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1.
Neurology ; 95(14): e1979-e1987, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32732293

RESUMO

OBJECTIVE: To assess the clinical course of multifocal motor neuropathy (MMN) in a large cohort of patients and to identify predictive factors of a progressive disease course. METHODS: Between May 2015 and February 2016, we collected clinical data from 100 patients with MMN, of whom 60 had participated in a nationwide cross-sectional cohort study in 2007. We documented clinical characteristics using standardized questionnaires and performed a standardized neurologic examination. We used multiple linear regression analysis to identify factors that correlated with worse outcome. RESULTS: We found that age at diagnosis (45.2 vs 48.6 years, p < 0.02) was significantly increased between 2007 and 2015-2016, whereas diagnostic delay decreased by 15 months. Seven out of 10 outcome measures deteriorated over time (all p < 0.01). Patients who had a lower Medical Research Council (MRC) sumscore and absence of 1 or more reflexes at the baseline visit showed a greater functional loss at follow-up (p = 0.007 and p = 0.016). CONCLUSIONS: Our study shows that MMN is a progressive disease. Although 87% of patients received maintenance treatment, muscle strength, reflexes, vibration sense, and the Self-Evaluation Scale score significantly deteriorated over time. Lower MRC sumscore and absence of reflexes predicted a more progressive disease course. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that lower MRC sumscore and the absence of reflexes predict a more progressive disease course in patients with MMN.


Assuntos
Doença dos Neurônios Motores/fisiopatologia , Polineuropatias/fisiopatologia , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade
2.
Muscle Nerve ; 59(6): 694-698, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30847948

RESUMO

INTRODUCTION: Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. METHODS: To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. RESULTS: Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. DISCUSSION: Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.


Assuntos
Citocinas/imunologia , Imunoglobulina M/imunologia , Paraproteinemias/imunologia , Polineuropatias/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Glicoproteína Associada a Mielina/imunologia , Fator de Necrose Tumoral alfa/imunologia
3.
Ann Neurol ; 80(1): 71-88, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27130524

RESUMO

OBJECTIVE: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). METHODS: iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement. RESULTS: IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations. INTERPRETATION: Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88.


Assuntos
Autoanticorpos/imunologia , Gangliosídeo G(M1)/imunologia , Imunoglobulina M/imunologia , Células-Tronco Pluripotentes Induzidas , Neurônios Motores/imunologia , Neurônios Motores/patologia , Polineuropatias/imunologia , Adulto , Autoanticorpos/sangue , Autoanticorpos/metabolismo , Cálcio/metabolismo , Estudos de Casos e Controles , Técnicas de Cocultura , Feminino , Gangliosídeo G(M1)/metabolismo , Humanos , Imunoglobulina M/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios Motores/metabolismo , Neurônios Motores/ultraestrutura , Neuritos/patologia , Polineuropatias/sangue , Polineuropatias/metabolismo , Polineuropatias/patologia , Ligação Proteica/imunologia
4.
J Neuroimmunol ; 290: 76-9, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26711574

RESUMO

Polyneuropathy associated with IgM monoclonal gammopathy (IgM-PNP) is a slowly progressive, sensorimotor neuropathy. It is assumed that complement activation contributes to IgM-PNP pathogenesis. We investigated whether innate differences in complement activity of the classical and mannose binding lectin (MBL) pathways are associated with IgM-PNP or its severity. We measured complement activity using ELISA and determined MBL serumc oncentrations and MBL gene polymorphisms in 83 patients and 83 healthy controls. We did not observe differences between IgM-PNP patients and healthy controls nor associations with different disease severities. Differences in innate complement activity are not likely to explain susceptibility to or severity of IgM-PNP.


