Search

The small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants’ own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted “natural” trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any “placebo effect,” the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient’s post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some “null” model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial’s Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research.

Myotubular myopathy, also called X-linked centronuclear myopathy (XL-CNM), is a severe congenital disease targeted for therapeutic trials. To date, biomarkers to monitor disease progression and therapy efficacy are lacking. The Mtm1−/y mouse is a faithful model for XL-CNM, due to myotubularin 1 (MTM1) loss-of-function mutations. Using both an unbiased approach (RNA sequencing [RNA-seq]) and a directed approach (qRT-PCR and protein level), we identified decreased Mstn levels in Mtm1−/y muscle, leading to low levels of myostatin in muscle and plasma. Myostatin (Mstn or growth differentiation factor 8 [Gdf8]) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing Dnm2 by genetic cross with Dnm2+/− mice or by antisense oligonucleotides blocked or postponed disease progression and resulted in an increase in circulating myostatin. In addition, plasma myostatin levels inversely correlated with disease severity and with Dnm2 mRNA levels in muscles. Altered Mstn levels were associated with a generalized disruption of the myostatin pathway. Importantly, in two different forms of CNMs we identified reduced circulating myostatin levels in plasma from patients. This provides evidence of a blood-based biomarker that may be used to monitor disease state in XL-CNM mice and patients and supports monitoring circulating myostatin during clinical trials for myotubular myopathy., Graphical Abstract, X-linked centronuclear myopathy (XL-CNM) is a severe congenital disease targeted for therapeutic trials. The authors identified decreased plasma myostatin levels in XL-CNM patients and mice. Decreasing Dnm2 in mice blocked or postponed disease progression and resulted in an increase in circulating myostatin, supporting monitoring circulating myostatin in XL-CNM clinical trials.

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimize quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne muscular dystrophy module of the Pediatric Quality of Life Inventory (PedsQLTMDMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQLTMDMD for pediatric patients with DMD, using French multicenter descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatments dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQLTMDMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice.

In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,We selected 53 patients with pathogenic variants onDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.This study contradicts previous literature stating an association between

Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients with GAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2-18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1-5), and progressive cerebellar ataxia and distal motor weakness were the initial symptoms in all cases. Proximal motor weakness and bulbar symptoms appeared at a mean age of 12 years (8-14), and patients used a wheelchair at a mean age of 16 years (14-18). One patient died at age 18 years from aspiration pneumonia. In all cases, nerve conduction studies showed a mixed demyelinating and axonal sensorimotor neuropathy and MRI showed brain and cerebellum white matter abnormalities. Polyneuropathy and encephalopathy both aggravated during the course of the disease. Patients also showed a variety of associated findings, including curly hair (100% of cases), pes cavus (80%), ophthalmic abnormalities (30%), and scoliosis (30%). Five new GAN mutations were found, including the first synonymous mutation and a large intragenic deletion. Our findings expand the genotypic spectrum of GAN mutations, with relevant implications for molecular analysis of this gene, and confirm that GAN is an age-related progressive neurodegenerative disease involving PNS and CNS.

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.

BACKGROUND Duchenne Muscular Dystrophy (DMD), the most common neuromuscular disease in children, is a severe, progressive disease that affects skeletal muscle. Abnormal gait patterns in children with DMD result from compensatory adaptations of their locomotor system to maintain free ambulation in response to the slow, progressive muscle weakness, contractures and osteoarticular changes caused by the disease. Identification of gait abnormalities can be challenging because current understanding of how gait patterns changes progressively in children with DMD is limited. 3D gait analysis could thus increase understanding about the effects of the disease on gait, guide treatments and help to predict key milestones, such as ambulation loss. This latter event is important because it is an endpoint for clinical trials and studies of DMD disease progression. OBJECTIVE The primary aim of this study was to analyze the gait characteristics of children with Duchenne Muscular Dystrophy (DMD) during their last 2 years of free ambulation. The secondary aim was to explore the capacity of gait variables to predict the time of loss of ambulation. METHODS The gait of eighteen children with DMD and fourteen age-matched control children was recorded using a 3D optoelectronic system. Statistical parametric mapping was used to compare kinematic and kinetic variables between groups. Multivariate regression was used to identify predictors of the time of ambulation loss among spatiotemporal, kinematic and kinetic variables. RESULTS Compared with the controls, anterior pelvic tilt was increased during the whole gait cycle, hip flexion was increased during the second part of stance phase and of the entire swing, knee flexion was increased during swing, dorsiflexion was reduced during stance, and plantar flexion occurred in swing in the DMD group. Maximal ground reaction force, ankle dorsiflexion moment at initial contact, knee power absorption and generation during loading response, and maximal power generation of the hip at the end of stance were all reduced. A combination of gait variables, mostly kinetic, predicted the duration before ambulation loss to be less than three months. CONCLUSIONS The gait of children with DMD who are close to losing ambulation is characterized by specific deviations. The time of ambulation loss was accurately predicted by 3D gait variables, particularly kinetic. Combined with data from the clinical examination, 3D gait analysis provides valuable information to guide physical therapy, including targeted muscle strengthening and stretching, to help patients maintain free ambulation as long as possible.

