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1.
Neurology ; 92(8): e852-e865, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30659139

RESUMO

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.

2.
Mol Ther ; 26(2): 618-633, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29221805

RESUMO

After intra-arterial delivery in the dystrophic dog, allogeneic muscle-derived stem cells, termed MuStem cells, contribute to long-term stabilization of the clinical status and preservation of the muscle regenerative process. However, it remains unknown whether the human counterpart could be identified, considering recent demonstrations of divergent features between species for several somatic stem cells. Here, we report that MuStem cells reside in human skeletal muscle and display a long-term ability to proliferate, allowing generation of a clinically relevant amount of cells. Cultured human MuStem (hMuStem) cells do not express hematopoietic, endothelial, or myo-endothelial cell markers and reproducibly correspond to a population of early myogenic-committed progenitors with a perivascular/mesenchymal phenotypic signature, revealing a blood vessel wall origin. Importantly, they exhibit both myogenesis in vitro and skeletal muscle regeneration after intramuscular delivery into immunodeficient host mice. Together, our findings provide new insights supporting the notion that hMuStem cells could represent an interesting therapeutic candidate for dystrophic patients.

3.
J Neurol Neurosurg Psychiatry ; 89(5): 499-505, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29070644

RESUMO

OBJECTIVE: To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000-70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres. METHODS: We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres. RESULTS: Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25-91.4) and 8.4 years (0.3-33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with 'atypical' clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7-12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7-12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU. CONCLUSION: Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.

4.
Acta Neuropathol ; 134(6): 889-904, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28685322

RESUMO

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.


Assuntos
Heterozigoto , Mutação , Miopatias Congênitas Estruturais/diagnóstico , Proteínas Tirosina Fosfatases não Receptoras/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Miopatias Congênitas Estruturais/fisiopatologia , Fenótipo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Índice de Gravidade de Doença
5.
Neuromuscul Disord ; 27(3): 214-220, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28161094

RESUMO

The present study aimed to assess the ability of muscle stiffness (shear modulus) and response to electrically-induced muscle contraction to detect changes in muscle properties over a 12-month period in children with Duchenne muscular dystrophy (DMD). Ten children with DMD and nine age-matched healthy male controls participated in two experimental sessions (T0 and T+12months) separated by 12.4 ± 0.9 months. Two contractions of the biceps brachii were electrically-induced during which an ultrasound probe was placed over the muscle. The resting shear modulus was measured using elastography from six muscles. Evoked maximal torque was increased at T+12months in controls (+11.2 ± 7.6%, P <0.001) but was not modified in children with DMD (P = 0.222). Electromechanical delay (+12.9 ± 11.3%, P <0.001) and its force transmission component (+10.1 ± 21.6%, P = 0.003) were significantly longer at T+12months than T0 for children with DMD. The results revealed an increase in muscle stiffness at T+12months in children with DMD for tibialis anterior (+75.1 ± 93.5%, P= 0.043), gastrocnemius medialis (+144.8 ± 180.6%, P= 0.050) and triceps brachii (+35.5 ± 32.2%, P= 0.005). This 12-month follow-up study demonstrates that electromechanical delay and elastography may help detect subtle muscle impairments in patients with DMD. These sensitive outcomes may improve the follow-up of innovative therapeutic interventions within the field of DMD.


Assuntos
Contração Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Adulto , Criança , Técnicas de Imagem por Elasticidade , Estimulação Elétrica , Seguimentos , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular de Duchenne/diagnóstico por imagem , Ultrassonografia , Adulto Jovem
8.
PLoS One ; 11(2): e0148264, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26849574

RESUMO

BACKGROUND: Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. METHODS: We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). RESULTS: Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. CONCLUSION: Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.


