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• Median CMAP amplitude showed the best improvement between baseline and M12. • High median CMAP amplitude at baseline was associated with unaided sitting at M6. • CHOPINTEND<30/64 and median CMAP<0.5 mV at M0 implied no unaided sitting at M6. • This result was confirmed on a second independent cohort. Spinal muscular atrophy 1 (SMA1) is a severe early genetic disease with degeneration of motor neurons. Motor development is still suboptimal after gene replacement therapy in symptomatic patients. In this study, compound muscle action potential (CMAP) amplitudes were explored as predictors of motor recovery after gene therapy. Thirteen symptomatic SMA1 patients were prospectively included at the Necker Enfants Malades Hospital, Paris, France (Cohort 1) and 12 at the other pediatric neuromuscular reference centers of the French Filnemus network (Cohort 2). In Cohort 1, median CMAP amplitudes showed the best improvement between baseline and the 12 months visit compared to the other tested nerves (ulnar, fibular and tibial). High median CMAP amplitudes at baseline was associated with unaided sitting achievement at M6 (AUC 90%). None of the patients with CHOPINTEND at M0 < 30/64 and median CMAP < 0.5 mV achieved unaided sitting at M6 and this result was confirmed on Cohort 2 used as an independent validation data. Thus, median CMAP amplitude is a valid biomarker for routine practice to predict sitting at M6. A median CMAP amplitude over 0.5 mV at baseline may predict better motor recovery. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA), a progressive genetic neuromuscular disorder resulting in neurodegeneration, skeletal muscle atrophy, and weakness, typically manifests in infancy and is associated with high morbidity. Current SMA therapies target motor neurons; however, motor function deficits remain due to muscle atrophy. Apitegromab, a fully human monoclonal antibody that inhibits activation of latent myostatin and enables muscle growth, is an investigational SMA treatment. The phase 3, randomized, double-blind, placebo-controlled SAPPHIRE (NCT05156320) study is evaluating efficacy and safety of apitegromab in nonambulatory patients with type 2 or 3 SMA aged ≥2y receiving SMN therapy (≥10mo nusinersen or ≥6mo risdiplam) with Hammersmith Functional Motor Scale Expanded (HFMSE) scores of ≥10 and ≤45 at screening. A main efficacy population (MEP; 2y–12y) and exploratory subpopulation (EXP; 13y–21y) will be assessed for 12mo. The MEP was randomized 1:1:1 to receive 10 or 20 mg/kg apitegromab or placebo every 4 weeks (Q4W) and the EXP 2:1 to receive 20 mg/kg apitegromab or placebo Q4W. At enrollment, the MEP (mean age, 7.8y, n=156) and EXP (15.8y; n=32) was 47.4% and 62.5% female, respectively. Mean±SD age at SMN therapy initiation was 3.2y±1.6y in the MEP, with 77.6% receiving nusinersen vs risdiplam, and 11.0y±3.8y in the EXP (nusinersen, 56.3%). Most participants had 3 SMN2 copies (MEP, 83.3%; EXP, 62.5%). Mean±SD baseline total HFMSE and Revised Upper Limb Module (RULM) scores were 26.2±10.1 and 26.2±6.1 in the MEP and 21.3±10.3 and 26.3±5.7 in EXP, respectively; World Health Organization (WHO) motor milestones met were 1.6±0.9 for MEP and 1.3±0.8 for EXP. Despite SMN-targeted therapy, low baseline HFMSE and RULM scores and WHO milestones met indicate prevalent motor function deficits. The study will assess if apitegromab addresses this unmet need by directly targeting muscle atrophy to enhance motor function. [ABSTRACT FROM AUTHOR]

The clinical presentation and prognosis of individuals harbouring four copies of SMN2 gene are not well-known and presymptomatic treatment remains controversial. The aim of this study was to describe the clinical phenotypes associated with 4 SMN2 copies in France. Collected data from all SMA patients with 0SMN1 and 4SMN2 enrolled in the national French Registry (Registre SMA France) were analyzed to better understand epidemiology, clinical presentation and course of the disease. SMN2 copy number was available in 872 patients of 1112 SMA enrolled patients. 140 patients (16.1%) carried four SMN2 copies (0 SMN1 4 SMN2). Median age at onset was 3.5 years (6 months to 20 years) and median follow-up was 32 years. 