RESUMO
BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
Assuntos
Miopatias Distais/genética , Proteínas de Choque Térmico HSP40/genética , Chaperonas Moleculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Linhagem , FenótipoAssuntos
Atrofia Óptica Hereditária de Leber/complicações , Transtornos Parkinsonianos/etiologia , Adulto , Biópsia , DNA Mitocondrial/genética , Distúrbios Distônicos/etiologia , Distúrbios Distônicos/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Transtornos Parkinsonianos/genética , Nervo Fibular/patologia , Mutação PuntualRESUMO
OBJECTIVES: The aim of the study was to compare prospectively indicator-condition (IC)-guided testing versus testing of those with non-indicator conditions (NICs) in four primary care centres (PCCs) in Barcelona, Spain. METHODS: From October 2009 to February 2011, patients aged from 18 to 65 years old who attended a PCC for a new herpes zoster infection, seborrhoeic eczema, mononucleosis syndrome or leucopenia/thrombopenia were included in the IC group, and one in every 10 randomly selected patients consulting for other reasons were included in the NIC group. A proportion of patients in each group were offered an HIV test; those who agreed to be tested were given a rapid finger-stick HIV test (6 per test). Epidemiological and clinical data were collected and analysed. RESULTS: During the study period, 775 patients attended with one of the four selected ICs, while 66,043 patients presented with an NIC. HIV screening was offered to 89 patients with ICs (offer rate 11.5%), of whom 85 agreed to and completed testing (94.4 and 100% acceptance and completion rates, respectively). In the NIC group, an HIV test was offered to 344 persons (offer rate 5.2%), of whom 313 accepted (90.9%) and 304 completed (97.1%) testing. HIV tests were positive in four persons [prevalence 4.7%; 95% confidence interval (CI) 1.3-11.6%] in the IC group and in one person in the NIC group (prevalence 0.3%; 95% CI 0.01-1.82%; P < 0.009). If every eligible person had taken an HIV test, we would have spent 4650 in the IC group and 396,258 in the NIC group, and an estimated 36 (95% CI 25-49) and 198 persons (95% CI 171-227), respectively, would have been diagnosed with HIV infection. The estimated cost per new HIV diagnosis would have been 129 (95% CI 107-153) in the IC group and 2001 (95% CI 1913-2088) in the NIC group. CONCLUSIONS: Although the number of patients included in the study was small and the results should be treated with caution, IC-guided HIV testing, based on four selected ICs, in PCCs seems to be a more feasible and less expensive strategy to improve diagnosis of HIV infection in Spain than a nontargeted HIV testing strategy.
Assuntos
Infecções por HIV/diagnóstico , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Adolescente , Adulto , Idoso , Feminino , Infecções por HIV/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Estudos Prospectivos , Espanha/epidemiologia , Adulto JovemRESUMO
Autosomal recessive Charcot-Marie-Tooth disease (AR-CMT) is often characterized by onset in early childhood and severe phenotype compared to the dominant forms. CMT disease associated with periaxin gene (PRX) is rare and characterized by demyelination limited to the major peripheral nerves. Following the discovery of a high frequency of a specific periaxin gene mutation (E1085fsX4 homozygote) in the Reunion Island, we examined all French patients known as carriers of the periaxin gene mutation. There were 24 patients. Eighteen were from the Reunion Island (6 families and 10 sporadic cases). The six remaining patients were in two families, each with two affected individuals, and two sporadic cases. The series included 17 female and seven male patients. Walking was acquired late, on average at 3.4±1.6 years. One patient never learned to walk. The Charcot Marie Tooth Neuropathy Score (CMTNS) averaged 24.5±8.1. Seven patients had been wheelchair-bound since the age of 24±22. Other symptoms were: scoliosis most often observed after the age of 12 years and sometimes complicated by a restrictive respiratory syndrome; foot deformity in 24 patients; strabismus; glaucoma; myopia. When conduction recordings are available, median nerve motor conduction was slow (<10m/s), associated with a major lengthening of distal latencies. Study of the periaxin gene should be considered in patients with severe demyelinating neuropathy associated with early infantile scoliosis. This disease leads to major disability (29% of patients in this series were wheelchair-bound) and to respiratory insufficiency. Genetic counselling is highly recommended for consanguineous families.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Proteínas de Membrana/genética , Mutação , Adulto , Doença de Charcot-Marie-Tooth/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Eletrofisiologia , Família , Feminino , França , Humanos , Lactente , Masculino , Reunião , Adulto JovemRESUMO
