RESUMO
BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075.
Assuntos
Doença de Charcot-Marie-Tooth/classificação , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ciclo Celular , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Conexinas/genética , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Masculino , Proteínas Mitocondriais/genética , Mutação/genética , Proteína P0 da Mielina/genética , Proteínas da Mielina/genética , Proteínas Nucleares , Proteínas/genética , Proteína beta-1 de Junções ComunicantesRESUMO
Mutations or rearrangements in the gene encoding the receptor tyrosine kinase RET result in Hirschsprung disease, cancer and renal malformations. The standard model of renal development involves reciprocal signaling between the ureteric bud epithelium, inducing metanephric mesenchyme to differentiate into nephrons, and metanephric mesenchyme, inducing the ureteric bud to grow and branch. RET and GDNF (a RET ligand) are essential mediators of these epithelial-mesenchymal interactions. Vitamin A deficiency has been associated with widespread embryonic abnormalities, including renal malformations. The vitamin A signal is transduced by nuclear retinoic acid receptors (RARs). We previously showed that two RAR genes, Rara and Rarb2, were colocalized in stromal mesenchyme, a third renal cell type, where their deletion led to altered stromal cell patterning, impaired ureteric bud growth and downregulation of Ret in the ureteric bud. Here we demonstrate that forced expression of Ret in mice deficient for both Rara and Rarb2 (Rara(-/-)Rarb2(-/-)) genetically rescues renal development, restoring ureteric bud growth and stromal cell patterning. Our studies indicate the presence of a new reciprocal signaling loop between the ureteric bud epithelium and the stromal mesenchyme, dependent on Ret and vitamin A. In the first part of the loop, vitamin-A-dependent signals secreted by stromal cells control Ret expression in the ureteric bud. In the second part of the loop, ureteric bud signals dependent on Ret control stromal cell patterning.
Assuntos
Proteínas de Drosophila , Epitélio/efeitos dos fármacos , Rim/embriologia , Mesoderma/efeitos dos fármacos , Vitamina A/farmacologia , Animais , Epitélio/metabolismo , Feminino , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial , Hibridização In Situ , Rim/anormalidades , Rim/efeitos dos fármacos , Rim/metabolismo , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Camundongos Transgênicos , Morfogênese/efeitos dos fármacos , Mutação , Técnicas de Cultura de Órgãos , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas c-ret , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases , Transdução de Sinais/efeitos dos fármacos , Vitamina A/administração & dosagem , Vitamina A/genética , Deficiência de Vitamina A/genética , Deficiência de Vitamina A/fisiopatologiaRESUMO
BACKGROUND: Charcot Marie Tooth disease (CMT) affects one in 2500 people. Genetic testing is often pursued for family planning purposes, natural history studies and for entry into clinical trials. However, identifying the genetic cause of CMT can be expensive and confusing to patients and physicians due to locus heterogeneity. METHODS: We analyzed data from more than 1000 of our patients to identify distinguishing features in various subtypes of CMT. Data from clinical phenotypes, neurophysiology, family history, and prevalence was combined to create algorithms that can be used to direct genetic testing for patients with CMT. FINDINGS: The largest group of patients in our clinic have slow motor nerve conduction velocities (MNCV) in the upper extremities. Approximately 88% of patients in this group have CMT1A. Those who had intermediate MNCV had primarily CMT1X (52.8%) or CMT1B (27.8%). Patients with very slow MNCV and delayed walking were very likely to have CMT1A (68%) or CMT1B (32%). No patients with CMT1B and very slow MNCV walked before 15 months of age. Patients with CMT2A form our largest group of patients with axonal forms of CMT. INTERPRETATION: Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we created a series of algorithms to guide testing. A more detailed review of this data is published in Annals of Neurology (1).
Assuntos
Administração de Caso/organização & administração , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Testes Genéticos/métodos , Condução Nervosa , Extremidade Superior , Idade de Início , Algoritmos , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Eletrodiagnóstico , Testes Genéticos/normas , Testes Genéticos/estatística & dados numéricos , Humanos , Padrões de Herança , Neurônios Motores/patologia , Seleção de Pacientes , Linhagem , Guias de Prática Clínica como Assunto/normas , Prevalência , Índice de Gravidade de Doença , Extremidade Superior/inervação , Extremidade Superior/fisiopatologiaRESUMO
Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell typespecific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.
Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Glicina-tRNA Ligase/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Estresse Fisiológico , Tirosina-tRNA Ligase/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Modelos Animais de Doenças , Feminino , Deleção de Genes , Genes Dominantes , Glicina-tRNA Ligase/genética , Masculino , Camundongos , Camundongos Mutantes , Neurônios Motores/fisiologia , Biossíntese de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Medula Espinal/fisiopatologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Transcriptoma , Tirosina-tRNA Ligase/genéticaRESUMO
There has been considerable progress in developing treatments for Charcot-Marie-Tooth disease with a number of therapies either completing or nearing clinical trials. In the case of CMT1A, the commonest subtype of CMT, there have been more than five randomised, double blind placebo-controlled trials. Although these trials were negative for the primary outcome measure, considerable lessons have been learnt leading to the collection of large prospective natural history data sets with which to inform future trial design as well as the development of new and sensitive outcome measures. In this review we summarise the difficulties of conducting clinical trials in a slowly progressive disease such as CMT1A and the requirement for sensitive, reproducible and clinically relevant outcome measures. We summarise the current array of CMT specific outcome measures subdivided into clinical outcome measures, functional outcome measures, patient reported outcome measures, biomarkers of disease burden and treatment specific biomarkers of target engagement. Although there is now an array of CMT specific outcome measures, which collectively incorporate clinically relevant, sensitive and reproducible outputs, a single outcome measure incorporating all three qualities remains elusive.
Assuntos
Doença de Charcot-Marie-Tooth/terapia , Ensaios Clínicos como Assunto , Avaliação de Resultados em Cuidados de Saúde , Biomarcadores/análise , HumanosRESUMO
The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot-Marie-Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has revolutionised our understanding of the peripheral nervous system and allowed the development of rational approaches to therapy. The first therapeutic trials in CMT are currently underway. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.
Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/terapia , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/terapia , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/terapia , Terapia Genética , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatia Hereditária Motora e Sensorial/classificação , Neuropatia Hereditária Motora e Sensorial/genéticaRESUMO
Mutations in P0 (MPZ), the major myelin protein of the peripheral nervous system, cause the inherited demyelinating neuropathy Charcot-Marie-Tooth disease type 1B. P0 is a member of the immunoglobulin superfamily and functions as a homophilic adhesion molecule. We now show that point mutations in the cytoplasmic domain that modify a PKC target motif (RSTK) or an adjacent serine residue abolish P0 adhesion function and can cause peripheral neuropathy in humans. Consistent with these data, PKCalpha along with the PKC binding protein RACK1 are immunoprecipitated with wild-type P0, and inhibition of PKC activity abolishes P0-mediated adhesion. Point mutations in the RSTK target site that abolish adhesion do not alter the association of PKC with P0; however, deletion of a 14 amino acid region, which includes the RSTK motif, does abolish the association. Thus, the interaction of PKCalpha with the cytoplasmic domain of P0 is independent of specific target residues but is dependent on a nearby sequence. We conclude that PKC-mediated phosphorylation of specific residues within the cytoplasmic domain of P0 is necessary for P0-mediated adhesion, and alteration of this process can cause demyelinating neuropathy in humans.
Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Proteína P0 da Mielina/metabolismo , Proteína Quinase C/metabolismo , Sequência de Aminoácidos , Aminoácidos , Animais , Sítios de Ligação , Adesão Celular/fisiologia , Doença de Charcot-Marie-Tooth/genética , Citoplasma/metabolismo , Doenças Desmielinizantes , Células HeLa , Humanos , Isoenzimas/metabolismo , Células L , Camundongos , Dados de Sequência Molecular , Proteína P0 da Mielina/genética , Proteína P0 da Mielina/fisiologia , Peptídeos/metabolismo , Fosforilação , Proteína Quinase C-alfa , Receptores de Quinase C Ativada , Deleção de SequênciaRESUMO
Mutations of myelin protein zero gene (MPZ) are found in 5% of Charcot-Marie-Tooth patients. In 2004, Shy et al. identified two main phenotypes associated with them: an early-onset subtype with mainly demyelinating features and a late-onset subgroup with prominent axonal impairment. We evaluated whether novel MPZ mutations described in literature during the last 14 years could still fit with this classification. We collected and revised reports of 69 novel MPZ mutations. Almost 90% of them could be alternatively classified as responsible for: (a) an early-onset phenotype, with first limitations starting before 3 years (2.5 ± 0.50 years), motor milestones delays, frequently severe course and upper limb MNCVs below 15 m/s; (b) late-onset neuropathy, with mean age of onset of 42.8 ± 1.5 years and mean upper limbs motor nerve conduction velocities (MNCVs) of 47.2 ± 1.4 m/s; (c) a phenotype more similar to typical CMT1A neuropathy, with onset during the 2nd decade, MNCV in the range of 15-30 m/s and slowly progressive course. The present work confirms that P0-related neuropathies may be separated into two main distinct phenotypes, while a third, relatively small, group comprehend patients carrying MPZ mutations and a childhood-onset disease, substantiating the subdivision into three groups proposed by Sanmaneechai et al. (Brain 138:3180-3192, 2015). Interestingly, during the last years, an increasing number of novel MPZ mutations causing a late-onset phenotype has been described, highlighting the clinical relevance of late-onset P0 neuropathies. Since the family history for neuropathy is often uncertain, due to the late disease onset, the number of patients carrying this genotype is probably underestimated.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Proteína P0 da Mielina/genética , Idade de Início , Humanos , Mutação , FenótipoRESUMO
Alternative products of the proteolipid protein gene (PLP), proteolipid protein (PLP) and DM20, are major components of compact myelin in the central nervous system, but quantitatively minor constituents of Schwann cells. A family with a null allele of PLP has a less severe CNS phenotype than those with other types of PLP mutations. Moreover, individuals with PLP null mutations have a demyelinating peripheral neuropathy, not seen with other PLP mutations of humans or animals. Direct analysis of normal peripheral nerve demonstrates that PLP is localized to compact myelin. This and the clinical and pathologic observations of the PLP null phenotype indicate that PLP/DM20 is necessary for proper myelin function both in the central and peripheral nervous systems.
Assuntos
Sistema Nervoso Central/metabolismo , Córtex Cerebral/patologia , Doenças Desmielinizantes/genética , Proteínas da Mielina/metabolismo , Proteína Proteolipídica de Mielina/genética , Sistema Nervoso Periférico/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Doenças Desmielinizantes/metabolismo , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Proteínas da Mielina/fisiologia , Proteína Proteolipídica de Mielina/fisiologia , LinhagemRESUMO
Charcot-Marie-Tooth disease type 1A (CMT1A) is the more frequent cause of demyelinating CMT, and CMT2A is the most common cause of axonal CMT. We conducted a magnetic resonance imaging (MRI) study on 39 CMT1A and 21 CMT2A patients to compare their neuroimaging patterns and correlate with clinical features. CMT1A patients showed selective fatty infiltration with a preference for anterior and lateral compartment muscles, whereas CMT2A patients showed a preference for superficial posterior compartment muscles. Early-onset CMT2A patients showed more severe leg fatty atrophy than late-onset CMT2A patients. In late-onset CMT2A, soleus muscle was the earliest, and most severely affected than the other leg muscles. Selective involvement of intrinsic foot muscles is a characteristic pattern of minimal CMT1A and CMT2A. Our MRI study demonstrates different patterns of fatty infiltration involving superficial posterior compartment muscles in CMT2A (partial T-type), and peroneal nerve innervated muscles in CMT1A (P-type).
Assuntos
Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/patologia , Tecido Adiposo/patologia , Adolescente , Adulto , Idade de Início , Idoso , Atrofia , Doença de Charcot-Marie-Tooth/genética , Criança , Pré-Escolar , DNA/genética , Edema/patologia , Feminino , Pé/patologia , Duplicação Gênica , Humanos , Extremidade Inferior/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Força Muscular/genética , Força Muscular/fisiologia , Músculo Esquelético/patologia , Mutação/genética , Mutação/fisiologiaRESUMO
In a previous report, we demonstrated that a first-generation (E1- and E3-deleted) recombinant adenovirus can transduce expression of the E. coli lacZ gene into Schwann cells, both in vitro and in vivo, suggesting that this method might be useful for future therapy of peripheral neuropathy, including CMT1. Adenovirus-mediated gene transfer was limited, however, by demyelination and Wallerian degeneration at the site of virus injection, as well as by attenuation of viral transgene expression over time. In our current work we have optimized adenoviral vector-mediated transgene expression after intraneural injection into sciatic nerve. Using an improved injection protocol, peak expression of lacZ occurs between 10 and 14 days after injection of 2-week-old rats, decreases thereafter, and there is minimal associated tissue injury. In contrast, few lacZ-expressing Schwann cells are found in nerve of adult animals 10 days after injection, probably owing to immune clearance of virus-infected cells. Consistent with this notion, high levels of LacZ are found in sciatic nerve 30 days after injection of adult SCID mice, which have a genetic defect in both cellular and humoral immunity, of adult beta2-microglobulin-deficient mice (beta2M4-/-), which have a genetic defect in cellular immunity, or of adult mice treated with the immunosuppressing agent FK506. In addition, adenovirus-infected Schwann cells cocultured with axons in vitro, in the absence of a host immune response, ensheathe axons and express lacZ for at least 8 weeks. These data thus demonstrate that lacZ transgene expression of first-generation recombinant adenovirus in sciatic nerve in adult mice, as in other tissues, is limited mainly by the host cellular immune response to the virus, which can be overcome by attenuation of host cell-mediated immunity. Adenoviral vectors might thus be used to modulate Schwann cell gene expression in patients with peripheral neuropathy after appropriate immunosuppression.