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination–Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. Results Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients. Patients under 2 years of age (n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking. Conclusion Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.

International audience; BACKGROUND: Spinocerebellar ataxia types 19 and 22 (SCA19/22) are rare conditions in which relatively isolated cerebellar involvement is frequently associated with cognitive impairment. Here, we report on new clinical features and provide details of the cognitive profile in two SCA19/22 families.METHODS: Two families displaying an autosomal-dominant form of cerebellar ataxia underwent clinical examinations and genetic testing.RESULTS: In addition to the classical clinical features of SCA, a wide spectrum of cognitive disorders (including visuospatial impairments) was observed. Eight patients had mild Parkinsonism, and five had epilepsy. Genetic testing showed that the KCND3 mutation (c.679_681delTTC, p.F227del) was present in both families.CONCLUSIONS: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.

Introduction Necrotizing autoimmune myopathies (NAMs) are acquired myopathies with myofibrillar necrosis and weak or absent inflammatory component, sometimes associated with anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. Observation The patient, a girl now aged 20 years, was first assessed at the age of 5 years for abnormal gait revealing frank pelvic deficit. Creatine kinase (CK) levels were as high as 7,500 IU/L. Subsequent muscle biopsy showed some necrosis, fiber regeneration, and fibrosis consistent with muscular dystrophy (MD). Protein immunohistochemistry was normal. The disease course was progressive until wheelchair use at the age of 9 years. At 12 years of age, a second muscle biopsy found an advanced MD with some perivascular inflammatory mononuclear cells. All molecular analyses done through 14 years of follow-up were negative till anti-HMGCR antibodies were detected at a significant amount when she was 19 years old. Discussion NAMs begin at a pediatric age and may have a chronic course mimicking MDs. Muscular biopsy can be misleading with a predominantly dystrophic pattern without inflammation. Conclusion This observation should prompt the assessment of NAMs in all MDs, even pediatric, without molecular solutions.

Les traitements pharmacologiques symptomatiques representent un appoint utile dans la prise en charge des maladies neuromusculaires, qu’ils soient cibles sur un processus physiopathologique corolaire de la maladie (fibrose musculaire, oxydation), sur un symptome physique tel que la myotonie, la douleur, ou sur les troubles cognitifs lies a l’atteinte centrale associee (dystrophinopathies, dystrophie myotonique de Steinert). Ils permettent d’ameliorer l’esperance et la qualite de vie, en attendant les progres des therapies curatives emergentes.

Background Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization. Objectives To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France. Methods Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11–25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barre syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008–2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations. Results With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41–0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results. Conclusion Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.

Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.

The Analgesia Nociception Index (ANI), based on heart rate (HR) variability analysis, is known to decrease after a painful stimulus during surgery under general anesthesia in adults. It is measured continuously and noninvasively. We studied ANI response to procedural pain in a pediatric population and ANI measurement's feasibility in this context, across age. A prospective, noninterventional pilot study was performed. All children (between 6 mo and under 18 y) undergoing muscle biopsy conducted under analgesia and light sedation were included. Medical staff was blind to the ANI monitor. HR and ANI were recorded and analyzed during 2 periods: T1 before incision and T2 after incision. Pain was assessed by the FLACC scale at T2. We observed ANI and HR variations after incision. ANI, HR, and FLACC were compared between children younger or older than 6 years. Enrollment or technical issues were reported. A total of 26 children were included (median age, 6 y; ranging from 6 mo to 16 y; 16 male). ANI decreased from T1 to T2. HR, ANI, or FLACC values were not different in children younger or older than 6 years. No parents or children refused to take part in the study. No technical issues was reported. In this pilot study, ANI measurement seems relevant in pediatric procedural pain, across age. Further studies are needed to confirm these results.

BackgroundSubtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing.MethodsUsing this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients.ResultsOur analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before.ConclusionOverall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.

In 2005, the French law on patients' rights at the end of life required that decisions to withdraw or withhold life-sustaining treatments be made and carried out by the physician in charge of the patient, after obtaining advice from an independent consulting colleague and the caregiving team. The purpose of this study was to identify theoretical and practical obstacles to this collaborative deliberation and to propose practical guidelines to organize it.

Resume L’encephalite auto-immune a anticorps antirecepteurs au N-Methyl-D-Aspartate (NMDA) est une atteinte grave du systeme nerveux central, encore peu connue des cliniciens, pouvant etre a l’origine de symptomes psychiatriques frustres comportant des symptomes psychotiques ou catatoniques. Nous rapportons ici le cas d’une jeune fille de 15 ans, sans antecedent personnel notable, hospitalisee pour decompensation psychotique de debut brutal, rapidement compliquee d’une catatonie agitee puis stuporeuse, repondant insuffisamment au traitement par benzodiazepines. Le diagnostic d’encephalite a anticorps anti-RNMDA a pu etre confirme par le dosage des auto-anticorps dans le liquide cephalorachidien (LCR). L’evolution sera favorable sous corticoides et immunosuppresseurs. Nous proposons a l’issue de ce cas, une mise au point sur l’encephalite a auto-anticorps anti-RNMDA et sur l’hypothese d’un desequilibre de la balance excitation/inhibition a l’origine de la catatonie.