Assuntos
Bases de Dados Factuais , Distrofia Miotônica/epidemiologia , Fenótipo , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Distrofia Miotônica/mortalidade , Distribuição por Sexo , Fatores Socioeconômicos
9.
Clin Neurophysiol Pract ; 1: 43-45, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-30214959

RESUMO

Objectives: The Sudoscan™ system (Impeto Medical, Paris, France) has been recently proposed as a standardized, easy, painless tool for sudomotor function assessment. It is now used as an additional diagnostic tool in small fibre neuropathy. So far, no work has been published in children. The aim of this study was to measure electrochemical skin conductance (ESC) using the Sudoscan™ system in children in order to assess its feasibility and to provide normative values. Methods: 100 children were included in the study: 55 girls and 45 boys, age rank 2-17, mean 10.5 y. They were accompanying their brother or sister who came as outclinic patients in the Department of Paediatrics or the Department of Paediatric surgery of the University Hospital. Results: All subjects underwent the test. It was performed without any difficulty, except for some of the youngest who sometimes had some trouble in keeping calm for 3 min over the plates. 4 subjects who took the test were excluded from the analysis (2 diabetic patients and 2 having had previous chemotherapy). ESC was quite stable along childhood with an overall 80.1 µS value for hands and 81.9 µS for feet, very similar to what is observed in adults. Conclusion: Maturation process seems to occur early in life, in accordance to sudomotor control when assessed by sympathetic skin response, which is also recorded early in infancy. Significance: ESC measurement is a simple and easy-to-perform test that can be performed in the clinical setting in children in 5 min.

10.
Orphanet J Rare Dis ; 10: 135, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26471370

RESUMO

BACKGROUND: Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients. METHODS: Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected. RESULTS: Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes. CONCLUSIONS: HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.


Assuntos
Proteínas de Ciclo Celular/genética , Contratura/genética , Doenças Musculares/genética , Fibrose Pulmonar/genética , Esclerose/genética , Anormalidades da Pele/genética , Dermatopatias Genéticas/genética , Tendões/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Contratura/complicações , Contratura/diagnóstico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doenças Musculares/complicações , Doenças Musculares/diagnóstico , Mutação/genética , Fibrose Pulmonar/complicações , Fibrose Pulmonar/diagnóstico , Esclerose/complicações , Esclerose/diagnóstico , Anormalidades da Pele/complicações , Anormalidades da Pele/diagnóstico , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/diagnóstico
11.
Neuromuscul Disord ; 25(10): 773-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26248958

RESUMO

Brody disease was first described as a benign pseudo-myotonic disorder with muscular stiffness, which increased with exercise. Biochemical and genetic studies have pointed out its close relationship to a functional defect of the fast-twitch sarcoplasmic reticulum Ca(++) ATPase pump (SERCA1) encoded by the ATP2A1 gene located on chromosome 16. The histopathological features in this form of myopathy were generally described as non-specific, i.e. moderate degree of type 2 fibre atrophy and excess of internal nuclei. We here present the clinical and histopathological features of a patient with Brody disease over a 19-year follow-up period. This patient had two heterozygous ATP2A1 mutations and complained about muscle stiffness immediately after effort. He had suffered from this since early childhood and exhibited clinical symptoms mimicking myotonia. Histological, ultrastructural and cytogenetic analyses revealed morphologically abnormal nuclei with polyploidy. In this report, we discuss the possible links between the consequences of the genetic abnormality and the peculiar aspect of the nuclei.


Assuntos
Núcleo Celular/patologia , Músculo Esquelético/ultraestrutura , Miotonia Congênita/patologia , Adulto , Seguimentos , Humanos , Masculino , Tono Muscular , Mutação , Miotonia Congênita/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética
12.
Muscle Nerve ; 52(4): 673-80, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25809233

RESUMO

INTRODUCTION: X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene. METHODS: Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed. RESULTS: A known VMA21 mutation, c.163+4A>G, and a new mutation, c.163+3A>G, respectively, were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole-body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement. CONCLUSIONS: This study highlights a distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA, even before muscle biopsy or genetic analysis.


