Publications by authors named "Guilhem Sole"

49 Publications

Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis.

Neurology 2021 Feb 10. Epub 2021 Feb 10.

Referral Center for Neuromuscular Diseases and ALS, Timone University Hospital, Aix-Marseille University, Marseille, France.

Objective: To describe the clinical characteristics and outcomes of COVID-19 among patients with MG and identify factors associated with COVID-19 severity in MG patients.

Methods: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS network (between March 1, 2020, and June 8, 2020), including MG patients with a confirmed or highly-suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a polymerase chain reaction (PCR) test from a nasopharyngeal swab and/or SARS-CoV-2 serology, thoracic computed tomography (CT-scan), or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes.

Results: Among 3,558 MG patients registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ±19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p=0.004); factors that were not associated included gender, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity.

Conclusions: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes [odds ratio: 102.6 (4.4; 2,371.9)]. These results are important for establishing evidence-based guidelines for the management of MG patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1212/WNL.0000000000011669DOI Listing
February 2021

Confounding clinical presentation and different disease progression in CMT4B1.

Neuromuscul Disord 2020 07 16;30(7):576-582. Epub 2020 May 16.

APHP, Centre de référence des maladies neuromusculaires, Institut de Myologie, Sorbonne Université, APHP, Hôpital Pitié-Salpêtrière; Paris, France. Electronic address:

We report seven Charcot-Marie-Tooth 4B1 (CMT4B1) patients from four families with distinctive features, presenting with severe distal weakness and cranial nerve involvement. Patient from family 1 presented with congenital varus foot deformity, progressive distal and proximal weakness leading to loss of ambulation at 14 years, bilateral facial palsy and prominent bulbar involvement. In three siblings from family 2, still ambulant in the second decade, neuropathy was associated with marked sweating and Arnold-Chiari syndrome. Patient from family 3, wheelchair-bound by 17 years, suffered from recurrent intestinal occlusion due to a mesenteric malformation. Patients from family 4, wheelchair-bound from age 6 years, were first diagnosed with type 1 Usher syndrome with congenital deafness and retinitis pigmentosa. CMT4B1 diagnosis was based upon suggestive clinical features and confirmed by the presence of recessive mutations in the MTMR2 gene. Our results expand the genetic and phenotypic spectrum of CMT4B1, which may include autonomic system involvement.
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http://dx.doi.org/10.1016/j.nmd.2020.05.003DOI Listing
July 2020

The ataxic neuropathies.

J Neurol 2020 Jun 15. Epub 2020 Jun 15.

Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux (Pellegrin Hospital), University of Bordeaux, 1 place Amélie Raba-Léon, 33076, Bordeaux, France.

Ataxia is a frequent symptom in neurological cases with many causes. Sensory ataxia (due to involvement of the proprioceptive pathways) is observed in conditions affecting the central nervous system (spinal cord disorder) and the peripheral nervous system (peripheral neuropathy). The latter correspond to what we refer to as 'ataxic neuropathies'. Ataxic neuropathies represent a wide and heterogeneous spectrum of disorders that may affect dorsal root nerves, dorsal root ganglia, nerve trunks, distal nerve endings or all of them together. The identification of a predominant sensory ataxia in a case of peripheral neuropathy should raise the possibility of some specific etiologies. We propose here to present the main causes of ataxic neuropathies, which are identified with diagnostic workflows that are dictated by the topography of the likely sites of lesions in the proprioceptive pathway together with the timing of their occurrence (acute, subacute, or chronic).
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http://dx.doi.org/10.1007/s00415-020-09994-yDOI Listing
June 2020

Long-term benefit of enzyme replacement therapy with alglucosidase alfa in adults with Pompe disease: Prospective analysis from the French Pompe Registry.

J Inherit Metab Dis 2020 11 27;43(6):1219-1231. Epub 2020 Jul 27.

Centre de référence des maladies neuromusculaires Nord-Est-Ile de France, Service de Neurologie, CHU Raymond Poincaré, AP-HP, Garches, France.

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.
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http://dx.doi.org/10.1002/jimd.12272DOI Listing
November 2020

Type 1 FSHD with 6-10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention.

Int J Mol Sci 2020 Mar 23;21(6). Epub 2020 Mar 23.