Assuntos
Técnicas de Transferência de Genes , Imunidade Celular/fisiologia , Nervo Isquiático/metabolismo , Adenoviridae/genética , Fatores Etários , Animais , Compostos Azo/metabolismo , Southern Blotting , Corantes/metabolismo , Primers do DNA , Vetores Genéticos , Imuno-Histoquímica , Imunossupressores/farmacologia , Óperon Lac , Medições Luminescentes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Naftalenos , Plasmídeos , Ratos , Ratos Sprague-Dawley , Células de Schwann/citologia , Células de Schwann/metabolismo , Nervo Isquiático/anatomia & histologia , Tacrolimo/farmacologia , Fatores de Tempo , beta-Galactosidase/metabolismoRESUMO
Demyelinating peripheral neuropathies are clinically divided into inherited and acquired types. Inherited demyelinating neuropathies are caused by mutations in genes expressed by myelinating Schwann cells, whereas acquired ones, including chronic inflammatory demyelinating polyneuropathy (CIDP), are probably caused by autoimmune mechanisms. We find that heterozygous P0 knockout (P0+/-) mice develop a neuropathy that resembles CIDP. By one year of age, P0+/- mice develop severe, asymmetric slowing of motor nerves, with temporal dispersion or conduction block, which are features of acquired demyelinating neuropathies including CIDP. Moreover, morphological analysis of affected nerves reveals severe and selective demyelination of motor fibers, focal regions of demyelination, and inflammatory cells. These data suggest that immune-mediated mechanisms may contribute to the pathogenesis of the neuropathy in P0+/- mice.
Assuntos
Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Camundongos Knockout/genética , Potenciais de Ação , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Doença Crônica , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/fisiopatologia , Inflamação/patologia , Camundongos , Condução Nervosa , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Fatores de TempoRESUMO
We have reported that immortalized Schwann cells (SC) express the insulin-like growth factor I receptor and IGF-binding protein-5 (IGFBP-5). IGF-I promotes SC survival and protects IGFBP-5 in SC-conditioned medium from proteolysis. In the current study we examined the roles of IGF-I and IGFBP-5 in primary SC. IGF-I enhances primary SC differentiation and gene and protein expression of IGFBP-5 and the myelinating protein, P0. SC that stably overexpress human IGFBP-5 also have higher levels of P0 gene expression. The phosphatidylinositol-3 kinase inhibitor (LY294002), but not the mitogen-activated protein kinase kinase inhibitor (PD98059), blocks IGF-I enhancement of IGFBP-5 gene and protein expression. Collectively, these results suggest that IGF-I promotes SC differentiation, and this may occur in part by enhancing IGFBP-5 expression via phosphatidylinositol-3 kinase activation. These data support a link between enhanced IGFBP-5 expression and cellular differentiation.
Assuntos
Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Células de Schwann/citologia , Células de Schwann/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Proteína P0 da Mielina/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologiaRESUMO
In 1885, Pelizaeus described 5 boys in a single family with nystagmus, spastic quadriparesis, ataxia, and delay in cognitive development. In 1910, Merzbacher reexamined this family, which then included 14 affected individuals, including 2 girls, and found that all affected family members shared a common female ancestor. Also, he noted that the disease was passed exclusively through the female line without male-to-male transmission. Pathological analysis of brain tissue from one affected individual showed that most of the central white matter lacked histochemical staining for myelin, although there were occasional small regions of preserved myelin, giving the sections a "tigroid" appearance. The description of this family provides the clinical, genetic, and pathological basis for Pelizaeus-Merzbacher disease (PMD): an X-linked disorder of myelination classically characterized by nystagmus, spastic quadriparesis, ataxia, and cognitive delay in early childhood.
