused by somatic mosaicism for a specific activating AKT1 mutation that would be lethal in a non-mosaic state. In this report, current knowledge of the aetiology, the diagnosis and the craniofacial manifestations of the disorder are reviewed. The short-term management of a 7-year-old patient with unusual oral manifestations is described. For the first time mutation of AKT1 (c.49G > A) gene was detected both in cranial exostosis and in central odontogenic fibroma of the lower jaw., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Structural alterations in chromosomes are a frequent cause of cancers and congenital diseases. Recently, the phenomenon of chromosome crisis, consisting of a set of tens to hundreds of clustered genomic rearrangements, localized in one or a few chromosomes, was described in cancer cells under the term chromothripsis. Better knowledge and recognition of this catastrophic chromosome event has brought to light two distinct entities, chromothripsis and chromoanasynthesis. The complexity of these rearrangements and the original descriptions in tumor cells initially led to the thought that it was an acquired anomaly. In fact, a few patients have been reported with constitutional chromothripsis or chromoanasynthesis. Using microarray we identified a very complex chromosomal rearrangement in a patient who had a cytogenetically visible rearrangement of chromosome 18. The rearrangement contained more than 15 breakpoints localized on a single chromosome. Our patient displayed intellectual disability, behavioral troubles and craniofacial dysmorphism. Interestingly, the succession of duplications and triplications identified in our patient was not clustered on a single chromosomal region but spread over the entire chromosome 18. In the light of this new spectrum of chromosomal rearrangements, this report outlines the main features of these catastrophic events and discusses the underlying mechanism of the complex chromosomal rearrangement identified in our patient, which is strongly evocative of a chromoanasynthesis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Pure distal monosomy of the long arm of chromosome 10 is a rare cytogenetic abnormality. The location and size of the deletions described in this region are variable. Nevertheless, the patients share characteristic facial appearance, variable cognitive impairment and neurobehavioral manifestations. A Minimal Critical Region corresponding to a 600 kb Smallest Region of deletion Overlap (SRO) has been proposed. In this report, we describe four patients with a distal 10q26 deletion, who displayed attention-deficit/hyperactivity disorders (ADHD). One of them had a marked behavioral profile and relatively preserved cognitive functions. Interestingly, the SRO was not included in the deleted segment of this patient suggesting that this deletion could contain candidate genes involved in the control of neurobehavioral functions. One of these candidates was the CALY gene, known for its association with ADHD patients and whose expression level was shown to be correlated with neurobehavioral disturbances in varying animal models. This report emphasizes the importance of the behavioral problems as a cardinal feature of the 10q microdeletion syndrome. Haploinsufficiency of CALY could play a crucial role in the development of the behavioral troubles within these patients., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Unlabelled: Pediatric seizures are a common symptom, especially when associated with fever. This phenomenon is still shocking and traumatic for parents. The study analyzed current parental perceptions of seizures in order to improve the quality of management, care, and explanations provided to families at our emergency unit., Methods: Using an anthropological approach, we analyzed 28 interviews of 37 parents whose child was admitted to our pediatric emergency unit between November 2007 and August 2008 due to a first seizure., Results: The parental experience of the crisis was marked by upsetting memories of a "scary"-looking body and the perception of imminent death. Parental interpretations of the pathophysiology of the event were often wrong; very few mentioned the possibility of its cerebral origin, leading to inappropriate rescue attempts (e.g., giving CPR). The meaning attributed by parents to the word "seizure" and "epilepsy" usually referred to an exact clinical description of the phenomenon, but many admitted being unfamiliar with the term or at least its origin. Many studies have found the expectation of imminent death as well as inappropriate behaviors. This is the first study to consider interpretations expressed by parents around the convulsive phenomenon and to confirm a low level of knowledge of the symptom. Some historical interpretations persisted (e.g., the influence of excessive mood, anger, menstruation, demonic possession)., Conclusion: Understanding and integrating these parental interpretations seems essential to improving care for families who first experience this symptom. This study motivated the implementation of a special educational workshop on seizures in 2010., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Aim: Because meningitis symptoms are not very specific under the age of 18 months, lumbar puncture (LP) was widely recommended in children presenting a febrile seizure (FS). Recent retrospective studies have challenged this age criterion. In 2011, the American Academy of Pediatrics updated its guidelines for the first episode of simple FS: LP is indicated if signs suggestive of meningitis are present and remains "an option" in case of prior antibiotic treatment or between the age of 6 and 12 months if the child is not properly vaccinated against Haemophilus and Streptococcus pneumoniae. Because the meningitis epidemiology and the vaccination coverage are different, the objective of this study was to evaluate whether these new guidelines were applicable in France., Patients and Methods: Between 2009 and 2010, we conducted a retrospective single-center study