T Stojkovic

Institute of Myology, Lutetia Parisorum, Île-de-France, France

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Publications (237)872.48 Total impact

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    ABSTRACT: Respiratory insufficiency in facioscapulohumeral muscular dystrophy has rarely been studied. We compared two age- and sex-matched groups of 29 patients, with and without respiratory dysfunction. Tests in the 29 patients with respiratory dysfunction suggested predominant expiratory muscle dysfunction, leading to ineffective cough in 17 patients. Supine and upright vital capacities were not different (P = 0.76), suggesting absence of diaphragmatic dysfunction. By stepwise regression, only expiratory reserve volume correlated with the Walton and Gardner-Medwin score (R(2) = 0.503; P = 0.001). Compared to controls, patients with respiratory dysfunction had higher values for the Walton and Gardner-Medwin score (6.1 ± 1.9 vs. 3.2 ± 1.2; P <0.0001) and body mass index (26.9 ± 6.0 vs. 22.9 ± 4.0 kg/m(2); P = 0.003) and a smaller number of D4Z4 allele repeats (4.8 ± 1.6 vs. 5.7 ± 1.8; P = 0.05). Mechanical ventilation was required eventually in 20 patients, including 14 who were wheelchair bound. Three patients had acute respiratory failure requiring mechanical ventilation; 16 patients had poor airway clearance, including 10 with sleep apnea syndrome, responsible in 7 for chronic hypercapnia. Two patients presented isolated severe sleep apnea syndrome. Respiratory dysfunction in facioscapulohumeral muscular dystrophy is predominantly related to expiratory muscle weakness. Respiratory function and cough effectiveness should especially be monitored in patients with severe motor impairment and high body mass index. Copyright © 2015 Elsevier B.V. All rights reserved.
    Neuromuscular Disorders 04/2015; DOI:10.1016/j.nmd.2015.04.011 · 3.13 Impact Factor
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    ABSTRACT: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease. All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed. Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation. This study expands the spectrum of phenotype in β-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression. © 2015 American Academy of Neurology.
    Neurology 04/2015; 84(17). DOI:10.1212/WNL.0000000000001519 · 8.30 Impact Factor
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    ABSTRACT: The aim of this study is to assess the long-term cardiac prognosis of adults with mitochondrial diseases. Between January 2000 and May 2014, we retrospectively included in this study 260 consecutive patients (60% women) ≥18 years (interquartile range 31-54), with genetically proven mitochondrial diseases, including 109 with mitochondrial DNA (mtDNA) single large-scale deletions, 64 with the m.3243A>G mutation in MT-TL1, 51 with other mtDNA point mutations, and 36 patients with nuclear gene mutations. Cardiac involvement was present at baseline in 81 patients (30%). Single and multiple variable analyses were performed in search of predictors of major adverse cardiac events (MACEs), and hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. Over a median follow-up of 7 years (3.6-11.7), 27 patients (10%) suffered a MACE, defined as sudden death, death due to heart failure (HF), resuscitated cardiac arrest, third-degree atrioventricular block, sinus node dysfunction, cardiac transplantation, or hospitalization for management of HF. Patients with single large-scale mtDNA deletions or m.3243A>G mutations had the highest incidence of MACE. By multiple variable analysis, intraventricular conduction block (HR = 16.9; 95% CI: 7.2-39.4), diabetes (HR = 7.0; 95% CI: 2.9-16.7), premature ventricular complexes (HR = 3.6; 95% CI: 1.4-9.2), and left ventricular (LV) hypertrophy (HR = 2.5; 95% CI: 1.1-5.8) were independent predictors of MACEs. In patients with zero, one, and two or more risk factors, the incidences of MACE were 1.7, 15 and 42%, respectively. Patients with mitochondrial diseases are at high risk of MACE, independently predicted by intraventricular conduction block, diabetes, ventricular prematurity, and LV hypertrophy. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    Archives of Cardiovascular Diseases Supplements 04/2015; 7(2):176-177. DOI:10.1016/S1878-6480(15)30127-0
  • T. Stojkovic
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    ABSTRACT: La camptocormie correspond à un déficit sélectif des muscles extenseurs du rachis. Les causes en sont très diverses, comprennent les maladies dégénératives telles que la maladie de Parkinson, les maladies neuromusculaires dont les myopathies qu’elles soient acquises ou héréditaires. L’examen clinique soigneux permet parfois d’évoquer d’emblée une étiologie. Dans d’autres cas, le recours aux examens complémentaires tels que l’électroneuromyographie, l’imagerie musculaire et les examens biologiques permettent d’orienter le diagnostic. La biopsie musculaire est encore souvent nécessaire. Elle est pratiquée dans la grande majorité des cas sur des sites musculaires faciles d’accès, comme le deltoïde, le trapèze ou le vaste externe. À ce titre, l’examen clinique et l’imagerie IRM « corps entier » permettent de guider le site de la biopsie. Les camptocormies sont à rapprocher des syndromes de la tête tombante avec laquelle elle partage les hypothèses physiopathologiques. Elle est peu évolutive et difficile à traiter, sauf dans les cas exceptionnels où une myosite est mise en évidence autorisant alors un traitement spécifique de la myosite.
    Pratique Neurologique - FMC 03/2015; 6(2). DOI:10.1016/j.praneu.2015.01.002
