Publications by authors named "Arnaud Isapof"

17 Publications

  • Page 1 of 1

JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study.

Rheumatology (Oxford) 2021 Feb 12. Epub 2021 Feb 12.

Department of Paediatric Hematology-Immunology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France.

Objective: To evaluate the efficacy and safety of JAK inhibitors (JAKi) in juvenile dermatomyositis (JDM).

Methods: We conducted a single-center retrospective study of patients with JDM treated by JAKi with a follow-up of at least 6 months. Proportion of clinically inactive disease (CID) within six months of JAKi initiation was evaluated using PRINTO criteria and skin Disease Activity Score. Serum IFN-α concentration was measured by SIMOA assay.

Results: Nine refractory and one new-onset patients with JDM treated with ruxolitinib (n = 7) or baricitinib (n = 3) were included. The main indications for treatment were refractory muscle involvement (n = 8) and ulcerative skin disease (n = 2). CID was achieved in 5/10 patients (2/2 anti-MDA5, 3/4 anti-NXP2, 0/3 anti-TIF1γ positive patients) within six months of JAKi introduction. All responders could withdraw plasmatic exchange, immunoadsorption and other immunosuppressive drugs. The mean daily steroid dose decreased from 1.1 mg/Kg (range 0.35-2 mg/Kg/d) to 0.1 (range, 0-0.3, p= 0.008) in patients achieving CID, and was stopped in two. Serum IFN-α concentrations were elevated in all patients at the time of treatment initiation and normalized in both responder and non-responder. A muscle biopsy repeated in one patient 26 months after the initiation of JAKi, showed a complete restoration of muscle endomysial microvascular bed. Herpes zoster and skin abscesses developed in three and two patients, respectively.

Conclusion: JAKis resulted in a CID in a subset of new-onset or refractory patients with JDM and may dramatically reverse severe muscle vasculopathy. Overall tolerance was good except for a high rate of herpes zoster infection.
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http://dx.doi.org/10.1093/rheumatology/keab116DOI Listing
February 2021

Congenital immobility and stiffness related to biallelic variants.

Neurol Genet 2020 Dec 24;6(6):e520. Epub 2020 Sep 24.

Département de Génétique (R.B., S.W., B.K., S.C.-B., M.-C.V., L.B., D.H., J.B., A.A., C.M.), Hôpital Armand Trousseau & Groupe Hospitalier Pitié-Salpêtrière, and Unité de Neuropédiatrie et Pathologie du Développement (D.D., M.M., D.R., A.I., T.B.V.), Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris; Centre de Référence des Maladies Neurogénétiques (D.D., D.R.); Centre de Référence Anomalies du Développement et Syndromes Malformatifs (S.W., C.M.); Hôpital de Pédiatrie et de Rééducation (K.M.), Bullion; INSERM UMR 1141 (D.R.), Paris; Réanimation Néonatale et Pédiatrique (P.-L.L.), and Service de Néonatologie (F.K., I.M.), Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris; Centre de Référence Déficience Intellectuelles de Causes Rares (D.H., A.A., T.B.V., C.M.); and INSERM (C.M.), U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France.

Objective: To delineate the phenotype associated with biallelic variants.

Methods: We describe 2 new patients with -related disorder diagnosed by whole-exome sequencing and compare their phenotype to 6 previous patients.

Results: Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. Both had absent brainstem evoked auditory responses (BEARs). Patient 1 carried the homozygous p.(His357Argfs*15) variant in . In the light of the finding in patient 1, a second reading of exome data for patient 2 revealed the novel homozygous p.(Gly128Val) variant.

Conclusions: Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia.
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http://dx.doi.org/10.1212/NXG.0000000000000520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577533PMC
December 2020

Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.

Orphanet J Rare Dis 2020 06 12;15(1):148. Epub 2020 Jun 12.

Centre de Référence des Maladies Neuromusculaires Nord/Ile de France/Est, Service de Neurologie pédiatrique, Hôpital Necker-Enfants Malades, APHP, Paris, France.