Reference Center of Neuromuscular disorders and ALS, Timone University Hospital, AP-HM, 264 rue Saint-Pierre, Cedex 05 13385 Marseille, France.

Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared (1) the phenotype and severity of FSHD1 between patients carrying 6-8 vs. 9-10 RUs, (2) the amount of methylation in different D4Z4 regions between patients with FSHD1 with different clinical severity scores (CSS). This cross-sectional multicenter study was conducted to measure functional scales and for genetic analysis. Patients were classified into two categories according to RUs: Group 1, 6-8; Group 2, 9-10. Methylation analysis was performed in 27 patients. A total of 99 carriers of a contracted D4Z4 array were examined. No significant correlations between RUs and CSS (r = 0.04, = 0.73) and any of the clinical outcome scales were observed between the two groups. Hypomethylation was significantly more pronounced in patients with high CSS (>3.5) than those with low CSS (<1.5) (in DR1 and 5P), indicating that the extent of hypomethylation might modulate disease severity. In Group 1, the disease severity is not strongly correlated with the allele size and is mostly correlated with the methylation of D4Z4 regions.
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http://dx.doi.org/10.3390/ijms21062221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139460PMC
March 2020

Prognostic factor of poor outcome in anti-MAG neuropathy: clinical and electrophysiological analysis of a French Cohort.

J Neurol 2020 Feb 8;267(2):561-571. Epub 2019 Nov 8.

Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux (Groupe Hospitalier Pellegrin), University of Bordeaux, Place Amélie Raba-Léon, 33000, Bordeaux, France.

Background: Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other immune-mediated neuropathies, is difficult to treat in most cases.

Method: We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12 years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used.

Results: Forty-seven patients were included in the study; of these, 61% had a classical 'distal demyelinating pattern', 34.2% had a 'CIDP-like pattern', and the others had an 'axonal pattern'. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination.

Conclusion: Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a 'red flag' for the prompt initiation of rituximab to try to delay long-term disability.
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http://dx.doi.org/10.1007/s00415-019-09618-0DOI Listing
February 2020

Papilledema and Peripheral Neuropathies.

Neurologist 2019 Nov;24(6):185-193

Neurology, CHU Limoges (Dupuytren University Hospital), Limoges.

Introduction: Papilledema is a common sign in ophthalmology and is typically associated with increased intracranial pressure (ICP) in neurological diseases. Since the beginning of the 20th century, some cases of papilledema have been reported in association with acute or chronic inflammatory neuropathies.

Case Report: We describe a 42-year-old man with acute-onset inflammatory polyradiculoneuropathy and bilateral papilledema.

Conclusions: Based on a personal case report and from an extensive review of the medical literature, we identify 2 distinct patterns. First, radiculoneuropathy may be a consequence of intracranial pressure (peripheral nerve involvement corresponding to a "false localizing sign"). Second, papilledema may occur after the onset of inflammatory neuropathy. For such cases, the pathophysiological mechanism remains unknown (eg, reactional inflammatory processes or actions of unknown autoantibodies) and requires further elucidation.
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http://dx.doi.org/10.1097/NRL.0000000000000250DOI Listing
November 2019

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

Myopathy and scleromyxedema.

J Neurol 2019 Aug 21;266(8):2051-2059. Epub 2019 May 21.

Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux (Groupe Hospitalier Pellegrin), University of Bordeaux, Place Amélie Raba-Léon, 33000, Bordeaux, France.

Scleromyxedema is a chronic, idiopathic disorder associated with monoclonal gammopathy, and characterized by dermal mucin deposition. However, systemic manifestations are frequent, including neuromuscular symptoms. We herein present a 71-year-old man who developed a vacuolar myopathy in a context of a known scleromyxedema, and we compare our observation with the nineteen other cases found in the medical literature. Such an association (especially with suggestive skin abnormalities) has to be known for two reasons. First, this diagnosis might be quite challenging because the myopathy may precede the typical skin changes. Secondly, conversely to other forms of vacuolar myopathy, some of the symptoms may respond (even partially) to immunomodulatory and/or immunosuppressant therapeutics.
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http://dx.doi.org/10.1007/s00415-019-09379-wDOI Listing
August 2019

A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs).

Ann Neurol 2019 07 27;86(1):55-67. Epub 2019 May 27.

Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.

Objective: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B.

Methods: We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score.

Results: There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations.

Interpretation: This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019.
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http://dx.doi.org/10.1002/ana.25500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581441PMC
July 2019

LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2.

Eur J Hum Genet 2019 09 17;27(9):1406-1418. Epub 2019 Apr 17.

AP-HP, G-H Pitié-Salpêtrière, Centre de Référence des Maladies neuromusculaires, Paris Nord/Est/Ile de france, Paris, France.

Currently only 25-30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.
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http://dx.doi.org/10.1038/s41431-019-0403-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777460PMC
September 2019

[Innovative therapies and organization of care facilities].

Med Sci (Paris) 2019 Mar 3;35 Hors série n° 1:51-53. Epub 2019 Apr 3.

Coordonnateur adulte du Centre de Référence des maladies neuromusculaires de Bordeaux, CHU de Bordeaux, place Amélie Raba Léon, 33000 Bordeaux, France Coordonnateur du Centre de Référence des maladies neuromusculaires Atlantique-Occitanie-Caraïbe, CHU de Bordeaux, place Amélie Raba Léon, 33000 Bordeaux, France.

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http://dx.doi.org/10.1051/medsci/2019027DOI Listing
March 2019

A novel nonsense PIEZO2 mutation in a family with scoliosis and proprioceptive defect.

Neuromuscul Disord 2019 01 8;29(1):75-79. Epub 2018 Nov 8.

Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile de France, Institut de Myologie, CHU La Pitié-Salpêtrière, APHP, Paris, France.

PIEZO2 mutations have been described in dominant arthrogryposis, but homozygous mutations of PIEZO2 may also be responsible for more complex clinical patterns, associating distal arthrogryposis, neonatal respiratory insufficiency, scoliosis and proprioceptive impairment. We report here two sisters presenting with these clinical and genetic features. They had a similar phenotype, with severe hypotonia and respiratory distress at birth, delayed acquisition of motor milestones and need of scoliosis surgery. Hypotonia and alteration of proprioception were at the forefront of clinical examination for both, along with areflexia, hyperlaxity, cutis laxa, and discrete facial dysmorphy. Electrophysiological studies, including electroneuromyography and sensory evoked potentials, showed a mild sensory axonopathy without any myopathic features, but revealed a peripheral proximal lemniscal defect. Creatine kinase, muscular MRI and biopsy were normal, as well as cerebral MRI and neurometabolic biological explorations. They had a moderate restrictive syndrome on respiratory function tests and cardiac function was normal. Molecular studies performed on a panel of genes involved in distal arthrogryposis disclosed a nonsense homozygous c.3241C > T (p.Arg1051*) mutation in the PIEZO2 gene, which was also present at the heterozygous state in their mother's DNA. This new PIEZO2 mutation was in accordance with the phenotype combining arthrogryposis, scoliosis, hyperlaxity and proprioceptive impairment.
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http://dx.doi.org/10.1016/j.nmd.2018.10.005DOI Listing
January 2019

Rituximab in the Treatment of Refractory Anti-HMGCR Immune-mediated Necrotizing Myopathy.

J Rheumatol 2019 06 15;46(6):623-627. Epub 2018 Dec 15.

From the Department of Internal Medicine and Clinical Immunology and Inflammation-Immunopathology-Biotherapy Department (I2B), Pitié-Salpêtrière University Hospital, AP-HP, East Paris Neuromuscular Diseases Reference Center, Inserm U974, Sorbonne Université, Paris, France; Center of Reference for Neuromuscular Disorders AOC, Department of Neurology, Bordeaux University Hospital, Bordeaux, France; Polyvalent and Oncologic Radiology Department, Musculoskeletal Unit, Pitié-Salpêtrière University Hospital, AP-HP, Paris, France.

Objective: A pathogenic role of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies has been proposed. Our objective was to assess efficacy of rituximab (RTX) in anti-HMGCR immune-mediated necrotizing myopathy.

Methods: All patients who had been treated with RTX were retrospectively reviewed to assess features and outcome.

Results: Three of 9 patients demonstrated stable or improved muscle strength ± decline in creatine kinase levels, or T2/short-tau inversion recovery hypersignal decrease on magnetic resonance imaging following RTX treatment. RTX permitted intravenous immunoglobulin discontinuation and corticosteroid reduction to low dose in 2 patients.

