Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied a patient with amyotrophic lateral sclerosis, multifocal motor conduction block, and IgM anti-GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes, and in some instances, they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve, the serum IgM bound to the nodes of Ranvier, and the binding activity was removed by preincubation with GM1. These observations suggest that anti-GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve.
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PMID:IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block. 189 16

There is no generalized disturbance of accommodation of peripheral motor axons in amyotrophic lateral sclerosis. Local sites of reduced accommodation are found proximally and distally with apparent correlation to spontaneous fasciculation. The possible mechanism of fasciculation provoked by acetylcholine is discussed and it is suggested that the local sites of low accommodation represent nodal sprouts with growth cones in extra-muscular as well as intra-muscular parts of peripheral motor axons.
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PMID:Local sites of low accommodation of peripheral motor axons and the pathogenesis of fasciculation in amyotrophic lateral sclerosis. 336 54

Injury of afferent motor axons or pathological loss of motoneurones from the spinal cord causes the remaining axons within a muscle to sprout and to reinnervate the denervated muscle fibres. Sprouting occurs at two sites along intramuscular axons, at nodes of Ranvier (nodal sprouting) and at the neuromuscular junction (terminal sprouting). Terminal sprouting is also produced by treatment with botulinum toxin and by other agents that render muscle inactive. The muscle probably provides a signal for terminal sprouting as restoration of muscle activity by direct electrical stimulation prevents sprouting. Such a signal might be a local change on the muscle fibre surface or a 'soluble' sprouting factor, although the failure to induce terminal sprouting in one muscle by denervating adjacent muscles argues against the latter hypothesis. I now report that rabbit antisera against a 56,000 (56K)-molecular weight protein secreted by denervated rat muscle suppress botulinum toxin-induced terminal sprouting in the mouse gluteus muscle. An immune response against this protein has also been detected in serum of patients with amyotrophic lateral sclerosis (ALS), a disease in which loss of motoneurones from the spinal cord is not accompanied by the degree of sprouting and reinnervation seen in other motoneurone diseases.
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PMID:Suppression of sprouting at the neuromuscular junction by immune sera. 669 45

Myelinated fibres in femoral nerves removed from amyotrophic lateral sclerosis (ALS) cases at post mortem were compared with age matched controls. A technique for processing whole transverse sections of the nerves for osmication and subsequent morphometric analysis is described. Although areas depleted in myelinated fibres were seen in the nerves from the ALS group, no statistically significant difference was shown due to wide variations in the controls. However, the ALS nerves showed a degree of disruption in the myelin which was not apparent in the controls. The most obvious effect was widespread "wrinkling" of the myelin in both large and small fibres from the ALS nerves. This phenomenon is the initial stage of a process which eventually results in uneven myelin thickness and nodal swellings and finally myelin ovoids and balls. We illustrate the steps in the progression of this degeneration with teased nerve studies and electron microscopy and propose that there are qualitative changes in the myelin of peripheral nerve in ALS. It seems likely that these are secondary effects resulting from axonal degeneration caused by deterioration and loss of anterior horn cells in the spinal cord.
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PMID:Changes in the myelinated axons of femoral nerve in amyotrophic lateral sclerosis. 836 Jun 62

The time constants and rheobase currents are properties of axonal membrane and their calculation may shed light on axonal properties when taken in conjunction with examinations of axonal excitability. Using double cable models of human myelinated motor and sensory axons and of their three simulated types amyotrophic lateral sclerosis (termed as ALS1, ALS2 and ALS3, respectively), the time constants and rheobase currents (nodal/internodal) are calculated in the case of action potential propagation and in the case of a uniformly polarized fibre. A polynomial function of degree 2 (parabola), which relates threshold charge to stimulus duration, provides an accurate fit for the axon data. The results are consistent with the interpretation that the considerably different nodal/internodal time constants and nodal/internodal rheobase currents depend not only on the cable properties of the axons, as well as on the nodes, but on the methods of stimulation.
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PMID:Strength-duration properties of human myelinated motor and sensory axons in normal case and in amyotrophic lateral sclerosis. 1169 88