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.
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http://dx.doi.org/10.1186/s13023-020-01414-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291731PMC
June 2020

Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM).

Hum Genet 2020 Oct 12;139(10):1325-1343. Epub 2020 May 12.

Reproductive Development Group, Murdoch Children's Research Institute, Melbourne, Australia.

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.
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http://dx.doi.org/10.1007/s00439-020-02176-wDOI Listing
October 2020

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

Authors:
Karim Wahbi Rabah Ben Yaou Estelle Gandjbakhch Frédéric Anselme Thomas Gossios Neal K Lakdawala Caroline Stalens Frédéric Sacher Dominique Babuty Jean-Noel Trochu Ghassan Moubarak Kostantinos Savvatis Raphaël Porcher Pascal Laforêt Abdallah Fayssoil Eloi Marijon Tanya Stojkovic Anthony Béhin Sarah Leonard-Louis Guilhem Sole Fabien Labombarda Pascale Richard Corinne Metay Susana Quijano-Roy Ivana Dabaj Didier Klug Marie-Christine Vantyghem Philippe Chevalier Pierre Ambrosi Emmanuelle Salort Nicolas Sadoul Xavier Waintraub Khadija Chikhaoui Philippe Mabo Nicolas Combes Philippe Maury Jean-Marc Sellal Usha B Tedrow Jonathan M Kalman Jitendra Vohra Alexander F A Androulakis Katja Zeppenfeld Tina Thompson Christine Barnerias Henri-Marc Bécane Eric Bieth Franck Boccara Damien Bonnet Françoise Bouhour Stéphane Boulé Anne-Claire Brehin Françoise Chapon Pascal Cintas Jean-Marie Cuisset Jean-Marc Davy Annachiara De Sandre-Giovannoli Florence Demurger Isabelle Desguerre Klaus Dieterich Julien Durigneux Andoni Echaniz-Laguna Romain Eschalier Ana Ferreiro Xavier Ferrer Christine Francannet Mélanie Fradin Bénédicte Gaborit Arnaud Gay Albert Hagège Arnaud Isapof Isabelle Jeru Raul Juntas Morales Emmanuelle Lagrue Nicolas Lamblin Olivier Lascols Vincent Laugel Arnaud Lazarus France Leturcq Nicolas Levy Armelle Magot Véronique Manel Raphaël Martins Michèle Mayer Sandra Mercier Christophe Meune Maud Michaud Marie-Christine Minot-Myhié Antoine Muchir Aleksandra Nadaj-Pakleza Yann Péréon Philippe Petiot Florence Petit Julien Praline Anne Rollin Pascal Sabouraud Catherine Sarret Stéphane Schaeffer Frederic Taithe Céline Tard Vincent Tiffreau Annick Toutain Camille Vatier Ulrike Walther-Louvier Bruno Eymard Philippe Charron Corinne Vigouroux Gisèle Bonne Saurabh Kumar Perry Elliott Denis Duboc

Circulation 2019 07 3;140(4):293-302. Epub 2019 Jun 3.

APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile de France, Paris-Descartes, Sorbonne Paris Cité University (K.W., D.D.).

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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.039410DOI Listing
July 2019

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Nat Commun 2019 May 2;10(1):2079. Epub 2019 May 2.

CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.

The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.
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http://dx.doi.org/10.1038/s41467-019-10161-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497626PMC
May 2019

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Nat Commun 2019 02 15;10(1):883. Epub 2019 Feb 15.

CHU Sainte-Justine Research Center, Montreal, QC, H3T 1C5, Canada.

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-08800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377600PMC
February 2019

A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management.

Neurology 2019 02 18;92(8):e852-e865. Epub 2019 Jan 18.