12 patients (8.6%) never walked independently (SMA type 2). 72% of the cohort was able to stand or walk with support. Independent walking was acquired in 91% (123 SMA3, 5 SMA4) and one third of them lost this ability (median 16 years). Loss of ambulation was significantly earlier in children with onset before 3 years (SMA3a). There was a significant predominance of men in the whole cohort (63%) and in sub-cohorts (SMA2-83%; SMA3-61%; adult population-68%). There was a significant lower risk for women to lose ambulation (p=0.01). 65% of patients used a wheelchair. Scoliosis surgery and ventilation was required in less than 15%. Most SMA patients with 4 S MN2 copies in the French population showed an onset during childhood and a progressive course with absence or loss of ambulation before adulthood. Presymptomatic treatment seems an acceptable option to consider, although identification of individual pejorative markers of early or severe phenotypes would allow more tailored approaches. Our results confirm the phenotypic variability reported in literature, suggesting an overall gender effect in this population. [ABSTRACT FROM AUTHOR]

Résumé: Les convulsions de l’enfant sont un symptôme fréquent et toujours mal vécu par les parents. L’objectif de cette étude était de connaître les représentations parentales actuelles de ces convulsions afin d’améliorer l’accueil, la prise en charge et les explications dispensées aux familles. Méthodes: Au moyen d’une approche anthropologique, nous avons analysé 28 entretiens enregistrés de 37 parents pour une première crise convulsive chez leur enfant admis entre novembre 2007 et août 2008 au service des urgences pédiatriques. Résultats: Le vécu de la crise était douloureux, par le souvenir d’un corps à l’allure terrifiante et la perception d’une mort imminente. Les interprétations physiopathologiques des parents étaient souvent erronées, très peu évoquaient la possibilité d’un phénomène d’origine cérébrale, rendant les conduites de secourisme inadaptées. La signification attribuée par les parents aux mots ű convulsion Ƈ et ű épilepsie Ƈ renvoyait de façon assez juste à l’expression clinique du phénomène mais beaucoup avouaient ne pas connaître le terme ou du moins sa signification. De nombreuses études déjà anciennes ont rapporté cette impression de mort imminente de l’enfant de même que les conduites inadaptées. À notre connaissance, cette étude est la première à envisager les représentations singulières exprimées par les parents autour du phénomène convulsif, permettant de relever un faible niveau de connaissances autour de ce symptôme. Des représentations historiques persistaient (excès d’humeur, colères, menstruations, possession). Conclusion: Appréhender ces représentations parentales paraît indispensable pour améliorer la prise en charge des familles hospitalisées pour ce symptôme. Ce travail a permis l’élaboration en 2010 d’un atelier éducatif spécifique actuellement très apprécié des parents. [ABSTRACT FROM AUTHOR]

Résumé: Les complications neurologiques des affections respiratoires de l’enfant liées au virus respiratoire syncytial (VRS) ont été rapportées dans la littérature avec des résultats variables allant de 1 à près de 40 % des cas. Elles sont essentiellement composées d’apnées centrales, souvent inaugurales de l’infection, de complications anoxo-ischémiques de malaises graves rencontrés chez les jeunes nourrissons et de tableaux de convulsions ou de troubles de la conscience parfois associés à des déficits neurologiques focalisés, traduisant une atteinte encéphalitique. Nous rapportons un cas de rhombencéphalite clinique chez un garçon de 7ans atteint d’une rhinopharyngite à VRS de type A. Une méningite prouvée par une réaction par polymérisation en chaîne (PCR) positive dans le liquide céphalorachidien (LCR) et des anomalies observées à l’imagerie par résonance magnétique (IRM) cérébrale permettent d’évoquer une encéphalite par réplication virale. Nous discutons à partir d’une revue de la littérature l’épidémiologie et la physiopathologie des principales complications neurologiques du VRS qui ne bénéficient pas pour la plupart d’investigations neurologiques paracliniques complètes et parmi lesquelles les encéphalites ont été très peu décrites. Concernant les apnées, le plus souvent considérées comme centrales, une hypothèse expérimentale chez l’animal évoque un mécanisme qui pourrait être d’origine périphérique. [ABSTRACT FROM AUTHOR]

