Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper reports the results achieved in the treatment of trigeminal neuralgia using two different percutaneous procedures: radiofrequency (RF) thermocoagulation (33 patients) and the new percutaneous microcompression (PMC; 74 patients) of the trigeminal ganglion. Acute pain relief was accomplished in 93.2% of the patients treated with PMC and in 81.8% of those treated with the RF method. Two years after the operation, neuralgia had recurred in 56% of the PMC patients and in 42.4% of the RF patients. The average recurrence time was 6.5 months after PMC and 18.5 months after RF. Side effects were essentially of 2 kinds: marked dysaesthesia that occurred after RF lesion in 24.2% and after PMC in 6.7% of the patients, and weakness of the masticatory muscles that was fairly common after PMC, although clinically relevant in only 1 case. The procedure has the benefit of simplicity and fewer side effects. The results obtained by using different compression times in different patients indicates that the most suitable compression time is between 4 and 6 min. When pain recurred the procedure was repeated unless the pain was in the third division, in which case an RF lesion was made. If the pain recurred a second time, RF lesions were made if the pain was in the second or third division.
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PMID:Percutaneous procedures for trigeminal neuralgia: microcompression versus radiofrequency thermocoagulation. Personal experience. 278 67

A Swedish family with Paramyotonia congenita (Eulenburg) (PMC) is presented. Clinical neurological examination, neurophysiological examination (n = 5) and muscle biopsy (n = 4) were performed. Different clinical features were found in various combinations in the individual family members. The clinical symptoms were: (1) cold-induced myotonia, (2) attacks of weakness, (3) persistent weakness and (4) no symptoms but other signs of muscle affection. In the patients with myotonia, the neurophysiological examination showed spontaneous myotonic discharges which were frequent at room temperature but disappeared after cooling. Furthermore, the amplitude of M. abductor digiti minimi compound action potential, during supramaximal ulnar nerve stimulation, decreased significantly after cooling. In the patients with persistent weakness there were no spontaneous myotonic discharges, but myopathic abnormalities were found in proximal muscle. In the patients with myotonia as well as in the patients with manifest muscle weakness, muscle biopsy showed a variation of muscle fibre diameters, centrally located nuclei, occasional atrophic fibers and an atrophy of type IIB muscle fibres. These findings are unspecific but have been described in PMC patients in earlier studies. An ancestor to the family, who had myotonia, lived in the same town and at the same time as Albert Eulenburg, which may suggest that this family is a part of the originally described family (1).
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PMID:Paramyotonia congenita (Eulenburg): clinical, neurophysiological and muscle biopsy observations in a Swedish family. 842 9

Muscle weakness and aberrant responses to neuromuscular relaxants after burn injury are associated with upregulation of acetylcholine receptors (AChRs). Typically, these functional, pharmacological, and biochemical changes occur after denervation, in which transcriptionally mediated qualitative changes in AChRs and Na+ channels and of myogenic regulatory proteins MyoD and myogenin also occur. This study in rats, by an examination of changes in the above-enumerated proteins or their transcripts in the gastrocnemius muscle distant from the burn, verifies whether a denervation-like state exists after burns. Scatchard analysis of [3H]saxitoxin binding revealed no changes in the affinity (K(d)) and total number (B(max)) of Na+ channels between control and burn-injured animals at both 7 and 14 days after injury. The mRNA levels of the immature proteins, SkM2 of the Na+ channels and the gamma-subunits of AChRs, the increase of which is pathognomic of denervation, were assessed by Northern analysis and were unchanged. The transcripts of mature Na+ channels, SkM1, were significantly increased at day 14 after the burn (1.24 +/- 0.10 in burn-injured vs. 1.06 +/- 0.12 in sham animals, arbitrary units, P = 0.006). Although MyoD levels were increased in burn-injured animals at 14 days (0.21 +/- 0.02 vs. 0.15 +/- 0.07 arbitrary units, P = 0.05), myogenin levels were unaltered. The absence of changes in AChR transcripts, including alpha-, delta-, and gamma-subunits, indicates that the upregulation of AChR in burns is not transcriptionally mediated. The unaltered levels of transcripts of myogenin, SkM2 of Na+ channels and gamma-subunit of AChR, confirm that there is no denervation-like prejunctional (nerve-related) component to explain the muscle weakness or the upregulation of AChRs at sites distant from burns.
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PMID:Na+ channel and acetylcholine receptor changes in muscle at sites distant from burns do not simulate denervation. 910 73