The Xq28 duplication involving the

High resolution oxymetry study (HROS) of skeletal muscle usually requires 90–120 min preparative phase (dissection, permeabilization and washing). This work reports on the suitability of a rapid muscle preparation which by-passes this long preparation. For a few seconds only, muscle biopsy from pigs is submitted to gentle homogenization at 8000 rotations per minute using an ultra-dispersor apparatus. Subsequent HROS is performed using FCCP instead of ADP, compounds crossing and not plasma membrane, respectively. This simplified procedure compares favorably with classical (permeabilized fibers) HROS in terms of respiratory chain complex activities. Mitochondria from cells undergoing ultradispersion were functionally preserved as attested by relative inefficacy of added cytochrome C (not crossing intact mitochondrial outer membrane) to stimulate mitochondrial respiration. Responsiveness of respiration to ADP (in the absence of FCCP) suggested that these intact mitochondria were outside cells disrupted by ultradispersion or within cells permeated by this procedure.

Resume Etat actuel du probleme La place des soins palliatifs dans des pathologies neurodegeneratives de l’enfant a conduit la commission neuromusculaire de la Societe francaise de neuropediatrie a realiser une enquete a propos de l’amyotrophie spinale de type 1, pathologie genetique neuromusculaire le plus souvent lethale avant l’âge de 1 an. Materiel et methode Une enquete retrospective multicentrique aupres de neuropediatres integres dans des centres de reference des maladies neuromusculaires pediatriques a ete realisee sur deux periodes de 10 ans (1989–1998 et 1999–2009). Resultats La periode (1989–1998) avait inclus 12 centres avec 106 patients, la periode (1999–2009), 13 centres avec 116 enfants. La comparaison des donnees des deux periodes a revele une histoire naturelle de la maladie comparable : âge moyen d’apparition des premiers signes cliniques de 2,1 mois [0–5,5 mois], âge median au diagnostic de 4 mois [0–9 mois] versus (vs) 3 mois, âge median de deces de 7,5 mois [0–24 mois] vs 6 mois. Les modalites de soins avaient evolue avec des soins devenus plus actifs : kinesitherapie motrice (90 %), kinesitherapie respiratoire (93 %), les installations de confort (61 % vs 26 %), nutrition enterale par sonde gastrique (54 % vs 24 %). Les aides respiratoires au domicile etaient plus utilisees dans la seconde periode : aspiration nasopharyngee dans 64 % des cas (vs 41 %), oxygene dans 8 % et ventilation non invasive dans 7 %. Le delai moyen entre le diagnostic et le deces etait reste tres court : 4 mois vs 3 mois. Le deces avait eu lieu au domicile dans 23 % vs 17 % et dans un service de pediatrie pour 62 % vs 41 %. L’usage de traitements antalgiques et sedatifs au moment du deces etait rapporte dans 60 % des cas : morphiniques 40 % (vs 18 %), benzodiazepines 48 % (vs 29 %). Au moment du deces, le support respiratoire etait variable : oxygenotherapie (55 %), ventilation non invasive (9 %), ventilation mecanique assistee (2 %). Discussion et conclusion Ces resultats confirment une evolution de nos pratiques et le developpement des soins palliatifs chez l’enfant avec des positions differentes des standards de soins nord-americains et plus proches de la reflexion des equipes anglosaxonnes. Une etude prospective dans le cadre d’un Programme hospitalier de recherche clinique (PHRC) national 2011 a debute en juin 2012 impliquant les familles dans l’evaluation de ses soins.

Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment.

Muscle biopsy is a mainstay diagnostic tool for investigating neuromuscular disorders in children. We report the yield of pediatric muscle biopsy in a population of 415 children by a retrospective study of 419 biopsies performed between 1/01/2000 and 31/12/2009 in a neuropediatric department, including mitochondrial respiratory chain analysis for 87 children. Two hundred and fifty-five biopsies were from boys (61%) 164 from girls (39%). Their mean age at biopsy was 6.5years; 155 (37%) biopsies were obtained before the child was 5years old. Final histopathological diagnoses were: congenital myopathy (n=193, including 15 structural congenital myopathies); progressive muscular dystrophy (n=75 [18%] including 57 dystrophinopathies); congenital muscular dystrophy (n=17, including six primary merosinopathies); dermatomyositis (n=11); spinal muscular atrophy (n=9, including six atypical spinal muscular atrophies); metabolic myopathy (n=32, including 19 mitochondrial myopathies); encephalomyopathy (n=53 [13%], including 27 with a mitochondrial respiratory chain defect). Pathological diagnosis remained undetermined in 16 cases. In 184 patients (44%), the muscle biopsy revealed specific histopathological anomalies (dystrophic process; specific ultrastructural abnormalities; perifascicular atrophy; neurogenic atrophy; metabolic anomalies) enabling a precise etiological diagnosis. For 85% of progressive muscular dystrophies, the biopsy resulted in a genetic diagnosis after identification of the protein defect. In 15% of the congenital myopathies, histopathological anomalies focused attention on one or several genes. Concerning dystrophinopathies, quantification of dystrophin deficiency on the biopsy specimen contributed to the definition of the clinical phenotype: Duchenne, or Becker. In children with a myopathy, muscle biopsy is often indispensable to establish the etiological diagnosis. Based on the results from this series, muscle biopsy can provide a precise orientation in 45% of patients, leading to a genetic hypothesis.