From CHRU de Tours (E.L.), Université François Rabelais de Tours, INSERM U1253, Tours; Neuromuscular Reference Center (C.D., M.D.A., R.G.), AP-HP, Hôpital Pitié-Salpêtrière, Paris; Inserm UMRS872 (M.D.A.), team22, Centre de recherche des Cordeliers, Paris; Service de neurologie pédiatrique (F.A.), pneumologie pédiatrique et médecine infantile, Hôpital de La Timone, Marseille; Service de pédiatrie médicale (N.B.), pôle Femme Enfant, CHU, Caen; Consultation myologie (C.B., I.D.), Cliniques des maladies du développement, Hôpital Necker-Enfants Malades, Paris; Centre hospitalier universitaire de Fort de France (R.B.), unité de neuromyologie, Fort de France; Service de pédiatrie-Neurologie Pôle enfants (C.C.), Hôpital des enfants, CHU Purpan, Toulouse; Service de neurologie pédiatrique (B.C.), pneumologie pédiatrique et médecine infantile, Hôpital de La Timone, Marseille; Service de Neuropédiatrie et Centre de Référence Maladies Neuromusculaires (J.-M.C.), Hôpital Roger-Salengro, Lille; Pôle mère-enfant (J.D.), neuropédiatrie et neurochirgurgie de l'enfant, CHU d'Angers; Service de pédiatrie médicale (C.E.), Hôpital Pellegrin, Bordeaux; Pôle de pédiatrie médico-chirurgicale et génétique Clinique (M.F.), CHU de Rennes-Hôpital Sud, Rennes; Centre de Référence Déficiences Intellectuelles (D. Héron), Département de Génétique et INSERM U975, Groupe hospitalier Pitié-Salpétrière, Paris; Service de neuropédiatrie et pathologie du développement (A.I., M.M.), Hôpital Trousseau, Paris; Service de neurophysiologie enfants et adultes (A.J.-P.), Hôpital F. Mitterrand, Dijon; Centre hospitalier Bretagne Atlantique (H.J.), Vannes; Hôpital de la mère et de l'enfant (C.L.-R.), Dominique Larrey, Limoges; Service de pédiatrie 1 (V.L.), Centre de référence pour les maladies neuromusculaires CENRNEST, Hôpital de Hautepierre-Hôpitaux Universitaires de Strasbourg; CHU Nantes (A.M., Y.P., J.P.-B.), Centre de Référence Maladies Neuromusculaires Nantes-Angers, Hôtel-Dieu, Nantes; Service d'Epileptologie Clinique (V.M.), des Troubles du Sommeil et de Neurologie Fonctionnelle de l'Enfant, Hôpital Femme Mère Enfant, Lyon; Département de pédiatrie et département de génétique médicale (S.P.), Hôpital Morvan, Brest; Département de pédiatrie (S.Q.-R.), Hôpital Raymond Poincaré, Garches; Service d'explorations fonctionnelles pédiatriques (S.R.-M.), Hôpital de Brabois, Vandœuvre-Lès-Nancy; Service de de pédiatrie et de neuropédiatrie (C.R.), Hôpital l'Archet 2, Pôle Femme Mère Enfant, Nice; Département de neuropédiatrie (F.R., U.W.-L.), Hôpital Gui de Chauliac, Montpellier; Service de pédiatrie A-Unité de neurologie pédiatrique (P.S.), American Memorial Hospital, Reims; Centre de référence des neuropathies rares et pathologies neuromusculaires (C.S.), Centre hospitalo-universitaire de Clermont-Ferrand, Clermont-Ferrand; Pôle de Psychiatrie (H.T.), Neurologie et Rééducation Neurologique, CHU Grenoble Alpes, Grenoble; Service de neurologie pédiatrique (C.V.), Pavillon Femme, mère et enfant, Hôpital Charles Nicolle, Rouen; Inserm UMR U955 E10 et Université Paris-Est Créteil (R.G.); Direction de la Recherche et de l'Innovation (D. Hamroun), CHRU de Montpellier; Sorbonne Université (G.B.), INSERM, UMRS974, Neuromuscular Reference Center, AP-HP, Hôpital Pitié-Salpêtrière, Paris; and FILNEMUS (E.L., C.D., M.D.A., F.A., N.B., C.B., R.B., C.C., B.C., J.-M.C., I.D., J.D., C.E., M.F., D. Héron, A.I., A.J.-P., H.J., C.L.-R., V.L., A.M., V.M., M.M., Y.P., J.P.-B., S.P., S.Q.-R., S.R.-M., C.R., F.R., P.S., C.S., H.T., C.V., U.W.-L., R.G., D. Hamroun, G.B.), French Neuromuscular Reference Centers, France.