Assuntos
Ativação do Complemento/fisiologia , Lectina de Ligação a Manose da Via do Complemento/fisiologia , Imunoglobulina M/sangue , Paraproteinemias/sangue , Polineuropatias/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Coortes , Feminino , Humanos , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Paraproteinemias/diagnóstico , Paraproteinemias/imunologia , Polineuropatias/diagnóstico , Polineuropatias/imunologia , Estudos Prospectivos
5.
Neurol Neuroimmunol Neuroinflamm ; 2(4): e119, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26161430

RESUMO

OBJECTIVE: To investigate whether high innate activity of the classical and lectin pathways of complement is associated with multifocal motor neuropathy (MMN) and whether levels of innate complement activity or the potential of anti-GM1 antibodies to activate the complement system correlate with disease severity. METHODS: We performed a case-control study including 79 patients with MMN and 79 matched healthy controls. Muscle weakness was documented with Medical Research Council scale sum score and axonal loss with nerve conduction studies. Activity of the classical and lectin pathways of complement was assessed by ELISA. We also determined serum mannose-binding lectin (MBL) concentrations and polymorphisms in the MBL gene (MBL2) and quantified complement-activating properties of anti-GM1 IgM antibodies by ELISA. RESULTS: Activity of the classical and lectin pathways, MBL2 genotypes, and serum MBL concentrations did not differ between patients and controls. Complement activation by anti-GM1 IgM antibodies was exclusively mediated through the classical pathway and correlated with antibody titers (p < 0.001). Logistic regression analysis showed that both high innate activity of the classical pathway of complement and high complement-activating capacity of anti-GM1 IgM antibodies were significantly associated with more severe muscle weakness and axonal loss. CONCLUSION: High innate activity of the classical pathway of complement and efficient complement-activating properties of anti-GM1 IgM antibodies are determinants of disease severity in patients with MMN. These findings underline the importance of anti-GM1 antibody-mediated complement activation in the pathogenesis and clinical course of MMN.

6.
J Neurol ; 262(3): 666-73, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25549972

RESUMO

Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.


Assuntos
Imunoglobulina M/sangue , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/imunologia , Paraproteinemias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Bibliográficas/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
J Neuromuscul Dis ; 2(2): 157-165, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-27858734

RESUMO

BACKGROUND: Multifocal motor neuropathy (MMN) is associated with IgM antibodies to GM1 ganglioside. The importance of the lipid milieu that might facilitate or inhibit antibody binding to GM1 in immunoassays is well recognised. Existing studies, using a range of different approaches, generally concur that anti-GM1 IgM antibody detection rates are improved by the addition of galactocerebroside (GalC) to the GM1 assay. OBJECTIVE: The current study sought to formally evaluate the clinical utility of the GM1:GalC complex assay in the diagnosis of MMN. METHODS: Anti-GM1 and -GM1:GalC antibodies were examined using ELISA and glycoarray (dot blot) in a fully blinded study design, consisting of 100 MMN patients, 100 ALS cases and 100 healthy controls. RESULTS: The detection of anti-GM1 Abs using glycoarray was 67% sensitive and 85% specific. The addition of GalC to GM1, (1:1 weight to weight ratio), increased the sensitivity to 81% , whilst dropping specificity to 80% . Increasing the GalC content to a 1:5 ratio (or higher) further decreased specificity, and in doing so limited the usefulness of the GM1:GalC assay to the level of GM1 alone. The addition of GalC to the ELISA method also significantly increased sensitivity compared with GM1 alone, albeit with a significant decrease in specificity. CONCLUSIONS: This study indicates that the GM1:GalC assay is an advantageous assay adaptation for detecting anti-GM1 antibodies in MMN, using either glycoarray or ELISA, and warrants introduction into clinical diagnostic practice.