Background Juvenile dermatomyositis (JDM) is the main cause of chronic idiopathic inflammatory myopathy of autoimmune origin in children. The aim of this multicenter prospective study was to describe respiratory status and treatment of children followed for JDM. Methods and patients Clinical manifestations, pulmonary function tests (PFT), chest high-resolution computed tomography (HRCT) scan results, and treatments and their adverse effects were analyzed in children followed for JDM. Results Twenty-one patients (median age: 9.9 years; range: 20 months–18 years) were included. The median of disease duration at the time of the analysis was 3 years (range: 6 months–9 years 4 months). Overall 16 (76%) of 21 children presented with a respiratory involvement related to JDM including interstitial lung disease (n = 3) and/or respiratory muscle involvement (n = 7). Seven patients presented with other nonspecific manifestations. Three children had aspiration pneumonia. A chest HRCT was performed in 15 children, and abnormalities were observed in 12. PFT were performed in 20 of 21 patients. Seven showed functional abnormalities: restrictive ventilatory defect (n = 3) or obstructive ventilatory defect (n = 4). Six patients had abnormal respiratory muscle tests, including three with a restrictive ventilatory defect and one with an obstructive ventilatory defect. One other child with an acute aspiration pneumonia had a clearly muscle respiratory involvement but was too young to perform respiratory muscle tests and confirm this diagnosis. Treatment comprised systemic corticosteroid for all patients and adjuvant immunosuppressive therapy for 11. Adverse effects linked to treatment were reported in eight patients. Conclusion The frequency of lung involvement in children with JDM justifies systematic respiratory assessment with PFT including measures of respiratory muscle strength. We suggest that a chest HRCT scan is indicated in cases of respiratory symptoms and/or PFT abnormalities. Longitudinal studies are needed to assess pediatric characteristics, long-term outcomes, and responses to treatment taking into account the risk–benefit ratio. Pediatr Pulmonol. 2013; 48:1016–1025. © 2012 Wiley Periodicals, Inc.

Traditional measures of respiratory function in children with Duchenne muscular dystrophy (DMD) are based on maximal inspiratory pressure (PImax) and vital capacity (VC). Sniff nasal inspiratory pressure (SNIP) measurements are easily performed by young children with neuromuscular disorders. The clinical value of SNIP in the longitudinal assessment of respiratory weakness remains to be assessed. The objective of the present study was to assess longitudinally the changes in SNIP, PImax and VC with age in DMD children. We hypothesised that their longitudinal assessment would show an earlier decline in SNIP than VC. A 3-year, prospective follow-up, at 6-month intervals of, 33 steroid-naïve, 5-20-year-old DMD patients was analysed using a linear mixed model. SNIP measurements were reliable (within-session coefficient of variation 8%). SNIP and VC increased until 10.5 and 12.5 years of age, respectively, and declined thereafter, while PImax did not change with age. SNIP was an earlier marker of decline in respiratory muscle strength (at 10.5 years) than VC (at 12.5 years) in young DMD patients. SNIP longitudinal assessment is useful in the detection of inspiratory strength decline in young DMD patients when VC values remain within normal values and as an outcome measure in clinical trials for emerging therapeutics in young DMD patients from the age of 5 years.

Mutations in genes required for the glycosylation of α-dystroglycan lead to muscle and brain diseases known as dystroglycanopathies. However, the precise structure and biogenesis of the assembled glycan are not completely understood. Here we report that three enzymes mutated in dystroglycanopathies can collaborate to attach ribitol phosphate onto α-dystroglycan. Specifically, we demonstrate that isoprenoid synthase domain-containing protein (ISPD) synthesizes CDP-ribitol, present in muscle, and that both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan. We also show that ISPD and FKTN are essential for the incorporation of ribitol into α-dystroglycan in HEK293 cells. Glycosylation of α-dystroglycan in fibroblasts from patients with hypomorphic ISPD mutations is reduced. We observe that in some cases glycosylation can be partially restored by addition of ribitol to the culture medium, suggesting that dietary supplementation with ribitol should be evaluated as a therapy for patients with ISPD mutations., Mutations in genes required for the glycosylation of α-dystroglycan lead to dystroglycanopathies. Here, the authors show that three of these enzymes (ISPD, FKTN and FKRP) work together to attach ribitol phosphate to α-dystroglycan.

International audience; The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity.