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    ABSTRACT: This was a retrospective study to assess the diagnostic value of the non-ischaemic forearm exercise test in detecting McArdle's disease. The study is a retrospective diagnostic study over 15 years (1999-2013) on a referred sample of patients suffering from exercise intolerance and various muscle complaints, generally with elevated creatine kinase (CK). In all, 1226 patients underwent the non-ischaemic forearm exercise test. Blood lactate, ammonia and CK levels were analyzed. DNA analyses and/or muscle biopsies were assessed to confirm the diagnosis of McArdle's disease. The results of 60 volunteers were used to compare with the results of study subjects. In this cohort, 40 patients were finally diagnosed with McArdle's disease. Absolute values of lactate and ammonia rise were used to discriminate all McArdle patients from healthy patients. A sensitivity and specificity of respectively 100% and 99.7% were calculated. The 24-h CK level showed no significant difference from the CK level at the day of the test and confirms the safety of the test. This study has formally assessed the diagnostic value of the non-ischaemic forearm exercise test in the detection of McArdle's disease. Very high sensitivity and specificity were observed. Furthermore, the test is easy to set up and to perform, it is non-traumatic and cost effective. It may circumvent a muscle biopsy in McArdle patients presenting the most common mutations. Hence, it is a perfect and safe screening instrument to detect patients with McArdle's disease. Glycogen storage disease type III patients, however, may show similar patterns to McArdle patients. © 2015 EAN.
    European Journal of Neurology 03/2015; 22(6). DOI:10.1111/ene.12685 · 4.06 Impact Factor
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    ABSTRACT: Collagen VI-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy (UCMD), intermediate phenotypes, to the milder Bethlem myopathy (BM). Both inter- and intra-familial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked inter-generational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional 5th simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2 and COL6A3) in genomic DNA (gDNA) from various tissues; including blood, saliva, and dermal fibroblasts. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared to the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intra-familial/inter-generational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected.This article is protected by copyright. All rights reserved
    Human Mutation 01/2015; 36(1). DOI:10.1002/humu.22691 · 5.05 Impact Factor
  • La Revue de Médecine Interne 12/2014; 35. DOI:10.1016/j.revmed.2014.10.028 · 1.32 Impact Factor
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    ABSTRACT: Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce. We retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases). Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease. Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of Neurology Neurosurgery & Psychiatry 12/2014; DOI:10.1136/jnnp-2013-307245 · 5.58 Impact Factor
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    ABSTRACT: Background Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3).Methods80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes.ResultsThis trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group.Conclusions These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.Trial registrationEudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).
    Orphanet Journal of Rare Diseases 12/2014; 9(1):199. DOI:10.1186/s13023-014-0199-0 · 3.96 Impact Factor
  • 19th International Congress of the World-Muscle-Society; 10/2014
  • T. Stojkovic · P. Richard · P. Charron · S. Rondeau · M. JeanPierre
    19th International Congress of the World-Muscle-Society; 10/2014
  • Article: T.P.27
    Neuromuscular Disorders 10/2014; 24(9-10):872-873. DOI:10.1016/j.nmd.2014.06.263 · 3.13 Impact Factor
  • 19th International Congress of the World-Muscle-Society; 10/2014
  • 19th International Congress of the World-Muscle-Society; 10/2014
  • 19th International Congress of the World-Muscle-Society; 10/2014
  • Article: G.P.214
    Neuromuscular Disorders 10/2014; 24(9-10):881. DOI:10.1016/j.nmd.2014.06.290 · 3.13 Impact Factor
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    ABSTRACT: Objective Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations. Design Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG+/− group) or two POLG alleles (POLG+/+ group). Phenotyping included clinical signs, electroneuromyography and brain imaging while mitochondrial investigations encompassed muscle histochemistry, respiratory chain assays and search for multiple mitochondrial deletions. The specificity and sensitivity of the signs associated with POLG mutations were analysed by comparison between POLG+/+ and patients without POLG mutation. Results High sensitivity but low specificity was observed with single signs such as axonal sensory neuropathy, cerebellar syndrome, movement disorders and weakness involving ocular, pharyngeal, axial and/or limb muscles. Specificity was increased with combination of previous signs plus psychiatric symptoms, cognitive impairment and epilepsy. High specificity and sensitivity was only obtained with sensory neuronopathy associated with one of the following signs: weakness of ocular, pharyngeal, axial and/or limb muscles. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule above 50 years of age leading to a very low probability of POLG mutations in patients with less than three signs and absent sensory neuropathy. Conclusions Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart.