8.
J Neurol Neurosurg Psychiatry ; 85(10): 1145-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24336791

RESUMO

BACKGROUND: Multifocal motor neuropathy (MMN) is often responsive to treatment with intravenous immunoglobulin (IVIg), but the optimal dose and intervals of IVIg maintenance treatment have not been established. Increase in IgG concentration (ΔIgG) after IVIg infusion has recently been identified as determinant of outcome in Guillain-Barré syndrome. ΔIgG may therefore represent a potentially useful biomarker to optimise IVIg dosing in patients with MMN. OBJECTIVE: The aims of this study were to determine variability of IVIg pharmacokinetics in patients with MMN in relation to treatment response, and to establish whether interindividual differences in IVIg pharmacokinetics were associated with genetic polymorphisms of the endothelial IgG receptor (FcRn) which determines IgG half-life. METHODS: Twenty-three patients with MMN receiving their first IVIg treatment at a cumulative dose of 2.0 g/kg in 5 days were included. A good treatment response was defined as an increase in muscle strength of at least one Medical Research Council point in minimally two muscle groups. IgG concentrations in serum were determined at baseline, at day 1 and day 5 of the IVIg course, and 3 weeks after treatment. FcRn copy number variation and differences in repeat length of the variable number of tandem repeats in the FcRn gene were determined by quantitative PCR and Sanger sequencing. RESULTS: Seventeen patients (74%) had a good response to treatment. Total IgG and ΔIgG levels showed large variation between patients. Mean ΔIgG was higher in IVIg responders than in non-responders, with the largest difference on day 1 (11.1 g/L vs 4.5 g/L, p=0.06), but our study lacked power to show statistically significant differences. Genetic variation in the FcRn gene was not associated with ΔIgG levels or response to treatment. CONCLUSIONS: IVIg pharmacokinetics varies in patients with MMN and may be associated with clinical response.


Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Imunoglobulinas Intravenosas/farmacocinética , Doença dos Neurônios Motores/tratamento farmacológico , Polineuropatias/tratamento farmacológico , Receptores Fc/genética , Adulto , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Força Muscular/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
9.
J Clin Immunol ; 33 Suppl 1: S38-42, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22941513

RESUMO

Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated chronic disorder characterized by asymmetric distal limb weakness and conduction block. The exact pathogenesis of MMN is still unclear, but IgM anti-GM1 antibodies, which can be detected in sera from approximately half of all MMN patients, are thought to play an important role. Treatment with intravenous immunoglobulin (IVIG) is effective in the vast majority of patients, but, despite IVIG maintenance treatment, many patients experience a slowly progressive decline in muscle strength. In this review we will summarize the results from studies on pathogenesis. We will discuss current treatment strategies of MMN and how insight into MMN pathogenesis may translate into novel therapies in the future.


Assuntos
Polineuropatias/imunologia , Polineuropatias/terapia , Autoanticorpos/imunologia , Autoimunidade , Gangliosídeo G(M1)/imunologia , Humanos , Polineuropatias/genética
10.
PLoS One ; 7(11): e48983, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23155438

RESUMO

Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Atrofia Muscular Espinal/genética , Mutação , Adulto , Idade de Início , Idoso , Proteínas de Ligação a DNA/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína FUS de Ligação a RNA/genética , Ribonuclease Pancreático/genética , Superóxido Dismutase/genética , Superóxido Dismutase-1
11.
Neurology ; 79(9): 878-82, 2012 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-22843265

RESUMO

OBJECTIVE: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). METHODS: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. RESULTS: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 × 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 × 10(-4)). CONCLUSIONS: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.


Assuntos
Doença dos Neurônios Motores/genética , Proteínas/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72 , Estudos de Coortes , Intervalos de Confiança , DNA/genética , Expansão das Repetições de DNA , Demência/complicações , Demência/genética , Feminino , Degeneração Lobar Frontotemporal/complicações , Degeneração Lobar Frontotemporal/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/genética , Mutação/fisiologia , Doença de Parkinson/complicações , Doença de Parkinson/genética , Reação em Cadeia da Polimerase , Modelos de Riscos Proporcionais , Sobrevida , Adulto Jovem
13.
Neurobiol Aging ; 33(8): 1852.e1-3, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22507827