Aim To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). Method Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7–24y) were assessed using standardized instruments and cognitive testing of general intelligence, visual attention, and visual–spatial construction abilities. Results Nineteen patients had repeated a school grade. The mean (SD) Full-scale IQ was 73.6 (17.5) and mean Verbal IQ was significantly higher than the mean Performance IQ: 80.2 (19.22) versus 72.95 (15.58), p=0.01. Fifteen patients had one or more diagnoses on the DSM-IV axis 1, including internalizing disorders (phobia, n=7; mood disorder, n=6; other anxiety disorders, n=5) and attention-deficit–hyperactivity disorder, inattentive subtype (n=8). Twelve out of 22 patients had alexithymia (inability to express feelings with words and to recognize and share emotional states). Cognitive testing found severe impairments in visual attention and visual–spatial construction abilities in four out of 18, and 14 out of 24 patients respectively. No diagnosis was correlated with the transmitting parent’s sex or with cytosine–thymine–guanine (CTG) repeat numbers. Patients with severe visual–spatial construction disabilities had a significantly longer CTG expansion size than those with normal visual–spatial abilities (p=0.04). Interpretation Children and adolescents with childhood DM1 have frequent diagnoses on DSM-IV axis 1, with internalizing disorders being the most common type of disorder. They also have borderline low intelligence and frequent impairments in attention and visual–spatial construction abilities.

The role of influenzalike illnesses and influenza vaccination in the development of Guillain-Barré syndrome (GBS), particularly the role of A/H1N1 epidemics and A/H1N1 vaccination, is debated. Data on all incident GBS cases meeting the Brighton Collaboration criteria that were diagnosed at 25 neurology centers in France were prospectively collected between March 2007 and June 2010, covering 3 influenzavirus seasons, including the 2009-2010 A/H1N1 outbreak. A total of 457 general practitioners provided a registry of patients from which 1,080 controls were matched by age, gender, index date (calendar month), and region to 145 cases. Causal relations were assessed by multivariate case-control analysis with adjustment for risk factors (personal and family history of autoimmune disorders, among others), while matching on age, gender, and calendar time. Influenza (seasonal or A/H1N1) or influenzalike symptoms in the 2 months preceding the index date was associated with GBS, with a matched odds ratio of 2.3 (95% confidence interval (CI): 0.7, 8.2). The difference in the rates of GBS occurring between influenza virus circulation periods and noncirculation periods was highly statistically significant (P = 0.004). Adjusted odds ratios for GBS occurrence within 6 weeks after seasonal and A/H1N1 vaccination were 1.3 (95% CI: 0.4, 4.1) and 0.9 (95% CI: 0.1, 7.6), respectively. Study results confirm that influenza virus is a likely risk factor for GBS. Conversely, no new concerns have arisen regarding influenza vaccination.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder associated with homozygous deletion of the survival motor neuron 1 gene (SMN1). Its centromeric copy gene, SMN2, is the major modifying factor. However, the genotype–phenotype correlation is incomplete and is therefore not useful in clinical practice. We studied a cohort of 103 patients in order to refine this correlation. In addition to standard disease severity data, we collected three additional criteria: age at death; brainstem involvement; and loss of ambulation. Gene dosage analysis was conducted by multiplex ligation-dependent probe amplification (MLPA). SMN2 copynumber was highly correlated with survival duration in SMA type I and ambulation conservation or loss in type III. Among SMA severity groups, it was not significantly different in cases with brainstem involvement. Although the SMN2 copynumber could provide prognostic indications, clinical discrepancies still exist among patients, suggesting the existence of unidentified modifying factors. Muscle Nerve, 2011

La possibilite d’une atteinte cognitive des maladies neuromusculaires est clairement evoquee dans leur definition qui designe des « affections chroniques dont l’expression clinique, paralytique, amyotrophique, sensitive ou trophique, depend d’une atteinte des neurones peripheriques, moteur, sensitif et autonome, de la jonction neuromusculaire ou du muscle strie, plus rarement du systeme nerveux central ». Dans les dysytrophinopathies de phenotype Duchenne, l’atteinte des transcrits cerebraux de la dystrophine rend compte des troubles neuropsychologiques : troubles mnesiques concernant principalement la memoire verbale immediate, troubles executifs et deficit de l’attention soutenue. L’atteinte cognitive de la dystrophie myotonique de Steinert ne se limite pas a un syndrome frontal mais comporte aussi une alexithymie ( : incapacite a exprimer verbalement ses affects et a reconnaitre les emotions d’autrui), des troubles visuospatiaux severes et un deficit attentionnel. Une atteinte cognitive, de gravite tres variable, est notee chez 58 % des enfants atteints de dystrophie musculaire congenitale. Dans l’amyotrophie spinale liee au gene SMN1, les performances cognitives sont normales, voire supra-normales, suggerant que la deficience motrice puisse faconner tres precocement des aspects specifiques de l’intelligence et du langage. Conclusion La possibilite d’une atteinte cognitive dans les maladies neuromusculaires de l’enfant ne doit pas etre rejetee de principe. Elle doit faire l’objet d’une description clinique precise dans toutes les affections ou l’atteinte centrale est patente, en particulier dans les dystrophinopathies, la dystrophie myotonique de Steinert et les dystrophies musculaires congenitales.