Assuntos
Autofagia , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/patologia , Adolescente , Adulto , Biópsia , Humanos , Imagem por Ressonância Magnética , Masculino , Músculo Esquelético/ultraestrutura , Mutação/genética , Miopatias Congênitas Estruturais/genética , ATPases Vacuolares Próton-Translocadoras/genética
13.
Muscle Nerve ; 52(6): 981-5, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25758843

RESUMO

INTRODUCTION: Vincristine is an antimitotic agent used for treatment of leukemia, lymphomas, and cancers. Its main side effect is a dose-related, length-dependent (LD) axonal neuropathy. METHODS: We performed electrodiagnostic (EDx) examinations in 17 children who had been treated with vincristine and who presented with the clinical picture of a peripheral neuropathy. RESULTS: The mean dose of vincristine was 8.5 ± 4.0 mg/m(2) . Clinical motor symptoms were more frequent and more severe than sensory ones. Thirteen children presented with a motor deficit, 4 of whom could no longer walk. EDx examination showed an axonal neuropathy with a non-length-dependent (NLD) pattern in 9 children and an LD pattern in 8. A major motor predominance was encountered in 12 patients. CONCLUSIONS: The electrophysiological and clinical motor predominance described differs from the mainly sensory neuropathy reported in adults. Incomplete myelination due to young age may have resulted in greater sensitivity of some nerves to neurotoxic agents.


Assuntos
Potenciais de Ação/fisiologia , Antineoplásicos Fitogênicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Vincristina/efeitos adversos , Adolescente , Criança , Pré-Escolar , Eletromiografia , Feminino , Humanos , Lactente , Masculino , Condução Nervosa/fisiologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Estudos Retrospectivos
14.
Neuromuscul Disord ; 25(2): 161-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25454168

RESUMO

Seipinopathies are a group of inherited diseases affecting upper and lower motor neurons due to mutations in the Berardinelli-Seip congenital lipodystrophy 2 gene (BSCL2). We report a French family carrying the N88S mutation in the BSCL2 gene. A 12-yr-old girl complained of bilateral asymmetrical pes cavus with right hand motor deficit and amyotrophy, asymmetrical leg amyotrophy and pyramidal signs. Electrophysiological examination showed axonal asymmetrical motor neuropathy with distal predominance. Her father complained of right hand rest tremor with bilateral hand weakness. Physical examination revealed left leg, hand and forearm amyotrophy, akinesia and right arm rigidity, brisk reflexes in the lower limbs and bilateral Babinski sign. Nerve conduction studies showed distal asymmetrical axonal neuropathy with slight sensitive impairment with moderate decrease of nerve conduction velocity in some nerves. DNA sequencing revealed the presence of the known N88S mutation in the BSCL2 gene (dideoxy-nucleotide method on a 3730 DNA Analyzer, Life Technologies). BSCL2 gene mutations are associated with a wide spectrum of clinical and electrophysiological phenotypes and should be suspected in cases of distal hereditary motor neuropathy with pyramidal signs or early hand involvement. There may also be associated mild demyelination which may vary in severity within the same family. Clinical diagnosis was more difficult in this particular case due to the association with Parkinson symptoms.


Assuntos
Saúde da Família , Subunidades gama da Proteína de Ligação ao GTP/genética , Lipodistrofia Generalizada Congênita/genética , Lipodistrofia Generalizada Congênita/fisiopatologia , Mutação/genética , Adolescente , Feminino , França , Humanos , Lipodistrofia Generalizada Congênita/patologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Condução Nervosa/fisiologia , Tempo de Reação/fisiologia
15.
Muscle Nerve ; 51(2): 284-6, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25187068

RESUMO

INTRODUCTION: Assessment of muscle mechanical properties may provide clinically valuable information for follow-up of patients with Duchenne muscular dystrophy (DMD) through the course of their disease. In this study we aimed to assess the effect of DMD on stiffness of relaxed muscles using elastography (supersonic shear imaging). METHODS: Fourteen DMD patients and 13 control subjects were studied. Six muscles were measured at 2 muscle lengths (shortened and stretched): gastrocnemius medialis (GM); tibialis anterior (TA); vastus lateralis (VL); biceps brachii (BB); triceps brachii (TB); and abductor digiti minimi (ADM). RESULTS: Stiffness was significantly higher in DMD patients compared with controls for all the muscles (main effect for population, P < 0.033 in all cases), except for ADM. The effect size was small (d = 0.33 for ADM at both muscle lengths) to large (d = 0.86 for BB/stretched). CONCLUSIONS: Supersonic shear imaging is a sensitive non-invasive technique to assess the increase in muscle stiffness associated with DMD.