RESUMO

Recently, repeat expansions in several genes have been shown to cause or be associated with amyotrophic lateral sclerosis (ALS). It has been demonstrated that an intronic hexanucleotide repeat expansion in C9ORF72 is a major cause of both familial (approximately 40%) and sporadic (approximately 5%) ALS, as well as frontotemporal dementia (FTD). In addition, a CAG-repeat expansion in exon 1 of ATXN2, otherwise known to cause spinocerebellar ataxia type 2, has been identified as a major risk factor for sporadic ALS. Intermediate repeat expansions in the fragile X mental retardation 1 (FMR1) gene (55-200 repeats) are known to cause fragile X-associated premature ovarian insufficiency [(FX)POI; female carriers] or fragile X-associated tremor/ataxia syndrome (FXTAS; male carriers) by CGG-mediated RNA toxicity. The present investigation involves screening FMR1 repeat length in 742 sporadic ALS patients and 792 matched controls. Our conclusion is that FMR1 repeat expansions are not associated with ALS.


Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências Repetitivas de Ácido Nucleico/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos de Associação Genética , Marcadores Genéticos/genética , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Fatores de Risco
14.
Neurobiol Aging ; 33(4): 837.e7-13, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22078486

RESUMO

Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause inclusion body myopathy (IBM) with Paget's disease (PDB) and frontotemporal dementia (FTD). The presence of VCP mutations in patients with sporadic ALS, sporadic ALS-FTD, and progressive muscular atrophy (PMA), a known clinical mimic of inclusion body myopathy, is not known. To determine the identity and frequency of VCP mutations we screened a cohort of 93 familial ALS, 754 sporadic ALS, 58 sporadic ALS-FTD, and 264 progressive muscular atrophy patients for mutations in the VCP gene. Two nonsynonymous mutations were detected; 1 known mutation (p.R159H) in a patient with familial ALS with several family members suffering from FTD, and 1 mutation (p.I114V) in a patient with sporadic ALS. Conservation analysis and protein prediction software indicate the p.I114V mutation to be a rare benign polymorphism. VCP mutations are a rare cause of familial ALS. The role of VCP mutations in sporadic ALS, if present, appears limited.


Assuntos
Adenosina Trifosfatases/genética , Esclerose Lateral Amiotrófica/genética , Proteínas de Ciclo Celular/genética , Saúde da Família , Predisposição Genética para Doença/genética , Mutação/genética , Esclerose Lateral Amiotrófica/classificação , Biologia Computacional , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Proteína com Valosina
15.
Nat Rev Neurol ; 8(1): 48-58, 2011 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-22105211

RESUMO

Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.


Assuntos
Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/fisiopatologia , Polineuropatias/diagnóstico , Polineuropatias/fisiopatologia , Humanos , Doença dos Neurônios Motores/terapia , Polineuropatias/terapia
16.
J Peripher Nerv Syst ; 16(3): 175-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22003931

RESUMO

The contribution of genetic heterogeneity to the pathogenesis of multifocal motor neuropathy (MMN) has not been elucidated. We investigated frequencies of single nucleotide polymorphisms (SNPs) in the candidate genes protein tyrosine phosphatase, non-receptor type 22 (PTPN22), B-cell scaffold protein with ankyrin repeats (BANK1), B lymphocyte kinase (Blk), and Fc gamma receptor class IIB (FCGR2B), which have been found to be associated with other autoimmune diseases, CD1A and CD1E, important for antigen presentation of glycolipids, and transient axonal glycoprotein 1 (TAG-1), which is associated with responsiveness to intravenous immunoglobulin in patients with chronic inflammatory demyelinating polyneuropathy. SNP frequencies were determined by means of TaqMan SNP genotyping assay and direct sequencing of candidate genes in 92 Dutch patients with MMN and 1152 healthy controls. SNP frequencies did not differ between patients and controls (all p-values >0.15) and disease characteristics were not associated with SNP genotypes. Our results suggest that allelic variation in these genes does not play a major role in determining MMN susceptibility.


Assuntos
Predisposição Genética para Doença/genética , Polineuropatias/genética , Polineuropatias/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Antígenos CD1/genética , Contactina 2/genética , Feminino , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Receptores de IgG/genética , Quinases da Família src/genética
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