Conclusion: One-third of patients with refractory anti-HMGCR had improved strength or other evidence of improved disease activity following RTX treatment.
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http://dx.doi.org/10.3899/jrheum.171495DOI Listing
June 2019

[Multidisciplinary Concertation Meetings (RCP): objectives and operating procedures].

Authors:
Guilhem Solé

Med Sci (Paris) 2018 Nov 12;34 Hors série n°2:23-25. Epub 2018 Nov 12.

Centre de référence des maladies neuromusculaires Atlantique Occitanie Caraïbe (AOC), Hôpital Pellegrin, CHU de Bordeaux, France.

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http://dx.doi.org/10.1051/medsci/201834s207DOI Listing
November 2018

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study.

J Inherit Metab Dis 2018 11 28;41(6):937-946. Epub 2018 Aug 28.

Centre de Référence des Maladies Neuromusculaires Nord-Est-Ile de France, Service de Neurologie, CHU Raymond Poincaré, AP-HP, 104 bd Raymond Poincaré, 92380, Garches, France.

Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.
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http://dx.doi.org/10.1007/s10545-018-0243-7DOI Listing
November 2018

Focal neurogenic muscle hypertrophy and fasciculations in multifocal motor neuropathy.

Muscle Nerve 2018 11 7;58(5):E36-E39. Epub 2018 Sep 7.

Department of Neurology, Nerve-Muscle Unit.

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http://dx.doi.org/10.1002/mus.26185DOI Listing
November 2018

Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant.

Eur J Med Genet 2019 Jun 22;62(6):103530. Epub 2018 Aug 22.

Service de Génétique Médicale, CHU de Bordeaux and Laboratoire MRGM, INSERM U1211, Univ. Bordeaux, Bordeaux, France; Centre de Référence Neurogénétique, Service de Génétique Médicale, CHU de Bordeaux, France.

The CACNA1A gene encodes a calcium-dependent voltage channel, localized in neuronal cells. Pathogenic variants in this gene are known to lead to a broad clinical spectrum including episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and more recently epileptic encephalopathy. We report a large family revealing a wide variability of neurological manifestations associated with a CACNA1A missense pathogenic variant. The index case had early-onset epileptic encephalopathy with progressive cerebellar atrophy, although his mother and his great-grandmother suffered from paroxystic episodic ataxia. His grandfather and great grand-aunt reported no symptoms, but two of her sons displayed early-onset ataxia with intellectual disability. Two of her little daughters suffered from gait disorders, and also from epilepsy for one of them. All these relatives were carriers of the previously described heterozygous variant in CACNA1A gene. We report here the first family leading to major clinical variability and incomplete penetrance. Our family highlights the difficulties to provide accurate genetic counselling concerning prenatal diagnosis regarding highly variable severity of the clinical presentation.
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http://dx.doi.org/10.1016/j.ejmg.2018.08.011DOI Listing
June 2019

Some new proposals for the classification of inherited myopathies.

J Neurol Sci 2018 08 19;391:118-119. Epub 2018 Jun 19.

Department of Neurology (National reference center 'neuropathies périphériques rares'), University Hospital Dupuytren, 2 avenue Martin Luther King, 87042 Limoges, France. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2018.06.014DOI Listing
August 2018

Value of nerve biopsy in the management of peripheral neuropathies.

Expert Rev Neurother 2018 07 25;18(7):589-602. Epub 2018 Jun 25.

d National Reference Center for 'rare peripheral neuropathies' , University Hospital , Limoges , France.

Introduction: Peripheral neuropathy is a common symptom throughout the population, with numerous possible etiologies. The diagnosis of peripheral neuropathies (and their causes) is mainly based on clinical, electrophysiological, biological, and imaging features. Areas covered: This paper reviews the main causes of neuropathy and discusses the usefulness of nerve biopsy (NB) in such cases. Expert commentary: In most cases, NB is not mandatory in the diagnostic work-up of a peripheral neuropathy. However, NB is clearly an indication in cases of vasculitis. It is also valuable in peripheral neuropathies with severe and rapid worsening (without clear cause) in order to uncover a pathological hallmark (amyloid deposits). Although NB is considered an invasive method, it may be useful in the management of peripheral neuropathy, especially to guide treatment in certain cases. In summary, although NB is not a systematic procedure, it is a useful tool that should be discussed on a case-by-case basis within the clinical context.
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http://dx.doi.org/10.1080/14737175.2018.1489240DOI Listing
July 2018

A Reliable Targeted Next-Generation Sequencing Strategy for Diagnosis of Myopathies and Muscular Dystrophies, Especially for the Giant Titin and Nebulin Genes.