    Journal of Neurology Neurosurgery & Psychiatry 08/2014; 86(6). DOI:10.1136/jnnp-2013-306799 · 5.58 Impact Factor
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    ABSTRACT: Importance Axonal Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous, with 11 genes identified. Axonal CMT has most frequently been associated with mutations in the MFN2 gene (CMT2A).Objectives To describe the clinical and molecular features of CMT2A, to delineate prognostic factors, to understand connections between a certain phenotype and more serious clinical consequences, and to identify interactions among the associated genes.Evidence Review We describe the clinical, molecular, electrophysiological, and additional features of 43 patients with CMT2A. The degree of physical disability was determined by the CMT neuropathy score and adapted to the CMT neuropathy score gradient to evaluate the clinical course. We evaluated all data within the context of the most recent and important publications concerning this issue.Findings Twenty-five patients had early-onset CMT2A and severe functional disability, with 9 being wheelchair bound, and 18 had late-onset disease and a milder phenotype. Optic atrophy, vocal cord palsy, and auditory impairment were observed in 5, 6, and 2 patients, respectively. Among the 24 patients who underwent magnetic resonance imaging of the spinal cord, 6 had evidence of spinal atrophy with or without hydromyelia. In 1 patient, magnetic resonance imaging revealed hydrocephalus. Twenty different MFN2 mutations were identified, and 14 were considered new variants. Their transmission was predominantly autosomal dominant, with vertical transmission in 8 and de novo occurrence in 3. However, we also identified rare types of transmission, especially a germinal mosaicism and an autosomal recessive inheritance. One patient carried a rare variant in the GDAP1 gene and another in the OPA1 gene in association with MFN2 mutation.Conclusions and Relevance Charcot-Marie-Tooth disease type 2A associated with MFN2 mutations is clinically very heterogeneous. Ranging from a mild to a severe form, CMT2A exhibits various types of transmission. Optic atrophy and vocal cord palsy were observed in patients with severe disability and an early-onset form and also in patients with later onset. Hydromyelia and spinal cord atrophy support central nervous system involvement in CMT2A.
    JAMA Neurology 06/2014; 71(8). DOI:10.1001/jamaneurol.2014.629 · 7.01 Impact Factor
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    Revue Neurologique 06/2014; 170(6-7). DOI:10.1016/j.neurol.2014.04.002 · 0.60 Impact Factor
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    ABSTRACT: To clarify the phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathies. We screened for TRPV4 mutations in 169 French unrelated patients with inherited axonal peripheral neuropathy. Ninety-five patients had dominant Charcot-Marie-Tooth type 2 (CMT2) disease, and 74 patients, including 39 patients with distal hereditary motor neuropathy, 14 with congenital spinal muscular atrophy and arthrogryposis, 13 with CMT2, and 8 with scapuloperoneal spinal muscular atrophy, presented with additional vocal cord paralysis and/or skeletal dysplasia. No deleterious TRPV4 mutation was identified in the 95 patients with "pure" CMT2 (0/95). In contrast, 12 of 74 patients (16%) with neuropathy and vocal cord paralysis and/or skeletal dysplasia presented pathogenic TRPV4 mutations, including 7 patients with distal hereditary motor neuropathy, 2 with scapuloperoneal spinal muscular atrophy, 2 with congenital spinal muscular atrophy and arthrogryposis, and one with CMT2. Investigation of affected relatives allowed us to study 17 patients. All patients had childhood-onset motor neuropathy and showed a variety of associated findings, including foot deformities (100% of cases), kyphoscoliosis (100%), elevated serum creatine kinase levels (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Eight missense mutations were observed in these 12 families, including 2 previously unreported. Six mutations were de novo events, and 2 asymptomatic carriers were identified. With 16% of patients affected in our series, this study demonstrates that TRPV4 mutations are a major cause of inherited axonal neuropathy associated with a large spectrum of additional features.
    Neurology 04/2014; 82(21). DOI:10.1212/WNL.0000000000000450 · 8.30 Impact Factor

Publication Stats

3k Citations
872.48 Total Impact Points

Institutions

  • 2009–2015
    • Institute of Myology
      Lutetia Parisorum, Île-de-France, France
  • 2014
    • Institut de France
      Lutetia Parisorum, Île-de-France, France
  • 2012–2014
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2009–2014
    • Pierre and Marie Curie University - Paris 6
      • Institut de myologie
      Lutetia Parisorum, Île-de-France, France
  • 2008–2014
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service de Biochimie Métabolique
      Lutetia Parisorum, Île-de-France, France
    • Université du Droit et de la Santé Lille 2
      Lille, Nord-Pas-de-Calais, France
  • 2007–2014
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
    • Centre Hospitalier de Valenciennes
      Valenciennes, Nord-Pas-de-Calais, France
  • 2013
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 2000–2012
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
  • 2010–2011
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2000–2009
    • Centre Hospitalier Régional Universitaire de Lille
      • • Division of Neurology
      • • Urology Service
      Lille, Nord-Pas-de-Calais, France
  • 2004
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2002
    • Centre Hospitalier de Lens
      Lens, Nord-Pas-de-Calais, France