BACKGROUND: Multiple mitochondrial DNA (mtDNA) deletions usually have a mendelian inheritance secondary to mutation in nuclear genes. One of these is the Twinkle gene whose mutation is responsible for autosomal dominant progressive external ophthalmoplegia (PEO). The number of reported cases with mainly myopathic symptoms and possible nervous system involvement related to Twinkle gene mutation is limited. We present a new French family of whom two members displayed myopathy and neuropathy associated with PEO, and we perform a clinical review in light of other observations reported in the literature. METHODS: The proband, one son and the daughter have been investigated. Southern blot analysis and long-range PCR assay have been performed from muscle biopsy specimens. Coding exons and flanking intron regions of polymerase gamma (POLG) and DNA helicase (Twinkle) genes were sequenced. RESULTS: Multiple mitochondrial DNA deletions have been found and sequencing of the Twinkle gene showed the change p.R374Q. CONCLUSION: Two other families from the literature also had the R374Q mutation. Symptoms reported in association with this mutation were myopathy, peripheral neuropathy, dysarthria and/or dysphagia, respiratory insufficiency and parkinsonism. Respiratory insufficiency caused by chest wall weakness was reported in other families with different Twinkle gene mutations, and one might provide exercise intolerance, dysarthria and/or dysphagia as symptoms in favor of the diagnosis. Occurrence of impressive emaciation was a peculiarity in our family.
Assuntos
DNA Helicases/genética , Mutação , Oftalmoplegia Externa Progressiva Crônica/genética , Biópsia , Southern Blotting , DNA Mitocondrial/genética , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/patologia , Oftalmoplegia Externa Progressiva Crônica/fisiopatologia , Linhagem , Reação em Cadeia da Polimerase , Adulto JovemRESUMO
BACKGROUND: Limb girdle muscular dystrophies are rare genetic diseases. Despite constant progress in genetics and biochemistry, the pathogenic mechanisms are not completely understood. Calpainopathy (LGMD2A) has been reported to be the most frequent autosomal recessive form of muscular dystrophy in several populations. Point mutations in CAPN3 are difficult to identify and the analysis is long and costly. The use of western blot does not seem to provide the expected sensitivity and specificity. PATIENTS AND METHOD: We studied all the patients diagnosed in the neuromuscular center of Bordeaux (France) with confirmed calpainopathy in order to establish the appropriate diagnostic approach (inclusion criteria: muscular biopsy with calpain 3 western blot study, two mutations in CAPN3). Patients with highly suspected calpainopathy (same criteria with only one mutation) were also analyzed. RESULTS: Our 13 patients belonged to 10 different families. Four patients had a normal western blot for calpain (WBn). We found high phenotypic variability with frequent atypical signs. The WBn group had less severe disease (a statistically significant later age of onset, a tendency toward lower CK levels and a slower disease course). We extended this comparison to the single mutation patients and we found the same results. CONCLUSION: Considering the lack of sensitivity of western blot protein analysis in LGMD2A, a normal western blot for calpain should not halt the genetic analysis. The western blot result seems to have prognostic value. A normal western blot may help genetic testing by highlighting some mutational hot spots in the CAPN3 gene.
Assuntos
Calpaína/fisiologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Adolescente , Adulto , Idade de Início , Western Blotting , Calpaína/genética , Criança , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Doenças Neuromusculares/diagnóstico , Fenótipo , Mutação Puntual , Prognóstico , Adulto JovemRESUMO
Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124_1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.