J Mol Diagn 2018 07 21;20(4):533-549. Epub 2018 May 21.

Molecular Diagnostic Laboratory, Centre Hospitalier Universitaire Montpellier, Montpellier, France; AOC (Atlantique-Occitanie-Caraïbe) Reference Center for Neuromuscular Disorders, Aquitaine, France; Rare Diseases Genetics Laboratory, Equipe Accueil EA7402, Université de Montpellier, Montpellier, France. Electronic address:

Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTN and NEB variants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit and Nextera Rapid Capture Custom Enrichment kit) and of two whole-exome sequencing kits (SureSelect V5 and TruSeq RapidExome capture) revealed best coverage with the SeqCap EZ Choice protocol. A marked decrease in coverage was observed with the other kits, affecting mostly the first exons of genes and the repeated regions of TTN and NEB. Bioinformatics analysis strategy was fine-tuned to achieve optimal detection of variants, including small insertions/deletions (INDELs) and copy number variants (CNVs). Analysis of a cohort of 128 patients allowed the detection of 52 substitutions, 13 INDELs (including a trinucleotide repeat expansion), and 3 CNVs. Two INDELs were localized in the repeated regions of NEB, suggesting that these mutations may be frequent but underestimated. A large deletion was also identified in TTN that is, to our knowledge, the first published CNV in this gene.
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http://dx.doi.org/10.1016/j.jmoldx.2018.04.001DOI Listing
July 2018

Safety of Intravenous Immunoglobulin (Tegeline®), Administered at Home in Patients with Autoimmune Disease: Results of a French Study.

Biomed Res Int 2018 15;2018:8147251. Epub 2018 Mar 15.

International Affairs Scientific Unit, LFB Biomedicaments, Les Ulis, France.

The efficacy of intravenous immunoglobulins (IVIg) in patients with autoimmune diseases (AID) has been known for several decades. Majority of these patients received IVIg in hospital. A retrospective study was conducted in 22 centers in France to evaluate the feasibility of the administration of Tegeline, an IVIg from LFB Biomedicaments, and assess its safety at home, compared to in hospital, in patients with AID. The included patients were at least 18 years old, suffering from AID, and treated with at least 1 cycle of Tegeline at home after receiving 3 consecutive cycles of hospital-based treatment with Tegeline at a dose between 1 and 2 g/kg/cycle. Forty-six patients with AID, in most cases immune-mediated neuropathies, received a total of 138 cycles of Tegeline in hospital and then 323 at home. Forty-five drug-related adverse events occurred in 17 patients who received their cycles at home compared to 24 adverse events in hospital in 15 patients. Serious adverse events occurred in 3 patients during home treatment, but they were not life-threatening and did not lead to discontinuation of Tegeline. Forty-five patients continued their treatment with Tegeline at home or in hospital; 39 (84.8%) were still receiving home treatment at the end of the study. In conclusion, the study demonstrates the good safety profile of Tegeline administered at home at high doses in patients with AID who are eligible for home administration of Tegeline.
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http://dx.doi.org/10.1155/2018/8147251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875056PMC
September 2018

Home versus hospital immunoglobulin treatment for autoimmune neuropathies: A cost minimization analysis.

Brain Behav 2018 02 26;8(2):e00923. Epub 2018 Jan 26.

Public Health, AP-HPUniversity Paris Est Creteil, & ECEVE UMR 1123 Paris France.

Background: Prior clinical trials have suggested that home-based Ig treatment in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variant Lewis-Sumner syndrome (LSS) is safe and effective and is less costly than hospital-administered intravenous immunoglobulin (IVIg).