Charcot–Marie–Tooth's disease type 2A (MCT2A), induced by mutation of the mitofusin 2 (MFN2) gene represents the main cause of MCT2. The aim of this study is to provide details of the clinical and electromyographic phenotype of MCT2A in a pediatric population. We conducted a French multicenter retrospective study, including all children with a genetic diagnosis of MCT2A. Thirteen MCT2A children were included with a beginning of symptoms before the age of 10 years ("early-onset group"). We report two new mutations: c.1070 A → T (p.Lys357.Met) and c.280 C → G (p.Arg94Gly). The evolution of the disease is marked by a fast worsening for three patients with loss of motor autonomy, while the evolution is relatively stable for eight patients. The group of early-onset MCT2A seems more heterogeneous than previously described, with a nonconstant severe phenotype. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Résumé Le syndrome de l’X fragile est la cause la plus fréquente de déficience intellectuelle héréditaire. La sémiologie clinique associe une déficience intellectuelle, une anxiété sociale, des troubles dysexécutifs, une hypervigilance émotionnelle et une dysmorphie faciale caractéristique. Il est induit par une mutation instable du gène FMR1 , de transmission liée à l’X, dominante, à pénétrance incomplète chez la femme. L’expansion de triplets CGG supérieure à 200 unités (mutation complète) conduit à un silence transcriptionnel du gène FMR1 et à l’absence de production de la protéine fragile X mental retardation protein (FMRP). Celle-ci a un rôle dans la plasticité synaptique. L’imagerie par résonance magnétique (IRM) cérébrale peut montrer une augmentation de volume des noyaux caudés et des hippocampes, associée à une hypoplasie du vermis cérébelleux. Le syndrome fragile X associated tremor ataxia syndrome (FXTAS) est un syndrome neurodégénératif rare débutant après 50 ans, associant un tremblement intentionnel ou une ataxie cérébelleuse, un syndrome parkinsonien et dysautonomique. L’IRM cérébrale montre des hypersignaux symétriques des pédoncules cérébelleux moyens. Ce syndrome est lié à une expansion de triplets CGG dont la taille est comprise entre 60 et 200 unités (prémutation) du gène FMR1 . Nous rapportons une fratrie de 2 garçons présentant un syndrome de l’X fragile avec des hypersignaux des pédoncules cérébelleux moyens mais sans ataxie. L’existence de ces hypersignaux chez des garçons porteurs d’une mutation complète du gène FMR1 pourrait être expliquée par un mosaïcisme somatique pour une prémutation, comme mentionnée dans le syndrome FXTAS. Summary 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. [ABSTRACT FROM AUTHOR]

Résumé Hormis l’amyotrophie spinale infantile (SMA) et la dystrophie myotonique de type 1 (DM1), les maladies neuromusculaires congénitales d’expression précoce, peu connues, constituent un défi diagnostique et éthique, notamment en l’absence d’autonomie respiratoire. Objectif Définir une stratégie d’exploration des nouveau-nés hypotoniques ventilés, suspects d’être atteints d’une affection neuromusculaire, par l’analyse d’une cohorte rétrospective et de la littérature. Patients et méthodes Enfants hypotoniques ayant nécessité un soutien ventilatoire dans leur premier mois de vie, après exclusion des SMA, DM1, syndrome Prader-Willi et des affections d’origine centrale. Étude rétrospective (2007–2012), d’après un questionnaire aux neuropédiatres référents des sites pédiatriques du Centre de référence des maladies neuromusculaires du Grand Sud-Ouest. Résultats Dix-neuf nouveau-nés ont été inclus. L’anamnèse anténatale et néonatale était similaire. L’évolution avait été sévère : 13 enfants étaient décédés (âge médian : 61 jours), 10 dans une démarche palliative. Un enfant avait bénéficié d’une ventilation prolongée par trachéotomie. Cinq enfants avaient pu être sevrés de leur assistance ventilatoire ; leur développement moteur était subnormal. Les