Assuntos
Genótipo , Proteínas Musculares/genética , Mutação , Síndromes Miastênicas Congênitas/genética , Fenótipo , Axônios/patologia , Axônios/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Síndromes Miastênicas Congênitas/patologia , Síndromes Miastênicas Congênitas/terapia , Junção Neuromuscular/patologia , Junção Neuromuscular/fisiopatologia , Gravidez , Tomografia Computadorizada por Raios XAssuntos
Ectrópio/tratamento farmacológico , Ectrópio/patologia , Pálpebras/patologia , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/patologia , Idoso , Inibidores da Colinesterase/uso terapêutico , Diagnóstico Diferencial , Ectrópio/diagnóstico , Pálpebras/efeitos dos fármacos , Feminino , Humanos , Miastenia Gravis/diagnóstico , Neostigmina/uso terapêutico , Brometo de Piridostigmina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Myotonic dystrophy type 1 may be associated with low circulating dehydroepiandrosterone (DHEA) levels. This study was aimed at investigating the efficacy and safety of DHEA in myotonic dystrophy type 1 patients. METHODS: This was a prospective, multicenter, randomized, double-blind, placebo-controlled trial conducted from February 2005 to January 2006 at 10 university-affiliated neuromuscular disease centers in France. Seventy-five ambulatory adults with myotonic dystrophy type 1 received an oral replacement dose (100 mg/d) or a pharmacologic dose (400 mg/d) of DHEA, or placebo. The primary endpoint was the relative change in the manual muscle testing (MMT) score from baseline to week 12. Secondary outcome measures included changes from baseline to week 12 in quantitative muscle testing and timed functional testing, respiratory and cardiac function, and quality of life. This study was registered with ClinicalTrials.gov identifier NCT00167609. RESULTS: The median (1st, 3rd quartile) relative changes in MMT score from baseline to week 12 after randomization were 3.1 (-0.9, 6.7), 1.9 (-2.7, 3.5), and 2.2 (0, 7.9), in the DHEA 100 mg, DHEA 400 mg, and placebo groups, respectively. There were no differences between placebo and combined DHEA groups (p = 0.34), placebo and DHEA 100 mg (p = 0.86), or placebo and DHEA 400 mg (p = 0.15). There were also no evidence for a difference between groups for the changes from baseline to week 12 in any secondary outcome. CONCLUSIONS: There is no evidence that a 12-week treatment with replacement or pharmacologic doses of dehydroepiandrosterone improves muscle strength in ambulatory myotonic dystrophy type 1 patients.
Assuntos
Desidroepiandrosterona/uso terapêutico , Distrofia Miotônica/tratamento farmacológico , Adulto , Desidroepiandrosterona/efeitos adversos , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/psicologia , Estudos Prospectivos , Qualidade de VidaRESUMO
Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder caused by mutations in the CAPN3 gene. Its definitive diagnosis is laborious, since the clinical phenotype is often similar to other types of muscular dystrophy and since the CAPN3 gene encompasses a large genomic region with more than 300 pathogenic mutations described to date. In fact, it is estimated that nearly 25% of the cases with a phenotype suggestive of LGMD2A do not have mutations in the CAPN3 gene and that, in up to 22% of the cases, only one mutation is identified. In the present work, we have characterised CAPN3 messenger RNA (mRNA) expression in peripheral blood, and we have performed a retrospective diagnostic study with 26 LGMD2A patients, sequencing a transcript of CAPN3 present in white blood cells (WBCs). The 25% of the mutations presented in this paper (7/28) act modifying pre-mRNA splicing of the CAPN3 transcript, including the first deep-intronic mutation described to date in the CAPN3 gene. Our results determine that the sequencing of CAPN3 transcripts present in WBCs could be applied as a new approach for LGMD2A diagnosis. This method improves and simplifies diagnosis, since it combines the advantages of mRNA analysis in a more accessible and rapidly regenerated tissue. However, the lack of exon 15 in the CAPN3 isoforms present in blood, and the presence of mRNA degradation make it necessary to combine mRNA and DNA analyses in some specific cases.