Methods: A French prospective, dual-center, cost minimization analysis was carried out to evaluate IVIg administration (5% concentrated) at home versus in hospital with regard to costs, patients' autonomy, and patients' quality of life. The primary endpoint was the overall cost of treatment, and we adopted the perspective of the payer (French Social Health Insurance).

Results: Twenty-four patients aged 52.3 (12.2) years were analyzed: nine patients with MMN, eight with CIDP, and seven with LSS. IVIg (g/kg) dosage was 1.51 ± 0.43 in hospital and 1.52 ± 0.4 at home. Nine-month total costs per patient extrapolated to 1 year of treatment were €48,189 ± 26,105 versus €91,798 ± 51,125 in the home and hospital groups, respectively (<.0001). The most frequently reported factors for choosing home treatment were the good tolerance and absence of side effects of IVIg administration, as well as a good understanding of the advantages and drawbacks of home treatment (75% of respondents). The mRankin scores before and after switch to home treatment were 1.61 ± 0.72 and 1.36 ± 0.76, respectively (=.027).

Discussion: The switch from hospital-based to home-based IVIg treatment for patients with immune neuropathy represents potentially significant savings in the management of the disease.
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http://dx.doi.org/10.1002/brb3.923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822576PMC
February 2018

Fluxomic assay-assisted diagnosis orientation in a cohort of 11 patients with myopathic form of CPT2 deficiency.

Mol Genet Metab 2018 04 12;123(4):441-448. Epub 2018 Feb 12.

Department of Biochemistry and Molecular Biology, Laboratory of Endocrinology, Metabolism-Nutrition, Oncology, Biology Pathology Center, CHRU Lille, 59037 Lille, France; Univ. Lille, RADEME - Maladies RAres du Développement et du Métabolisme: du phénotype au génotype et à la Fonction, Lille, EA 7364, France; Inserm, Lille, France. Electronic address:

Carnitine palmitoyltransferase type 2 (CPT2) deficiency, a mitochondrial fatty acid oxidation disorder (MFAOD), is a cause of myopathy in its late clinical presentation. As for other MFAODs, its diagnosis may be evocated when blood acylcarnitine profile is abnormal. However, a lack of abnormalities or specificity in this profile is not exclusive of CPT2 deficiency. Our retrospective study reports clinical and biological data in a cohort of 11 patients with circulating acylcarnitine profile unconclusive enough for a specific diagnosis orientation. In these patients, CPT2 gene studies was prompted by prior fluxomic explorations of mitochondrial β-oxidation on intact whole blood cells incubated with pentadeuterated ([16-H, 15-H])-palmitate. Clinical indication for fluxomic explorations was at least one acute rhabdomyolysis episode complicated, in 5 of 11 patients, by acute renal failure. Major trigger of rhabdomyolysis was febrile infection. In all patients, fluxomic data indicated deficient CPT2 function showing normal deuterated palmitoylcarnitine (C16-Cn) formation rates associated with increased ratios between generated C16-Cn and downstream deuterated metabolites (Σ deuterated C2-Cn to C14-Cn). Subsequent gene studies showed in all patients pathogenic gene variants in either homozygous or compound heterozygous forms. Consistent with literature data, allelic frequency of the c.338C > T[p.Ser113Leu] mutation amounted to 68.2% in our cohort. Other missense mutations included c.149C > A[p.Pro50His] (9%), c.200C > G[p.Ala200Gly] (4.5%) and previously unreported c.1171A > G[p.ser391Gly] (4.5%) and c.1420G > C[p.Ala474Pro] (4.5%) mutations. Frameshift c.1666-1667delTT[p.Leu556val*16] mutation (9%) was observed in two patients unknown to be related.
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http://dx.doi.org/10.1016/j.ymgme.2018.02.005DOI Listing
April 2018

An in-frame deletion in BICD2 associated with a non-progressive form of SMALED.

Clin Neurol Neurosurg 2018 03 30;166:1-3. Epub 2018 Jan 30.

CHU Bordeaux, Service de Génétique Médicale, F-33000 Bordeaux, France; Univ. Bordeaux, INSERM 1211, F-33000 Bordeaux, France.

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http://dx.doi.org/10.1016/j.clineuro.2018.01.013DOI Listing
March 2018

Acute Brachial Radiculoplexopathy and Giant Cell Arteritis.