The ketogenic diet (KD) and the modified Atkins diet are effective therapies for intractable epilepsy. We compared retrospectively the KD and modified Atkins diet in 27 children and also assessed serum long chain fatty acid profiles. After 3 months, using an intent-to-treat analysis, the KD was more successful, with >50% seizure reduction in 11/17 (65%) vs. 2/10 (20%) with the modified Atkins diet, p=0.03. After 6 months, however, the difference was no longer significant: 7/17 (41%) vs. 2/10 (20%) (p=0.24). We observed a preventive effect of both diets on the occurrence of status epilepticus. After 1 and 3 months of either diet, responders experienced a significant decrease in serum arachidonic acid concentration compared to non-responders. The KD and modified Atkins diet led to seizure reduction in this small pilot series, with slightly better results after 3 months with the KD, but not after 6 months. The decrease of serum arachidonic acid levels might be involved in the anticonvulsive effects of KD or modified Atkins diet.

Gastrointestinal symptoms are very frequent in myotonic dystrophy but largely unrecognized. They can be the revealing factors of the disease. We report 2 cases of 10 and 17-year-old children with persistent encopresis starting at the age of 3 and 5 years in spite of laxative treatment. Neurological examination and anorectal manometry provided the diagnosis of myotonic dystrophy. Procainamide treatment was introduced and the digestive symptoms improved. Any child with encopresis should have complete evaluation to rule out the diagnosis of myotonic dystrophy and physicians should look for upper and/or lower gastrointestinal symptoms in every patient with myotonic dystrophy.

Chronic daily headache (CDH) affects 2-4% of adolescent females and 0.8-2% of adolescent males. Chronic daily headache is diagnosed when headaches occur more than 4h/day, 15 headache days per month or more, over a period of 3 consecutive months, without an underlying pathology. It is manifested by severe intermittent, migraine-like headaches as well as by chronic baseline headaches. Both Silberstein-Lipton criteria and the second edition of the International Classification of Headache Disorders (ICHD) can be used to classify chronic daily headache in children and adolescents. Chronic daily headache is classified into four diagnostic categories: transformed (Silberstein-Lipton criteria)/chronic (ICHD) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Children and adolescents with chronic daily headache frequently have sleep disturbance, pain at other sites, dizziness, medication-overuse headache, and a psychiatric comorbidity (anxiety and mood disorders). Chronic daily headache frequently results in school absence. Successful approaches to treatment include reassurance, education, use of preventative medication, avoidance of analgesics, and helping the child return to a functional daily routine and a regular school schedule.

Objective: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. Methods: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. Results: The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a “dropped head” syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers. Interpretation: The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD). Ann Neurol 2008;64:177–186

Spinal Muscular Atrophies (SMA) are a group of degenerative diseases primarily affecting the anterior horn cells of the spinal cord and resulting in muscle weakness and atrophy. Diagnostic criteria were proposed by the International SMA Consortium (ISMAC) to differentiate“classical” proximal SMA caused by homozygous deletion or conversion of the SMN1 gene (5q13) from atypical SMA unlinked to chromosome 5q (non-5q-SMA entities). The aim of our study was to emphasize the unusual clinical features encountered in infantile SMA. Patients and methods: We retrospectively analyzed 63 children with SMA hospitalized between 1985 and 2006. Results: Forty-eight children suffered from classical SMA and 15 from atypical SMA, including 4 distal SMA, 2 scapuloperoneal SMA, one pontocerebellar hypoplasia type I, 7 neurogenic arthrogryposis multiplex congenita (2 of them associated with a central nervous system (CNS) involvement) and one undetermined case. Conclusion: This study confirmed the clinical variety of proximal SMA and put in perspective some exclusion criteria (CNS involvement, phrenic or facial palsy). Some symptoms allowed us to anticipate the normality of the SMN1 gene : improvement of motor condition, distal predominance and, more relatively, assymetry of motor weakness. Diagnosis difficulties were especially encountered in case of predominant distal deficit, arthrogryposis multiplex congenita and associated clinical abnormalities. Detailed phenotypical description and syndromic regrouping of cases of atypical SMA lead to a better understanding of underlying physiopathological processes and to the identification of other genes involved in infantile SMA.

Resume Introduction Le regime cetogene est employe dans le traitement des epilepsies pharmacoresistantes de l’enfant depuis 1921, bien que son mode d’action soit mal connu. Observation Nous rapportons le cas d’un homme de 54 ans presentant un etat de mal epileptique partiel, prolonge, resistant aux antiepileptiques usuels et d’evolution favorable sept jours apres introduction d’un regime cetogene en association aux traitements antiepileptiques. Discussion Tres peu de travaux dans la litterature sont disponibles concernant l’interet du regime cetogene dans le traitement des epilepsies de l’adulte ou des etats de mal epileptique. C’est un traitement bien tolere qui a montre son efficacite chez l’enfant. Il existe toutefois des contraintes d’observance et la necessite d’une collaboration multidisciplinaire etroite lors de son instauration. Conclusion Le regime cetogene pourrait constituer une alternative pour le traitement des epilepsies pharmacoresistantes de l’adulte et dans le traitement des etats de mal resistants, comme chez l’enfant. Des etudes complementaires permettront de preciser son possible effet prolonge et son impact dans la reduction des traitements antiepileptiques.