Assuntos
Contração Isométrica/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Adolescente , Análise de Variância , Estudos de Casos e Controles , Criança , Pré-Escolar , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular de Duchenne/diagnóstico por imagem , Ultrassonografia , Adulto Jovem
16.
Orphanet J Rare Dis ; 9: 199, 2014 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-25519680

RESUMO

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). METHODS: 80 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. RESULTS: This 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 REGISTRATION: EudraCT 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).


Assuntos
Baclofeno/administração & dosagem , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/tratamento farmacológico , Naltrexona/administração & dosagem , Sorbitol/administração & dosagem , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
J Appl Physiol (1985) ; 117(6): 658-62, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25103971

RESUMO

The decrease in muscle strength in patients with Duchenne muscular dystrophy (DMD) is mainly explained by a decrease in the number of active contractile elements. Nevertheless, it is possible that other electrochemical and force transmission processes may contribute. The present study aimed to quantify the effect of DMD on the relative contribution of electrochemical and force transmission components of the electromechanical delay (i.e., time lag between the onset of muscle activation and force production) in humans using very high frame rate ultrasound. Fourteen patients with DMD and thirteen control subjects underwent two electrically evoked contractions of the biceps brachii with the ultrasound probe over the muscle belly. The electromechanical delay was significantly longer in DMD patients compared with controls (18.5 ± 3.9 vs. 12.5 ± 1.4 ms, P < 0.0001). More precisely, DMD patients exhibited a longer delay between the onset of muscle fascicles motion and force production (13.6 ± 3.1 vs. 7.9 ± 2.0 ms, P < 0.0001). This delay was correlated to the chronological age of the DMD patients (r = 0.66; P = 0.01), but not of the controls (r = -0.45; P = 0.10). No significant difference was found for the delay between the onset of muscle stimulation and the onset of muscle fascicle motion. These results highlight the role of the alteration of muscle force transmission (delay between the onset of fascicle motion and force production) in the impairments of the contraction efficiency in patients with DMD.


Assuntos
Força Muscular , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Braço/fisiopatologia , Criança , Pré-Escolar , Técnicas de Imagem por Elasticidade , Estimulação Elétrica , Feminino , Humanos , Lactente , Masculino , Contração Muscular , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular de Duchenne/diagnóstico por imagem , Transmissão Sináptica , Adulto Jovem
18.
BMJ Case Rep ; 20142014 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-24939454

RESUMO

Mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. Focal paresis has sometimes already been described. We report a case with atypical clinical manifestation comprising paramyotonia and cold-induced persistent and focal paralysis. A 27-year-old woman presented with paramyotonia congenita since her childhood. She experienced during her childhood one brief episode of generalised weakness. At the age of 27, she experienced a focal paresis lasting for several months. The known mutation p.Val1293Ile was found in the muscle sodium channel gene (SCN4A). Channel inactivation is involved in most Na(+) channelopathies. Fast inactivation is known to be responsible for the myotonia phenotype. We hypothesise that the V1293I mutation may also alter the slow inactivation in specific conditions, for example, prolonged cold exposure or prolonged and intensive exercise. This observation broadens the spectrum of clinical manifestations of this sodium channel mutation.


Assuntos
Miotonia Congênita/complicações , Paralisia/etiologia , Feminino , Humanos , Mexiletina/uso terapêutico , Mutação/genética , Miotonia Congênita/tratamento farmacológico , Miotonia Congênita/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Paralisia/tratamento farmacológico , Resultado do Tratamento , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Adulto Jovem
20.
Am J Hum Genet ; 93(6): 1100-7, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24268661

RESUMO

Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.


Assuntos
Proteínas de Ciclo Celular/genética , Contratura/fisiopatologia , Doenças Musculares/complicações , Mutação , Fibrose Pulmonar/complicações , Síndrome de Rothmund-Thomson/complicações , Síndrome de Rothmund-Thomson/genética , Tendões/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Síndrome de Rothmund-Thomson/diagnóstico , Adulto Jovem
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