A new score combining compound muscle action potential (CMAP) amplitudes and motor score is predictive of motor outcome after AVXS-101 (Onasemnogene Abeparvovec) SMA therapy.

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.

Clinical Phenotype in an Early-Onset French Pediatric Population: Charcot-Marie-Tooth's Disease Type 2A.

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.

Clinical features of spinal muscular atrophy (SMA) type 2.

Infantile spinal muscular atrophy (SMA) type 2 is sometimes called intermediate SMA to indicate the disease severity. Generally, psychomotor development is normal until the age of 6 to 8 months, with the acquisition of a stable sitting position. The early signs are muscle weakness, mostly affecting the lower limbs, generalized hypotonia and areflexia. The consequences of motor neuron degeneration are functional and orthopaedic, respiratory, nutritional, socio-professional, and psychological. The implementation of standardized care (i.e., standard of care recommendations) has improved the quality of life and survival outcome of patients. The emergence of innovative therapies, some of which are now available, should further improve the clinical evolution of this disease. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Etiology of neonatal seizures and maintenance therapy use: a 10-year retrospective study at Toulouse Children's hospital.

BACKGROUND: No guidelines exist concerning the maintenance antiepileptic drug to use after neonatal seizures. Practices vary from one hospital to another. The aim of this study was to investigate etiologies and to report on the use of maintenance antiepileptic therapy in our population of full-term neonates presenting neonatal seizures. METHODS: From January 2004 to October 2014, we retrospectively collected data from all full-term neonates with neonatal seizures admitted to the Children's Hospital of Toulouse, France. RESULTS: Two hundred and forty-three neonates were included (59% males, 48% electroencephalographic confirmation). The frequencies of etiologies of neonatal seizures were: hypoxic-ischemic encephalopathy (HIE) (n = 91; 37%), ischemic infarction (n = 36; 15%), intracranial hemorrhage (n = 29; 12%), intracranial infection (n = 19; 8%), metabolic or electrolyte disorders (n = 9; 3%), inborn errors of metabolism (n = 5; 2%), congenital malformations of the central nervous system (n = 11; 5%), epileptic syndromes (n = 27; 12%) and unknown (n = 16; 7%). A maintenance therapy was prescribed in 180 (72%) newborns: valproic acid (n = 123), carbamazepine (n = 28), levetiracetam (n = 17), vigabatrin (n = 2), and phenobarbital (n = 4). In our cohort, the choice of antiepileptic drug depended mainly on etiology. The average duration of treatment was six months. CONCLUSIONS: In our cohort, valproic acid was the most frequently prescribed maintenance antiepileptic therapy. However, the arrival on the market of new antiepileptic drugs and a better understanding of the physiopathology of genetic encephalopathies is changing our practice. TRIAL REGISTRATION: Retrospectively registered. Patient data were reported to the "Commission Nationale Informatique et Libertés" under the number 2106953 .

Arthrogryposis in children: Etiological assessments and preparation of a protocol for etiological investigations.

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.

[Fragile X syndrome and white matter abnormalities: Case study of two brothers]. / Syndrome de l'X fragile et anomalies de la substance blanche : à propos d'une fratrie.

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.

[Congenital neuromuscular diseases with neonatal respiratory failure excluding myotonic dystrophy type 1 and infantile spinal muscular atrophy. Diagnosis strategy according to a 19-child series]. / Maladies neuromusculaires congénitales à expression respiratoire néonatale à l'exclusion de la dystrophie myotonique de type 1 et de l'amyotrophie spinale infantile. Stratégie d'exploration d'après une série de 19 enfants.

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.

[Multicentric study of medical care and practices in spinal muscular atrophy type 1 over two 10-year periods]. / Amyotrophie spinale type 1 : enquête multicentrique des pratiques de soins et d'accompagnement palliatif sur deux périodes successives de 10ans.

AIM: Questions about care practices and the role of palliative care in pediatric neurodegenerative diseases have led the Neuromuscular Committee of the French Society of Neurology to conduct a retrospective study in spinal muscular atrophy type 1, a genetic disease most often leading to death before the age of 1 year. MATERIAL AND METHODS: A retrospective multicenter study from pediatricians included in the reference centers of pediatric neuromuscular diseases was carried out on two 10-year periods (1989-1998 and 1999-2009). RESULTS: The 1989-1998 period included 12 centers with 106 patients, the 1999-2009 period 13 centers with 116 children. The mean age of onset of clinical signs was 2.1 months (range, 0-5.5 months), the median age at diagnosis was 4 months (range, 0-9 months) vs 3 months. The median age of death was 7.5 months (range, 0-24 months) vs 6 months. The care modalities included physiotherapy (90 %), motor support (61 % vs 26 % for the previous period), enteral nutrition by nasogastric tube (52 % vs 24 %), and 3.4 % of children had a gastrostomy (vs 1.8 %). At home, pharyngeal aspiration was used in 64 % (vs 41 %), oxygen therapy in 8 %, noninvasive ventilatory support in 7 %. The mean age at death was 8.1 months (range, 0-24 months) vs 7 months, the time from diagnosis to death was 4 months vs 3 months. Death occurred at home in 23 % vs 17 %, in a pediatric unit in 62 % vs 41 %. The use of analgesics and sedative drugs was reported in 60 % of cases: 40 % morphine (vs 18 %) and benzodiazepines in 48 % (vs 29 %). Respiratory support was limited mostly to oxygen by nasal tube (55 % vs 54 %), noninvasive ventilation in 9 % of the cases, and intubation and assisted mechanical ventilation (2 %). DISCUSSION AND CONCLUSION: These results confirm a change in practices and the development of palliative care in children with a French consensus of practices quite different from the standard care in North-America and closer to the thinking of English medical teams. A prospective study within the 2011 national hospital clinical research program (PHRC 2011) is beginning in order to evaluate practices and the role of families and caregivers.