Assuntos
Calpaína/sangue , Calpaína/genética , Leucócitos/enzimologia , Proteínas Musculares/sangue , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/enzimologia , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Processamento Alternativo , Sequência de Bases , Estudos de Casos e Controles , Criança , Análise Mutacional de DNA , DNA Complementar/genética , Feminino , Humanos , Isoenzimas/sangue , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Músculos/enzimologia , Distrofia Muscular do Cíngulo dos Membros/classificação , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Mutação , RNA Mensageiro/sangue , RNA Mensageiro/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
There are several reviews devoted to neurosarcoidosis and a few reports restricted to sarcoid neuropathy. Since 1989, we have investigated 4 new cases of sarcoid neuropathy, 1 with chronic sensory motor neuropathy (CSMN), another with painful neuropathy and 2 with atypical chronic inflammatory demyelinating polyneuropathy (CIDP). In each case, biopsy specimens from the superficial peroneal nerve and peroneus brevis muscle were taken by the same cutaneous incision and studied on paraffin sections, semi-thin sections and under electron microscope. We compared neuropathological findings from our 4 cases with those from 34 well-studied nerve biopsies previously reported in the literature, and which concerned 16 cases of CSMN, 13 cases ofmononeuropathy multiplex, 2 cases of painful neuropathy and three cases of CIDP. In all of these 38 cases of sarcoid neuropathy, the characteristic noncaseiting granulomas (NCG) were observed on the nerve in 11 cases, on the muscle alone in 5, on both muscle and nerve in 10, and in the nerve and another parenchyma in 4. In the 8 remaining cases, NCG were observed in another parenchyma, mainly lung or lymph nodes. Moreover, necrotizing vasculitis was present in nerve biopsies from 8 cases and microvasculitis without obvious necrosis in 2 others. Nerve fiber lesions, which are mainly axonal, are probably related to mechanical compression by NCG and/or to an ischemic process due to vasculitis. Cytokines and immune factors may also play a role, especially in certain cases with a clinical presentation of CIDP.
Assuntos
Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Sarcoidose/patologia , Sarcoidose/fisiopatologia , Idoso , Feminino , Granuloma/patologia , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças do Sistema Nervoso Periférico/etiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/etiologia , Sarcoidose/complicaçõesRESUMO
BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP). OBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission. METHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing. RESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect. CONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.
Assuntos
Metaloendopeptidases/genética , Mutação , Paraplegia Espástica Hereditária/genética , ATPases Associadas a Diversas Atividades Celulares , Encéfalo/patologia , Análise Mutacional de DNA , Europa (Continente) , Éxons , Variação Genética , Humanos , Polimorfismo Genético , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Paraplegia Espástica Hereditária/patologiaRESUMO
We present here the clinical, molecular and biochemical findings from 238 limb-girdle muscular dystrophy type 2A (LGMD2A) patients, representing approximately 50% (238 out of 484) of the suspected calpainopathy cases referred for the molecular study of the calpain 3 (CAPN3) gene. The mean age at onset of LGMD2A patients was approximately 14 years, and the first symptoms occurred between 6 and 18 years of age in 71% of patients. The mean age at which the patients became wheelchair bound was 32.2 years, with 84% requiring the use of a wheelchair between the age of 21 and 40 years. There was no correlation between the age at onset and the time at which the patient became wheelchair bound, nor between the sex of the patient and the risk of becoming wheelchair bound. Of the cases where the CAPN3 gene was not affected, approximately 20% were diagnosed as LGMD2I muscular dystrophy, while facioscapulohumeral muscular dystrophy (FSHD) was uncommon in this sample. We identified 105 different mutations in the CAPN3 gene of which 50 have not been described previously. These were distributed throughout the coding region of the gene, although some exons remained free of mutations. The most frequent mutation was 2362AG-->TCATCT (exon 22), which was present in 30.7% of the chromosomes analysed (146 chromosomes). Other recurrent mutations described were N50S, 550DeltaA, G222R, IVS6-1G-->A, A483D, IVS17+1G-->T, 2069-2070DeltaAC, R748Q and R748X, each of which was found in >5 chromosomes. The type of mutation in the CAPN3 gene does not appear to be a risk factor for becoming dependent on a wheelchair at a determined age. However, in the cases with two null mutations, there were significantly fewer patients that were able to walk than in the group of patients with at least one missense mutation. Despite the fact that the results of phenotyping and western blot might be biased due to multiple referral centres, producing a diagnosis on the basis of the classical phenotype is neither sufficiently sensitive (86.7%) nor specific (69.3%), although western blot proved to be even less sensitive (52.5%) yet more specific (87.8%). In this case LGMD2I was a relevant cause of false-positive diagnoses. Considering both the clinical phenotype and the biochemical information together, the probability of correctly diagnosing a calpainopathy is very high (90.8%). However, if one of the analyses is lacking, the probability varies from 78.3 to 73.7% depending on the information available. When both tests are negative, the probability that the sample comes from a patient with LGMD2A was 12.2%.