Neurologist 2018 Jan;23(1):23-28

Department of Neurology, Nerve-Muscle Unit.

Introduction: Giant cell arteritis (GCA), a vasculitis involving large-sized and medium-sized vessels (which most commonly involves temporal arteries), is easily recognized in older patients presenting with headache, scalp tenderness, and raised inflammatory markers. Neurological complications (either central or peripheral) are classically described in GCA.

Case Report: We report the case of an 85-year-old woman with bilateral acute brachial radiculoplexopathy, a rare neurological complication of GCA. She also presented right oculomotor palsy (with ptosis) and raised inflammatory markers, but she did not complain of the other classic cranial symptoms of the disease. We compare this case with 16 similar cases reported in the medical literature.

Conclusions: In assessing a patient over 50 years of age with unexplained (unilateral or bilateral) brachial radiculoplexopathy (especially if C5-C6 nerve roots are affected) and elevated inflammatory markers, we would recommend specific enquiries with regard to the manifestations of GCA. The purpose is to reduce the risk of missing the wider spectrum of this condition and minimize the subsequent risk for disability of this treatable disease.
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http://dx.doi.org/10.1097/NRL.0000000000000162DOI Listing
January 2018

History and current difficulties in classifying inherited myopathies and muscular dystrophies.

J Neurol Sci 2018 Jan 2;384:50-54. Epub 2017 Nov 2.

Department of Neurology, University Hospital Dupuytren, 2 avenue Martin Luther King, 87042 Limoges, France; National reference center 'neuropathies périphériques rares', University Hospital Dupuytren, 2 avenue Martin Luther King, 87042 Limoges, France. Electronic address:

The wide spectrum of hereditary muscular disorders leads to unavoidable difficulties in their classification, even for specialists. For this reason, new proposals are required that would ultimately replace our current rather complex classifications by a simpler structure. Our proposal will be limited to dystrophic and non-dystrophic myopathies (excluding metabolic disorders, mitochondriopathies, and channelopathies) for which similar proposals would also be relevant. Various genes (encoding structural proteins associated with the sarcolemma, nuclear membrane proteins, and proteins involved in myofiber metabolism have now been sequenced and mutations ascribed to specific forms of inherited muscular disorders. Based on our observations and our recent proposals in other neurogenetic conditions and informal discussions with specialists of neuromuscular disorders, the prerequisite for a simple and sound classification for inherited muscular disorders should encompass the clinical and pathological phenotypes (described in a simple and clear manner), the mode of inheritance, and the mutated gene. We think that the denomination of the different subtypes could be simplified considerably, although any new proposal of classification of muscular disorders will need to be discussed in the neurological and genetic communities.
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http://dx.doi.org/10.1016/j.jns.2017.10.051DOI Listing
January 2018

Chronic inflammatory demyelinating polyradiculoneuropathy-causing myelopathy.

Muscle Nerve 2018 02 17;57(2):E102-E103. Epub 2017 Aug 17.

Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux (Pellegrin Hospital), Place Amélie Raba-Léon, 33000, Bordeaux, France.

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http://dx.doi.org/10.1002/mus.25756DOI Listing
February 2018

Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death.

Acta Neuropathol Commun 2017 07 14;5(1):55. Epub 2017 Jul 14.

Unité fonctionnelle de neurogénétique moléculaire, CHU de Lyon - HCL groupement Est, Bron, France.

Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.
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http://dx.doi.org/10.1186/s40478-017-0457-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513089PMC
July 2017

Effect of enzyme replacement therapy with alglucosidase alfa (Myozyme®) in 12 patients with advanced late-onset Pompe disease.

Mol Genet Metab 2017 09 20;122(1-2):80-85. Epub 2017 Jun 20.

Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.

Background: The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease.

Methods: We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared.

Results: Twelve patients (7 males) were identified. Median age at symptom onset was 24years [IQR=15.5; 36.0]. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24h [IQR=21.88; 24.00] (min 20; max 24). ERT was initiated at a median age of 52.5years [IQR=35.75; 66.50]. Median treatment duration was 55months [IQR=39.5; 81.0]. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90min and two increased their assisted walking distance, by 80 and 20m.

Conclusion: Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities.
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http://dx.doi.org/10.1016/j.ymgme.2017.06.007DOI Listing
September 2017