Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

International audienceThe genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD

Correction to: Use of MFM-20 to monitor SMA types 1 and 2 patients treated with nusinersen.

peer reviewe

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

International audienceTo the Editor:The Aicardi–Goutières syndrome is a genetic encephalopathy that is associated with childhood illness and death. The syndrome is hypothesized to be due to misidentification of self-derived nucleic acids as nonself and the subsequent induction of a type I interferon–mediated response that simulates an antiviral reaction.1 Endogenous retroelements, mobile genetic elements that can be transcribed to RNA and then to DNA by reverse transcription, constitute 40% of the human genome and represent a potential source of immunostimulatory nucleic acid in patients with this syndrome.

Maladies neuromusculaires congénitales d'expression respiratoire néonatale, après exclusion des diagnostics de dystrophie myotonique de Steinert et amyotrophie spinale infantile (expérience du Centre de Référence des Maladies Neuromusculaires du Grand Sud-Ouest, 2007 - 2012)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

ADEM (épisode ou mode d'entrée dans une pathologie chronique du SNC? Clés diagnostiques)

L'ADEM et la SEP sont deux pathologies qui partagent la même présentation clinique et radiologique et, probablement, une physiopathologie commune. Des observations d'ADEM récurrentes viennent renforcer ces similitudes. A partir des données de la littérature et de l'étude de 10 dossiers pédiatriques de premier épisode de démyélinisation multifocale du SNC nous avons tenté de proposer des critères de diagnostic différentiel entre ces deux entités. Aucun critère, hormis les données du suivi, n'apparaît à ce jour suffisamment fiable pour asseoir définitivement le diagnostic d'ADEM en phase aiguë d'un épisode de démyélinisation.TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

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

International audienceBACKGROUND: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

Unexpected Intermediate Nerve Conduction Velocity Findings in Charcot-Marie-Tooth Syndromes Classified as Demyelinated or Axonal in a Pediatric Population

International audienceIntroduction: Among the hereditary motor and sensory neuropathies (HMSN), demyelinating forms are the best characterized, with a clear predominance of CMT1A. The axonal and intermediate forms are less described. The aim of this study is to report the genetic diagnosis of Charcot-Marie-Tooth (CMT) according to the nerve conduction velocity (NCV) findings in a pediatric population.Methods: We retrospectively described a population of HMSN children with a confirmed genetic diagnosis of demyelinated, intermediate, or axonal forms. We compared the results of the genetic analyses with those of motor NCV in median nerve according to whether they were below 25 m/s (demyelinating group); between 25 and 45 m/s (intermediate group), or above 45 m/s (axonal group).Results: Among the 143 children with an HMSN, 107 had a genetic diagnosis of which 61 had an electromyogram. On NCV findings: seven (11%) pertain to the axonal group, 20 (32%) to the intermediate group, and 34 (55%) to the demyelinating group. When NCV was above 45 m/s, CMT2A was the predominant genetic diagnosis (70%) when NCV were below 25 m/s, CMT1A was the predominant genetic diagnosis (71%). Intermediate NCV findings group was the more heterogeneous with seven genetic CMT subgroups (60% CMT1A, CMT1B, CMT1X, CMT2A, CMT2N, CMT4G).Conclusion: Taking NCV values between 25 and 45 m/s to define an intermediate group of CMT in children leads to the inclusion of non-typically “intermediate”, especially CMT1A. We emphasize the broad spectrum of NCV in CMT1A that justified the systematic search of PMP22 duplication/deletion screening before next generation sequencing panel

Prognostic factors for the sequelae and severity of Guillain‐Barré syndrome in children

International audienceIntroduction: Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuritis.Our aim in this study was to describe the clinical characteristics and the long-termsequelae of GBS in a French pediatric population.Methods: In this multicenter, retrospective study we evaluated clinical signs, radio-logical examinations, laboratory tests, treatments, and outcomes.Results: One hundred ten children were included in this investigation. These childrenpresented with walking difficulties, muscle weakness, and cranial nerve impairment.Electrodiagnostic testing revealed 70% with acute inflammatory demyelinating poly-radiculoneuropathy (AIDP) and 16% with acute motor axonal neuropathy (AMAN).One hundred children received immunoglobulins. At follow-up, 77% were cured,whereas 9% had sequelae, associated with an axonal form (P < .01) and a short inter-val between symptom onset and hospitalization (P < .01). The need for intubationwas correlated with peripheral facial paralysis (P < .01) and dysautonomia (P < .01).Discussion: Although AIDP and AMAN present in a similar way, the axonal form isassociated with a worse outcome

Prognostic factors for the sequelae and severity of Guillain‐Barré syndrome in children

International audienceIntroduction: Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuritis.Our aim in this study was to describe the clinical characteristics and the long-termsequelae of GBS in a French pediatric population.Methods: In this multicenter, retrospective study we evaluated clinical signs, radio-logical examinations, laboratory tests, treatments, and outcomes.Results: One hundred ten children were included in this investigation. These childrenpresented with walking difficulties, muscle weakness, and cranial nerve impairment.Electrodiagnostic testing revealed 70% with acute inflammatory demyelinating poly-radiculoneuropathy (AIDP) and 16% with acute motor axonal neuropathy (AMAN).One hundred children received immunoglobulins. At follow-up, 77% were cured,whereas 9% had sequelae, associated with an axonal form (P < .01) and a short inter-val between symptom onset and hospitalization (P < .01). The need for intubationwas correlated with peripheral facial paralysis (P < .01) and dysautonomia (P < .01).Discussion: Although AIDP and AMAN present in a similar way, the axonal form isassociated with a worse outcome