Objective: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management.

Methods: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed.

Results: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce.

Conclusions: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.
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http://dx.doi.org/10.1212/WNL.0000000000006948DOI Listing
February 2019

Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study.

Neuromuscul Disord 2019 02 31;29(2):114-126. Epub 2018 Oct 31.

Department of Neuropediatrics, Children's Hospital of the University of Toulouse, 330 Great Britain Avenue, TSA 70034 Toulouse, France.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin μ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p < 0.01). Among the 6 patients who were still alive, all were tracheostomized. Only one case survived beyond 2 years without artificial ventilation. The remaining patients died at a median age of 7 months. Our results may help pediatricians to provide medical information to parents and improve the decision-making process of setting up life support.
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http://dx.doi.org/10.1016/j.nmd.2018.10.002DOI Listing
February 2019

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Nat Commun 2018 11 5;9(1):4619. Epub 2018 Nov 5.

CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
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http://dx.doi.org/10.1038/s41467-018-06014-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218476PMC
November 2018

Muscle ischaemia associated with NXP2 autoantibodies: a severe subtype of juvenile dermatomyositis.

Rheumatology (Oxford) 2018 05;57(5):873-879

Reference Center for Neuromuscular Diseases, FILNEMUS, Paris, France.

Objectives: Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM. The aim of our study was to explore without a priori hypotheses whether MSAs are associated with distinct clinical-pathological changes and severity in a monocentric JDM cohort.

Methods: Clinical, biological and histological findings from 23 JDM patients were assessed. Twenty-six histopathological parameters were subjected to multivariate analysis.

Results: Autoantibodies included anti-NXP2 (9/23), anti-TIF1γ (4/23), anti-MDA5 (2/23), no MSAs (8/23). Multivariate analysis yielded two histopathological clusters. Cluster 1 (n = 11) showed a more severe and ischaemic pattern than cluster 2 (n = 12) assessed by: total score severity ⩾ 20 (100.0% vs 25.0%); visual analogic score ⩾6 (100.0% vs 25.0%); the vascular domain score >1 (100.0% vs 41.7%); microinfarcts (100% vs 58.3%); ischaemic myofibrillary loss (focal punched-out vacuoles) (90.9 vs 25%); and obvious capillary loss (81.8% vs 16.7). Compared with cluster 2, patients in cluster 1 had strikingly more often anti-NXP2 antibodies (7/11 vs 2/12), more pronounced muscle weakness, more gastrointestinal involvement and required more aggressive treatment. Furthermore, patients with anti-NXP2 antibodies, mostly assigned in the first cluster, also displayed more severe muscular disease, requiring more aggressive treatment and having a lower remission rate during the follow-up period.

Conclusion: Marked muscle ischaemic involvement and the presence of anti-NXP2 autoantibodies are associated with more severe forms of JDM.
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http://dx.doi.org/10.1093/rheumatology/kex516DOI Listing
May 2018

How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome.

Am J Med Genet A 2018 01 12;176(1):151-155. Epub 2017 Nov 12.

AP-HP, Département de Génétique Médicale, Hôpital Armand Trousseau, UPMC, Paris, France.

A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3.
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http://dx.doi.org/10.1002/ajmg.a.38515DOI Listing
January 2018

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.