Assuntos
Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/etiologia , Doença de Pelizaeus-Merzbacher/genética , Sequência de Aminoácidos , Humanos , Dados de Sequência MolecularRESUMO
Patients with motor neuron disease with thyroid disorders have been described, although the relationship between the two conditions is unclear. We treated a patient with amyotrophic lateral sclerosis who also had a follicular adenoma of the thyroid gland. Because thyroid gland plasma membranes contain high concentrations of complex gangliosides, such as GD1b, and some patients with motor neuron disease have IgM antibodies to GD1b, we decided to assay serum from this patient for the presence of antiganglioside antibodies. IgM antibodies to GD1b were detectable at serum dilutions of 1:500 and 1:1000 by enzyme-linked immunosorbent assay. While these titers are less than those usually described in patients with plasma cell dyscrasia, they are well in excess of normal values. Antibody to GM1 was also detectable at a lower (1:100) dilution. We do not know the importance of the anti-GD1b antibodies in this patient, but it is possible that antibodies to GD1b are involved in this and other cases of motor neuron disease associated with thyroid disease.
Assuntos
Adenoma/imunologia , Esclerose Lateral Amiotrófica/imunologia , Anticorpos/análise , Gangliosídeos/imunologia , Neoplasias da Glândula Tireoide/imunologia , Adenoma/complicações , Esclerose Lateral Amiotrófica/complicações , Gangliosídeo G(M1)/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/complicaçõesRESUMO
Filter bandpass characteristics are important elements in all modalities of evoked potential recordings. We studied the brainstem auditory evoked potentials by changing the bandpass of the recording system between 150 to 1500 Hz and 150 to 3000 Hz. The 150- to 1500-Hz bandpass prolonged the absolute latencies of the various waves, whereas the interpeak latencies (I to III, IIII to V, III to IV/V, I to V, or I to IV/V) were not significantly altered. The 150- to 1500-Hz filter reduced notched or multipeaked wave forms by decreasing the raw high-frequency input activity.
Assuntos
Tronco Encefálico/fisiologia , Potenciais Evocados Auditivos , Adulto , Feminino , Filtração/instrumentação , HumanosRESUMO
We report three patients who developed chronic inflammatory demyelinating polyneuropathy (CIDP) in association with malignant melanoma. In two cases, melanoma was discovered during the initial evaluation for neuropathy. Two patients also had vitiligo, an antibody-mediated disorder that may complicate melanoma. Melanoma cells and Schwann cells are both of neuroectodermal cell origin, with shared surface antigens. Shared immunoreactivity may account for the association between melanoma and CIDP, as with vitiligo.
Assuntos
Doenças Desmielinizantes/complicações , Doenças Linfáticas/complicações , Melanoma/complicações , Doenças do Sistema Nervoso Periférico/complicações , Adulto , Doença Crônica , Humanos , Linfonodos/patologia , Doenças Linfáticas/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Vitiligo/complicaçõesRESUMO
IgM lambda monoclonal antibodies in two patients with motor neuron disease showed the same unique antigenic specificity. They bound to gangliosides GM1 and GD1b and to lacto-N-tetraose-BSA. By immunofluorescence microscopy they bound to central and peripheral nerve tissue and to motor end-plates at the neuromuscular junction. Sera from control subjects did not contain antibodies of similar specificity. Monoclonal IgMs with the same unique specificity could be responsible for motor neuron disease in some patients with monoclonal gammopathies.
Assuntos
Anticorpos Monoclonais/imunologia , Gangliosídeos/imunologia , Imunoglobulina M/imunologia , Neurônios Motores , Doenças Neuromusculares/enzimologia , Oligossacarídeos/imunologia , Autoanticorpos/imunologia , Epitopos , Feminino , Imunofluorescência , Gangliosídeo G(M1)/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Tecido Nervoso/imunologiaRESUMO
We followed a patient with a lower motor neuron form of motor neuron disease whose neurologic disorder improved following immunotherapy. The patient did not have an M protein but did have IgM antibodies to ganglioside GM1 detectable at serum titers of 1:2,000 by ELISA. These antibodies were found only in the IgM fraction with lambda light chains and immunoreacted with GD1b and Gal (beta 1-3) GalNAc.