Assuntos
Calpaína/genética , Isoenzimas/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Idade de Início , Teorema de Bayes , Western Blotting , Criança , Análise Mutacional de DNA/métodos , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Mutação de Sentido Incorreto , Fenótipo , Estudos RetrospectivosRESUMO
INTRODUCTION: Limb girdle muscular dystrophy type 1b (LGMD1B), due to LMNA gene mutations, is a relatively rare form of LGMD characterized by proximal muscle involvement associated with heart involvement comprising atrio-ventricular conduction blocks and dilated cardiomyopathy. Its clinical and genetic diagnosis is crucial for cardiac management and genetic counselling. Seven LMNA mutations have been previously reported to be responsible for LGMD1B. PATIENTS AND METHODS: We describe the neurological and cardiologic features of 14 patients belonging to 8 families in whom we identified 6 different LMNA mutations, 4 of them having never been reported. Results. Eleven patients had an LGMD1B phenotype with scapulohumeral and pelvic-femoral involvement. Thirteen patients had cardiac disease associating conduction defects (12 patients) or arrhythmias (9 patients). Seven patients needed cardiac device (pacemaker or implantable cardiac defibrillator) and two had heart transplantation. CONCLUSION: This study allowed us to specify the clinical characteristics of this entity and to outline the first phenotype/genotype relations resulting from these observations.
Assuntos
Laminas/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Condução Nervosa/fisiologia , Adolescente , Adulto , Idoso , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Biomarcadores , Creatina Quinase/sangue , Ecocardiografia , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias/diagnóstico por imagem , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Lamina Tipo A , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/complicações , Mutação/genética , Mutação/fisiologia , Linhagem , Fenótipo , Tomografia Computadorizada por Raios XRESUMO
Mutations in LMNA, the gene that encodes nuclear lamins A and C, cause up to eight different diseases collectively referred to as "laminopathies." These diseases affect striated muscle, adipose tissue, peripheral nerve, and bone, or cause features of premature aging. We investigated the consequences of LMNA mutations on nuclear architecture in skin fibroblasts from 13 patients with different laminopathies. Western-blotting showed that none of the mutations examined led to a decrease in cellular levels of lamin A or C. Regardless of the disease, we observed honeycomb nuclear structures and nuclear envelope blebs in cells examined by immunofluorescence microscopy. Concentrated foci of lamin A/C in the nucleoplasm were also observed. Only mutations in the head and tail domains of lamins A and C significantly altered the nuclear architecture of patient fibroblasts. These results confirm that mutations in lamins A and C may lead to a weakening of a structural support network in the nuclear envelope in fibroblasts and that nuclear architecture changes depend upon the location of the mutation in different domains of lamin A/C.