J Med Genet 2016 08 17;53(8):511-22. Epub 2016 Mar 17.

Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR S 1127, CNRS UMR 7225, ICM, Paris, France.

Objective: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations.

Methods: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.

Results: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15.

Conclusions: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
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http://dx.doi.org/10.1136/jmedgenet-2015-103451DOI Listing
August 2016

Isolated corpus callosum agenesis: a ten-year follow-up after prenatal diagnosis (how are the children without corpus callosum at 10 years of age?).

Prenat Diagn 2012 Mar;32(3):277-83

Service de Neuropédiatrie, Pathologie du développement, Hôpital Trousseau, Paris, France.

Background: Corpus callosum agenesis (CCA) is generally diagnosed in utero. Outcome appears to be better if the malformation is isolated. The aim of this study, which is the first one with a long (10 years) and standardized follow up, was to report cognitive abilities of children with isolated CCA diagnosed prenatally.

Methods: We prospectively evaluated 17 children. Clinical examinations, neuropsychological tests were performed each year. School achievement and personal and familial data were collected.

Results: Twelve children completed the entire follow up. One child was finally considered to have associated CCA, because signs of fetal alcohol syndrome had become obvious. Of the 11 other children, three (27%) had borderline intelligence whereas the intelligence levels of eight (73%) were in the normal range, although half of these children experienced some difficulties in scholastic achievement. Neither epilepsy nor intellectual deficiency was noted and intellectual quotient scores correlated strongly with the mother's education level.

Conclusion: Although prenatal diagnosis of isolated CCA is reliable, false postnatal diagnoses remain possible (10-20%) even with complete prenatal screening. Outcome is mostly favorable because intelligence is within the normal range for nearly 3/4 of the children. However, they frequently have mild learning difficulties.
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http://dx.doi.org/10.1002/pd.3824DOI Listing
March 2012

Klüver Bucy syndrome following hypoglycaemic coma in a patient with glycogen storage disease type Ib.

J Inherit Metab Dis 2010 Dec 20;33 Suppl 3:S477-80. Epub 2010 Nov 20.

APHP, Service de Pédiatrie, Hôpital Antoine Béclère, Clamart, France.

Patients with type I glycogen storage disease (GSD) have poor tolerance to fasting, sometimes less than 3 hours during infancy. Even though most patients are able, as they get older, to tolerate a longer fasting period, they are at permanent risk for fast-induced hypoglycaemia, even in adulthood. Klüver Bucy syndrome, is characterized by psychic blindness (inability to recognize familiar objects), hypermetamorphosis (strong tendency to react to visual stimulus), increased oral exploration, placidity, indiscriminate hyper-sexuality and change in dietary habits. In this case report, we describe the development of Klüver Bucy syndrome in a 28-year-old man with type Ib GSD, following prolonged and severe hypoglycaemia triggered by a common respiratory infection.
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http://dx.doi.org/10.1007/s10545-010-9243-yDOI Listing
December 2010

Tacrolimus nephrotoxicity: beware of the association of diarrhea, drug interaction and pharmacogenetics.

Pediatr Nephrol 2010 May 21;25(5):965-9. Epub 2010 Jan 21.

Department of Pediatric Nephrology, Armand-Trousseau Hospital, AP-HP and University Paris VI, 26 Avenue du Docteur Arnold Netter, Paris, France.

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition.
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http://dx.doi.org/10.1007/s00467-009-1402-8DOI Listing
May 2010

Gross proteinuria post transplant in a child with nephrotic syndrome of the Finnish type--mechanical vs immunological pathogenesis.

Nephrol Dial Transplant 2006 Dec 25;21(12):3579-82. Epub 2006 Aug 25.

Department of Pediatric Nephrology, Hôpital Armand Trousseau, 26, Avenue du Docteur Arnold Netter, 75012 Paris, France.

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http://dx.doi.org/10.1093/ndt/gfl459DOI Listing
December 2006