The extracellular potentials of human motor myelinated fibres in an unbounded volume conductor, in normal case and in amyotrophic lateral sclerosis (ALS) are studied. Using our previous double-cable models of the fibres, the spatial and temporal distributions of the intracellular potentials are obtained. The intracellular potentials are then used as input to a line source model that allows to calculate the corresponding spatial and temporal distributions of the extracellular potentials at various radial distances in the surrounding volume conductor. For the normal and ALS cases, the radial decline of the peak-to-peak amplitude of the extracellular potential depends on the radial distance of the field point and increases with the increase of the distance. For given radial distances, two cases of spatial distributions of the extracellular potentials are investigated: the first case, based on the intracellular potentials at the times of nodal potential maxima and the second case, based on the intracellular potentials at the time interval from 0.2 ms to 1.0 ms at increments of 0.1 ms. For the same radial distances, the temporal distributions of the extracellular potentials are also explored. It is shown that in the case of adaptation, the temporal distributions of the extracellular potentials in the normal and ALS cases correspond well with electromyograms (EMG) from healthy subjects and ALS patients as reported in the literature. Simulation results indicate that the used models are rather promising tools in studying the main properties of compound action potentials in ALS patients which up till now have not been sufficiently well understood.
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PMID:Extracellular potentials of human motor myelinated nerve fibers in normal case and in amyotrophic lateral sclerosis. 1239 19

The first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles are innervated by the same ulnar nerve, but studies have shown that the former is much more severely affected in amyotrophic lateral sclerosis. In this study, threshold tracking was used to investigate whether membrane properties differ between FDI and ADM motor axons. In 12 normal subjects, compound muscle action potentials were recorded from FDI and ADM after ulnar nerve stimulation at the wrist. The strength-duration time constant was significantly longer in the FDI axons than in the ADM axons, and latent addition studies showed greater threshold changes at the conditioning-test stimulus of 0.2 ms in FDI than in ADM axons. These findings suggest that nodal persistent sodium conductances are more prominent in FDI axons than in ADM axons, and therefore excitability is physiologically higher in FDI axons. Even in the same nerve at the same sites, membrane properties of FDI and ADM motor axons differ significantly, and thus their axonal/neuronal responses to disease may also differ.
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PMID:Differences in excitability properties of FDI and ADM motor axons. 1920 10

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.
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PMID:Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. 2210 11

Fasciculation is a characteristic feature of ALS. Nerve excitability studies have shown increased persistent sodium currents and reduced potassium currents in motor axons of ALS patients, both of which lead to axonal hyperexcitability and thereby generation of fasciculations. The present study was undertaken to investigate whether abnormal axonal excitability indices are correlated with survival in ALS patients. A total of 112 consecutive patients with sporadic ALS were followed-up until endpoint (death or tracheostomy). Univariate analyses revealed longer strength-duration time constant (SDTC) was associated with a shorter survival. In multivariate analyses using the Cox proportional hazard model, onset age>60 years and longer SDTC were strong predictors of shorter survival. Assuming that SDTC depends on nodal persistent sodium conductances, our results showed that an increased persistent sodium current is strong and independent predictor for short survival of ALS patients. These findings support the hypothesis that membrane hyperexcitability would contribute to motor neuronal death in ALS.
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PMID:[Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis]. 2227 2

Electrotonic potentials allow the accommodative processes to polarizing stimuli to be assessed. Electrotonic potential transients in response to applied polarizing stimuli are caused by the kinetics of underlying axonal conductances. Here, we study these transients using our multi-layered model of the human motor nerve, in three simulated cases of the motor neuron disease amyotrophic lateral sclerosis (ALS): ALS1, ALS2 and ALS3 are three consecutively greater degrees of uniform axonal dysfunctions along the human motor nerve fibre. The results show that the responses in the ALS1 case are quite similar to the normal case. In contrast, in the ALS2 and ALS3 cases, long-lasting (100 ms) subthreshold depolarizing stimuli activate the classical "transient" Na(+) channels in the nodal and in the internodal axolemma beneath the myelin sheath; this leads to action potential generation during the early parts of the electrotonic responses in all compartments along the fibre length. The results also show that the electrotonic potentials in response to long-lasting (100 ms) subthreshold hyperpolarizing stimuli in the ALS1 and ALS2 cases are quiet similar to those of the normal case. However, the current kinetics in the ALS3 case differs from the normal case after the termination of the long-lasting hyperpolarizing stimuli. In the most abnormal ALS3 case, the activation of the Na(+) channels in the nodal and in the internodal axolemma leads to repetitive action potential generation in the late parts (100-200 ms) of the hyperpolarizing electrotonic responses. The results show that the repetitive firing, due to the progressively increased nodal and internodal ion channel dysfunction, are consistent with the loss of functional potassium channels involving both the fast and the slow potassium channel types. The results confirm that the electrotonic potentials in the three simulated ALS cases are specific indicators for the motor neuron disease ALS. The mechanisms underlying the simulated ALS are also discussed.
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PMID:Mechanisms defining the electrotonic potential abnormalities in simulated amyotrophic lateral sclerosis. 2274 22


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