Summary Epilepsia partialis continua (EPC) is characterized by continuous myoclonic or clonic jerks repeated at short intervals followed by a slowly progressive neurological disorder. We report three patients with EPC and a defect in the mitochondrial respiratory chain. Methods Clinical, neuroradiological, and biochemical data were reported. Results The patients presented continuous myoclonic jerks at age of 8 months, 11 months and 6 years, respectively. Two of the three patients had a previous developmental delay. Neurological examination at first admission revealed extrapyramidal symptoms in all patients. Initial biological investigations suggested mitochondrial dysfunction. Initial EEG showed a continuous discharge of periodic spikes (0.5–1 Hz). MRI studies were initially normal then progressed to cerebral hemiatrophia. EEG revealed both correlation and absence of correlation between spikes or sharp waves and myoclonic jerks. The activity of one or several complexes of the mitochondrial respiratory chain was reduced in the muscle samples of the three patients. No mutation of mtDNA was found. Conclusion Our report suggests that EPC can be due to mitochondrial respiratory chain disorders. Some clinical findings and initial investigations were indicative of a disorder of mitochondrial metabolism. Previous developmental delay, extrapyramidal symptoms and other organ involvement should suggest a possible mitochondrial etiology of EPC. In case of infant presenting EPC, mitochondrial respiratory chain disorder should be considered first.

Objectives.—This study sought to examine the treatment of children with migraine headaches in a prospective sample of children referred to a tertiary center for headaches. Background.—Despite the wide diffusion of guidelines for headache management in children, their application in general practice is far from optimal. Methods.—This prospective study analyzed previous headache treatment by general practitioners in 151 consecutive children (F/M: 0.82; mean age 10.4 ± 3.2 years) referred for migraines to the Lille University Hospital Neuropediatric department between October 1, 2003, and November 30, 2005. The physician completed a questionnaire according to the parents' responses to questions about previous advice about life-style adjustments (diet, exercise, and sleep hygiene) and abortive and prophylactic treatment. Questions about abortive treatment covered ergot derivatives, triptans, and 3 aspects of ibuprofen use—appropriate dose (ie, more than 7.5 mg/kg), recommendation to administer the drug early in attacks, and warnings about drug abuse. Under the topic of prophylactic treatment, we asked about information from general practitioners about preventive therapy and advice to keep a headache diary. Results.—Fewer than 15% of patients had received advice about life-style adjustments. Only 30.3% had received ibuprofen at a correct dose (more than 7.5 mg/kg); only 26.5% were told to use it early during the headache; and only 9.1% were warned about drug abuse. Ergot derivatives were prescribed to 4.6% of children and triptans to 9.1%. Families of 17.9% reported that the general practitioners gave them information about prophylactic treatment. Only 8.0% were advised to keep a headache diary. Conclusion.—This study shows the need to increase the role and the involvement of family doctors in the management of primary headache in children in general, and of pediatric migraine in particular.

Resume Introduction La dystrophie musculaire des ceintures de type 2I est secondaire aux mutations du gene de la Fukutin-related protein ( FKRP ). Cette etude a pour objectif d’evaluer les caracteristiques cliniques, biologiques et genetiques des patients presentant une dystrophie des ceintures de type LGMD2I. Methodes Onze patients issus de 9 familles non consanguines du Nord de la France ont ete selectionnes. Nous rapportons les donnees demographiques, le testing musculaire, l’examen cardiaque, respiratoire, et l’etude anatomopathologique des biopsies musculaires de meme que l’analyse moleculaire du gene FKRP de ces 11 patients se repartissant en 5 hommes et 6 femmes. Resultats L’âge moyen de debut des symptomes etait de 9,7 ans. Six avaient un phenotype musculaire dit « Duchenne-like », 5 un phenotype dit « Becker-like ». Neuf patients souffraient d’un syndrome restrictif ventilatoire, deux hommes d’une cardiomyopathie dilatee severe. La mutation homozygote L276I du gene FKRP a ete observee chez 10 des 11 patients. Trois nouvelles mutations heterozygotes : L322V, L489R ou R275G associees a la mutation L276I ont ete identifiees. Conclusion Cette etude rend compte des differences phenotypiques inter et intra familiale de cette dystrophie musculaire et souligne la preponderance de la cardiopathie chez les hommes et de l’atteinte respiratoire restrictive chez les femmes.

Benign hereditary chorea is a rare autosomal dominant disorder presenting with a childhood-onset and slowly progressive chorea. The objective of this study was to describe the clinical and genetic features of 3 patients who developed childhood-onset chorea. Three affected patients from three generations of a family with benign hereditary chorea associated with a multisystemic disorder of the basal ganglia, thyroid, lungs, salivary glands, bowels, and teeth. The TITF-1 gene was screened by microsatellite analysis, gene sequencing, and fluorescence in situ hybridization. Genetic analysis revealed a novel 0.9-Mb deletion on chromosome 14, which includes the TITF-1 and PAX9 genes. We have identified a novel deletion responsible for a new syndrome of benign hereditary chorea, including symptoms of brain-thyroid-lung syndrome associated with bowels, salivary glands, and teeth disorders. Associated signs, sometimes of slight expression, remain of high interest for the clinical and genetic diagnosis of benign hereditary chorea.

We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.