including 157 children aged less than 18 months admitted to the pediatric emergency department (Children's Hospital, Toulouse, France) for their first febrile seizure. The data collected were: type of seizure, knowledge of prior antibiotic treatment, neurological status, signs of central nervous system infection, and biological results (LP, blood cultures)., Results: Lumbar puncture was performed in 40% of cases (n=63). The diagnosis of meningitis/encephalitis was selected in eight cases: three cases of viral meningitis, three bacterial meningitis (Streptococcus pneumoniae), and two non-herpetic viral encephalitis. The incidence of bacterial meningitis in our study was 1.9%. The risk of serious infection, bacterial meningitis or encephalitis, was increased when there was a complex FS (14% versus 0% with a simple FS, P=0.06). The presence of other suggestive clinical symptoms was strongly associated with a risk of bacterial meningitis/encephalitis (36% in case of clinical orientation versus 0% in the absence of such signs, P<0.001)., Discussion: All severe clinical presentations were associated with complex FS (prolonged, focal, and/or repeated seizures) and the presence of other suggestive clinical signs (impaired consciousness lasting longer than 1h after the seizure, septic aspect, behavior disorders, hypotonia, bulging fontanel, neck stiffness, petechial purpura). The risk of bacterial meningitis or encephalitis associated with a simple FS and followed by a strictly normal clinical examination is extremely low., Conclusion: After a simple febrile seizure without any other suggestive signs of meningitis, systematic lumbar puncture is not necessary even in children younger than 18 months. LP remains absolutely indicated if clinical symptoms concentrate on central nervous system infection and should be discussed in case of complex seizures, prior antibiotic treatment, or incomplete vaccination., (Copyright © 2013. Published by Elsevier SAS.)

The literature reports that neurological complications of childhood respiratory diseases due to respiratory syncytial virus (RSV) fluctuate between 1 and 40% of cases. They mostly involve central apnea - often the first symptom of infection - anoxia, and ischemic brain damage due to severe sudden weakness in infants, and seizures and consciousness disorders more or less associated with focalized neurological deficiency proving an encephalitis lesion. We report the case of brainstem encephalitis in a 7-year-old boy with RSV A nasopharyngitis, with meningitis, positive polymerase chain reaction in cerebrospinal fluid and magnetic resonance imaging (MRI) abnormalities, which was explained by viral replication encephalitis. Based on a literature review, we discuss the main aspects of epidemiology and physiopathology of the main neurological complication of RSV. Most of them have not been fully investigated and only a few articles report encephalitis. As far as central apnea is concerned, an animal experimental hypothesis surprisingly suggests a peripheral mechanism., (Copyright © 2013. Published by Elsevier SAS.)

Aim: Idiopathic intracranial hypertension (IIH) may cause severe visual loss due to the optic nerve damage. Routine management involves mainly medical treatment. The aim of this study was to improve diagnosis and management of IIH in children., Methods: The medical records of all patients with definite IIH seen at the children's hospital of Toulouse between 1995 and 2009 were reviewed. Cases of secondary intracranial hypertension were included because they did not present any cerebral lesions and underwent a similar therapeutic approach. The clinical and ophthalmological data at the beginning and at the end of their treatment was collected., Results: Eighteen children were included in this study. The average age was 10 years and the sex-ratio was equal to 1. There were 3 cases of secondary idiopathic intracranial hypertension in this pediatric group. The main features encountered were headache (15 children) and diplopia (8 children). Abnormal neurological examination was found for 11 patients with abducens nerve paresis in 8 cases, rachialgia in 6 cases, and neurogenic pains (neuralgia, dysesthesia, paresthesia, hyperesthesia) in the other cases. Papilledema was noted in 16 patients. At the initial phase, loss of visual acuity was documented in 6 patients and altered visual field in nine patients. All patients had a medical treatment. When recurrence occurred, each new treatment was documented, for a total of 23 treatments analyzed. Lumbar puncture was the only treatment for 2 patients. In 16 cases, first-line treatment was acetazolamide and it was the second choice in 1 case, with an average dosage of 11.2mg/kg and a mean duration of 2.5 months (15 treatments could be analyzed). This treatment was effective in 11 cases out of 15. Steroids were the initial treatment in 4 cases and second-line treatment in 4 cases (after failed acetazolamide therapy). The dosage was 1.5-2mg/kg for a mean duration of 1.5 months (6 treatments could be analyzed). This treatment was effective in 5 patients out of 6. One patient had dual therapy. No surgical procedure was necessary in this pediatric cohort. Three patients presented relapses of IIH. The outcome was good with no residual visual impairment in the 13 patients analyzed. One patient was still under medication., Comments: Therapeutic management of IIH in a pediatric population is essentially medical, in some cases limited to lumbar puncture. The first-line treatment is acetazolamide, but this study shows that low doses and short duration are usually chosen. Doses must be increased and treatment prolonged to avoid the use of corticosteroids as a second-line treatment and prevent possible relapses that require close monitoring of visual function., Conclusion: The visual prognosis is generally better for this age group compared to adults and no risk factors for visual sequelae were identified. A standardized protocol for management of IIH was proposed., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)