Assuntos
Cardiomiopatias/genética , Fibroblastos/patologia , Lamina Tipo A/genética , Lipodistrofia/genética , Distrofias Musculares/genética , Membrana Nuclear/genética , Adolescente , Adulto , Western Blotting , Cardiomiopatias/patologia , Contagem de Células , Núcleo Celular/patologia , Criança , Feminino , Humanos , Lipodistrofia/patologia , Masculino , Proteínas de Membrana/genética , Microscopia de Fluorescência , Pessoa de Meia-Idade , Distrofias Musculares/patologia , Mutação/genética , Mutação/fisiologia , Membrana Nuclear/patologia , Proteínas Nucleares , Fenótipo , Timopoietinas/genéticaRESUMO
POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. POEMS syndrome is also called Crow-Fukase syndrome, chiefly in Japan. The 5 above mentioned features are not always present at the first examination. The minimal criteria to establish the diagnosis are the presence of a demyelinating and axonal polyneuropathy associated with an IgA or IgG monoclonal gammopathy, the light chain being almost always lambda, and at least 2 of the 8 other features: sclerosing plasmocytoma, endocrinopathy, skin changes, organomegaly, Castleman's disease, anasarca, papillary edema or thrombocytosis. Among these features, only cutaneous glomeruloid angioma are specific. Ultrastructural identification of uncompacted myelin lamellae on the peripheral nerve biopsy is also a strong argument in favor of the diagnosis. An associated "osteosclerotic" bone lesion must be carefully searched, because its treatment may improve the other features of the syndrome, especially the neuropathy. Cytokines and the vascular growth endothelial factor might play a role in the pathogenesis of this rare multisystemic disorder.
Assuntos
Síndrome POEMS , Humanos , Síndrome POEMS/complicações , Síndrome POEMS/diagnóstico , Síndrome POEMS/etiologia , Síndrome POEMS/terapiaAssuntos
Doença de Charcot-Marie-Tooth/genética , Genes Dominantes/genética , Cardiopatias/genética , Lamina Tipo A/genética , Distrofias Musculares/genética , Mutação/genética , Unhas Malformadas , Adulto , Sequência de Aminoácidos , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/fisiopatologia , Feminino , Cardiopatias/complicações , Humanos , Lamina Tipo A/química , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Distrofias Musculares/complicações , Distrofias Musculares/fisiopatologia , LinhagemRESUMO
BACKGROUND: Peripheral neuropathies (PN) associated with monoclonal gammopathy (MG) are widely considered as autoimmune disorders, but the putative role of incriminated antigens is still not understood. OBJECTIVE: Fifty five patients with PN associated with MG were studied to investigate whether new antigens could be found, and to evaluate their relation to clinical manifestations. METHODS: An immunological study was conducted on patient sera to identify autoreactivities against nerve proteins by western blotting. Antigen proteins were purified and analysed by proteomic tools. Correlation with ultrastrucural and clinical features was then studied. RESULTS: Of the 55 patients suffering from PN associated with MG, 17 exhibited IgG autoantibodies directed against peripheral nerve proteins of 35, 58, and 60 kDa. N-terminal microsequencing and mass spectrometry analyses of the 35 kDa protein revealed perfect peptidic matching with 47% of the amino acid sequence of P0, whereas the 58 and 60 kDa proteins were identified as the reduced and non-reduced forms of a P0 dimer. Deglycosylation did not affect IgG binding to the 35 kDa P0 related protein, suggesting a peptidic epitope. In contrast, deglycosylation abolished IgG recognition of the P0 dimer protein, so that a carbohydrate moiety may be implicated in the epitope formation. This confirmed the existence of two different types of IgG, one recognising the 58 and 60 kDa proteins and one directed against the 35 kDa protein. CONCLUSIONS: This is the first report of antibody activity directed against the dimeric association of P0. Although P0 oligomerisation and adhesion properties play a crucial part in the myelin sheath compaction, the pathogenic significance of these autoantibodies needs further investigations to be elucidated.
Assuntos
Antígenos/análise , Imunoglobulina G/análise , Proteína P0 da Mielina/imunologia , Paraproteinemias/imunologia , Animais , Autoanticorpos/análise , Western Blotting , Ensaio de Imunoadsorção Enzimática , Humanos , Proteína P0 da Mielina/análogos & derivados , Paraproteinemias/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Autopsy findings are reported from a patient with chorea-acanthocytosis treated for 2 years by deep brain stimulation (DBS) of the motor thalamus. Postoperative testing showed a progressive improvement in axial truncal spasms. Although relatively high currents were used for 2 years in this patient, postmortem analysis showed minimal tissue damage in the vicinity of the electrode tip. It is concluded that DBS has little impact on the surrounding tissues.