explorations diagnostiques, hétérogènes, avaient abouti à une identification anatomopathologique et génétique chez 6 patients seulement alors que pour un tiers, aucune orientation diagnostique n’avait été retenue. Ces difficultés diagnostiques ont motivé l’élaboration d’une stratégie d’exploration, à partir de l’analyse de la littérature. Conclusions Les données de notre cohorte, comparables aux séries publiées, illustrent la nécessité d’harmoniser les pratiques, notamment la démarche d’investigation des nouveau-nés suspects de maladie neuromusculaire congénitale. La stratégie proposée pourrait constituer un outil de travail auprès des professionnels concernés. Summary 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. [ABSTRACT FROM AUTHOR]

Résumé: Contexte: La ponction lombaire (PL) est classiquement indiquée devant une convulsion fébrile (CF) avant l’âge de 18 mois pour éliminer une méningite. Suite à plusieurs études récentes, l’American Academy of Pediatrics (AAP) a actualisé en 2011 les recommandations de prise en charge des premières CF simples : le critère d’âge seul n’est plus une indication de PL. L’objectif de ce travail était d’évaluer si ces nouvelles recommandations peuvent s’appliquer en France. Patients et méthodes: Étude rétrospective monocentrique incluant 157 enfants de moins de 18 mois vus dans un service d’urgences pour une première CF entre 2009 et 2010. Résultats: Trois méningites bactériennes et 2 méningo-encéphalites virales non herpétiques ont été diagnostiquées. Le risque était majoré en cas de CF complexe (prolongées, focalisées ou répétées) (14 % versus 0 % en cas de CF simple, p =0,06) et de signes cliniques évocateurs (trouble de conscience, hypotonie, fontanelle bombée, trouble du comportement, purpura, aspect septique) (36 % contre 0 % en l’absence d’orientation clinique, p <0,01). La probabilité d’une méningite bactérienne ou d’une encéphalite devant une CF simple sans aucun autre signe est extrêmement faible, quel que soit l’âge de l’enfant. Discussion/Conclusion: Devant une CF simple sans aucun signe évocateur de méningite ou d’encéphalite, la PL n’est pas nécessaire, même avant 18 mois. Elle reste formellement indiquée en présence de signes évocateurs et doit être discutée en cas de CF complexe, d’antibiothérapie préalable ou de vaccination incomplète. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that skip exon 51, 44, 45, and 53 are currently evaluated in clinical trials. Knowing the precise phenotype of potentially eligible patients is important for designing the clinical trials. It is generally believed that there are few if any phenotypic differences between these different groups of patients or between these patients and the general DMD population. In preparation of exon 53 skipping mediated by an AAV8 construct, we recruited 24 patients aged from 6 to 20years in an observational study of upper limb strength and function, using the Motor Function Measure (MFM), the Myogrip, the MyoPinch and the MoviPlate, three tools already validated in a large non ambulant DMD population. Data of 14 non ambulant DMD patients (13.8±2.7years) at inclusion were compared with 14 age and size-matched DMD controls (13.7±2.6years) with all types of mutation. DMD 53 patients scored significantly lower in the MFM (D3: 66±17% vs. 82±13% for DMD 53 vs. DMD control), had significant lower handgrip and key pinch strength on both hands. They had lost ambulation 13months earlier (Age: 105±20 vs. 118±19 p =0.04 for DMD 53 vs. DMD control). In order to rule out that this is due to a selection bias, we compared DMD 53 patients with other DMD patients carrying a deletion not involving the 45–55 region and looked at DMD patient cohort identified at the Cochin hospital’s routine diagnostic laboratory. We found that 91 DMD ex53 patients had lost ambulation at 108 ±15months, whilst other 400 non 45–55 DMD patients with a deletion had lost ambulation at 139±54months. Taken together, these preliminary data demonstrate that non-ambulant patients treatable by exon 53 skipping present a more severe phenotype than the general DMD population. This must be taken into account in the design of studies concerning this population. [ABSTRACT FROM AUTHOR]