[Anthropological approach to current parental perceptions of children's seizures]. / Approche anthropologique des représentations parentales actuelles des convulsions chez l'enfant.

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.

[Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases]. / Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données.

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

[Value of lumbar puncture after a first febrile seizure in children aged less than 18 months. A retrospective study of 157 cases]. / Utilité de la ponction lombaire lors de la première convulsion fébrile chez l'enfant de moins de 18 mois. Étude rétrospective de 157 cas.

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.

[Respiratory syncytial virus brainstem encephalitis in a 7-year-old boy]. / Rhombencéphalite liée au virus respiratoire syncytial chez un garçon de 7 ans.

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.

[Guillain-Barré syndrome in a child with normal tendon reflexes]. / Un cas pédiatrique de syndrome de Guillain-Barré à réflexes conservés.

We describe the case of a 10-year-old child with the acute motor axonal neuropathy (AMAN) form of Guillain-Barré syndrome (GBS) with preserved tendon reflexes, 6 days after a bout of gastroenteritis. The child quickly showed weakness of the distal muscles of his four limbs, with preserved tendon reflexes and a raised CSF protein concentration with no cells. Nerve conduction studies showing motor axonal degeneration confirmed the diagnosis of GBS in spite of preserved tendon reflexes. The serum was positive for IgG antibodies to gangliosides GM1 and GD1b. The child received intravenous immunoglobulins, which resulted in a favorable progression. This case proves that GBS with normal tendon reflexes exists. The other cases of SGB with preserved tendon reflexes already described in the literature were the AMANs form with antibodies to gangliosides in the serum and only adults were affected.

[Treatment and prognosis of idiopathic intracranial hypertension in children. Retrospective study (1995-2009) and literature review]. / Traitement et pronostic de l'hypertension intracrânienne idiopathique de l'enfant. Étude rétrospective (1995-2009) et revue de la littérature.

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.

Isolated lymphocytic infiltration of pituitary stalk preceding the diagnosis of germinoma in 2 prepubertal children treated with growth hormone.

We report the clinical course of 2 patients with central diabetes insipidus and evolving to panyhypopituitarism which prompted the diagnosis of an isolated pituitary stalk thickening (PST). In both patients, all etiological investigations were normal and the first biopsy revealed an isolated lymphocytic infiltrate with no sign of malignancy. Close clinical follow-up accompanied by serial brain MRIs was proposed to determine a precise diagnosis and for early detection and treatment of neoplastic disease. In our first case, the diagnosis of germinoma was made 9 months after the PST diagnosis owing to tumor progression. In the second case, the time course was even longer with the diagnosis of germinoma 6 years following initial presentation. In these cases, it is speculated that the lymphocytic infiltrates represent the first sign of a host reaction to an occult germinoma. To our knowledge, this is the third case reported of lymphocytic infiltrates preceding a germinoma in a prepubertal girl, and the only case reported in a prepubertal boy. These cases underline the difficulties in establishing the diagnosis of germinoma in a patient with isolated PST.

Intracranial hypotension in a girl with Marfan syndrome: case report and review of the literature.

INTRODUCTION: A 14-year-old girl, followed in our department for Marfan syndrome, presented with postural headache for a month. Neurological examination was normal. The diagnosis of intracranial hypotension syndrome was suspected. DISCUSSION: Bilateral subdural hematomas were found on brain magnetic resonance imaging (MRI), and spinal MRI showed large lumbosacral arachnoid diverticula; no cerebrospinal fluid leaks could be found. Despite bed rest and hydration for 2 weeks, postural headache remained. Epidural blood patching was also performed. Subsequently, the patient became asymptomatic and could stand up after 1 day. Brain MRI did not find recurrent subdural hematoma after 1 month. Dural ectasia is one of the major criteria of Marfan syndrome, and it is often poorly symptomatic. Intracranial hypotension is a rare complication especially in children, and management is not standardized. In this case report, blood patching was sufficient. Further research into the diagnosis and management of spontaneous intracranial hypotension is required.

Bardet-biedl syndrome and brain abnormalities.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical and genetic heterogeneity. The main features are obesity, polydactyly, pigmentary retinopathy, learning disabilities, hypogonadism, and renal abnormalities. To date, eleven genes have been cloned but there is still little knowledge about genotype/phenotype correlations. We describe three additional cases with BBS and cerebral abnormalities and focus on cerebellar abnormalities in BBS.