Background: Duchenne muscular dystrophy (DMD) is often associated with obesity, which worsens the handicap early in the course ofthedisease.Nutritionalassessment,however,canbedifficultand often misleading in DMD. Objective: Two methods of estimating body composition in DMD, skinfold-thickness (ST) measurement and bioelectrical impedance analysis (BIA), were compared with a reference method, labeled water dilution (WD). Design: Body composition was estimated by using ST measurements and BIA (50 kHz, 800 mAmp), as well as the WD method (1 mL H2 18 O/kg) in 11 DMD patients with a mean (SD) age of 10.0 2.5 y. Results: When compared with the WD method, ST measurement significantly(P0.01)overestimatedfat-freemass(FFM)(x SD ST: 24.5 5.9 kg; x SD WD: 18.2 2.5 kg), which led to an underestimation of the percentage of fat mass (%FM) (ST: 23.3 10.4%; WD: 40.1 17.1%; P 0.05). In contrast, estimates obtainedwithBIA(FFM:21.54.5kg;%FM:31.313.9%)didnot differ from those obtained with WD. The difference from the reference method was less for BIA (x: 3.3 kg; 95% CI: 0.8, 4.9 kg) than for ST (6.3 kg; 2.2, 8.6 kg). WD and BIA defined 73% and 55%, respectively, of the children as obese (%FM associated with body mass index cutoffs for obesity), whereas ST measurements defined 9% as obese (P 0.01). Conclusions: Body-composition estimates by BIA are closer to those by WD than are those by ST measurement. Early detection of fat accumulation and longitudinal monitoring of nutritional care are 2 relevant applications of BIA to prevent obesity and hence lessen the burden of DMD. Am J Clin Nutr 2006;83:65–9.

Autism is defined by 3 main criteria: disturbance of reciprocal social interaction, disturbance of communication (including language comprehension and spoken language) and disturbance of normal variation in behaviour and imaginative activities; an onset before age 36 months is also required. The neuropediatric contribution to autism is dominated by the search for an underlying organic etiology, especially if there are arguments for an associated encephalopathy: ante- or perinatal medical history, dysmorphic signs, skin spots, neurological abnormalities, somatic abnormalities compatible with a neurometabolic disorder. The main associated conditions with autism are: chromosome anomalies, monogenic syndrome (including fragile X syndrome), neurocutaneous syndromes, epileptic encephalopathies, neurometabolic diseases, and dystrophinopathies. The identification of an associated medical condition to autism is primordial in prospect of genetic counselling, and by the change induced in familial perception of autism.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by motoneuron degeneration in the anterior horn of the spinal cord and in the bulbar nuclei. The various types of SMA are linked to the 5q13 locus in 95 % of cases. In the absence of an effective specific treatment, orthopaedic and respiratory management can significantly improve the prognosis. To study the contemporary natural history of SMA and to identify clinical and non invasive prognostic criteria, 168 patients with SMA were recruited in 6 hospital units (Lille, Lyon, Marseille, Paris) during a 4-year prospective multicenter follow-up study (1998-2002). Follow-up has now lasted at least 4 years in 151 cases (90%), and 24 of these patients have died Disease outcome was appraised by using three criteria: muscle strength, the sum of the motor function and examination index (IFM), the respiratory muscle paralysis index (IMR), and the dorsal decubitus forced vital capacity/theoretical index (ICV/CT). Statistical analysis showed a significant worsening (about 20%) of the three criteria during follow-up. The motor function and examination index (IFM) is particularly interesting: the difference between initial and final status was significant in all age groups and in all three types of the disease. The IFM may thus be useful as the main outcome measure during therapeutic trials.

Resume Introduction La maladie de Niemann-Pick de type C (NPC) est une lipidose lysosomale a expression neuroviscerale, de transmission autosomique recessive. Observation Une patiente de 31 ans, droitiere, etait suivie pour une schizophrenie depuis l’âge de 18 ans. A 25 ans, apparurent des troubles de l’equilibre, une dysarthrie et des troubles cognitifs. La patiente presentait un syndrome cerebelleux cinetique et statique, une dysarthrie, une paralysie de la verticalite du regard, une alteration du jugement, de la comprehension et une desorientation temporospatiale. L’imagerie cerebrale etait normale. Une hypercholesterolemie et une cytolyse hepatique motiverent une echographie abdominale, revelant une hepatosplenomegalie. L’ensemble des signes et symptomes faisait suspecter une maladie de Niemann-Pick de type C. Le diagnostic a ete affirme sur une culture de fibroblastes par la mise en evidence d’une surcharge lysosomale en cholesterol (test a la filipine) et un defaut d’esterification du cholesterol induite par les LDL. Le gene implique (determine par complementation genetique) etait NPC1. Discussion L’expression phenotypique de la maladie de NPC est tres heterogene. La forme de l’adulte est moins frequente et d’evolution lente. Elle peut etre dominee par des troubles psychiatriques avec manifestations neurologiques tardives. De plus, la prise chronique de psychotropes retarde souvent le diagnostic. Conclusion L’association de troubles psychiatriques a un syndrome cerebelleux et a une paralysie de la verticalite du regard (± splenomegalie) sont evocateurs d’une maladie de Niemann-Pick C. Le diagnostic biologique repose sur une biopsie cutanee et un test a la filipine.