Several heritable forms of myotonia and hyperkalemic periodic paralysis (HyperPP) are caused by missense mutations in the alpha subunit of the skeletal muscle Na channel (SkM1). These mutations impair fast inactivation or shift activation toward hyperpolarized potentials, inducing persistent Na currents that may cause muscle depolarization, myotonia, and onset of weakness. It has been proposed that the aberrant Na current and resulting weakness will be sustained only if Na channel slow inactivation is also impaired. We therefore measured slow inactivation for wild-type and five mutant Na channels constructed in the rat skeletal muscle isoform (rSkM1) and expressed in HEK cells. Two common HyperPP mutations (T698M in domain II-S5 and M1585V in IV-S6) had defective slow inactivation. This defect reduced use-dependent inhibition of Na currents elicited during 50-Hz stimulation. A rare HyperPP mutation (M1353V in IV-S1) and mutations within the domain III-IV linker that cause myotonia (G1299E) or myotonia plus weakness (T1306M) did not impair slow inactivation. We also observed that slow inactivation of wild-type rSkM1 was incomplete; therefore it is possible that stable membrane depolarization and subsequent muscle weakness may be caused solely by defects in fast inactivation or activation. Model simulations showed that abnormal slow inactivation, although not required for expression of a paralytic phenotype, may accentuate muscle membrane depolarization, paralysis, and sensitivity to hyperkalemia.
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PMID:Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis. 913 67

Genetic analysis of the adult muscle sodium channel alpha-subunit, SCN4A gene on chromosome 17q, was performed by means of PCR technique in a Swedish family with paramyotonia congenita (Eulenburg) (PMC). The mutation was found in four family members and consisted of a C to T transition affecting the fourth domain of the sodium channel protein. This mutation has earlier been described in other families with paramyotonia congenita. All family members carrying the mutation had cold-induced paradoxical myotonia, myotonic bursts on EMG, and a type IIB atrophy on muscle biopsy. Three of them had slight CK elevation and two had episodes of paralysis. On the basis of clinical findings in this family, persistent proximal muscle weakness, myopathic EMG abnormalities, a type IIB atrophy on muscle biopsy and no symptoms but other signs of muscle affection, were earlier suggested as clinical features of PMC. However, genetic analysis revealed that family members with these symptoms and findings did not have the mutation, indicating that these features are not due to PMC.
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PMID:C4342T-mutation in the SCN4A gene on chromosome 17q in a Swedish family with paramyotonia congenita (Eulenburg)--correlations with clinical, neurophysiological and muscle biopsy data. 919 4

The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor. In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672-->His and -->Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel alpha subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers from a patient heterozygous for Arg-672-->Gly displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wild-type channel population only. Heterologous expression of the two sodium channel mutations revealed a 10-mV left shift of the steady-state fast inactivation curve enhancing inactivation and a sodium current density that was reduced even at potentials at which inactivation was removed. Decreased current and small action potentials suggested a low channel protein density. The alterations are decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels particularly at sustained membrane depolarization. The results prove that SCN4A, the gene encoding the sodium channel alpha subunit of skeletal muscle is responsible for HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease caused by enhanced channel inactivation and current reduction showing no myotonia.
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PMID:Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. 1095 43

In a myasthenic syndrome associated with fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth, nerve stimulation at physiologic rates rapidly decremented the compound muscle action potential. Intercostal muscle studies revealed no abnormality of the resting membrane potential, evoked quantal release, synaptic potentials, acetylcholine receptor channel kinetics, or endplate ultrastructure, but endplate potentials depolarizing the resting potential to -40 mV failed to excite action potentials. Pursuing this clue, we sequenced SCN4A encoding the skeletal muscle sodium channel (Nav1.4) and detected two heteroallelic mutations involving conserved residues not present in 400 normal alleles: S246L in the S4/S5 cytoplasmic linker in domain I, and V1442E in the S3/S4 extracellular linker in domain IV. The genetically engineered V1442E-Na channel expressed in HEK cells shows marked enhancement of fast inactivation close to the resting potential, and enhanced use-dependent inactivation on high-frequency stimulation; S246L is likely a benign polymorphism. The V1442E mutation in SCN4A defines a novel disease mechanism and a novel phenotype with myasthenic features.
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PMID:Myasthenic syndrome caused by mutation of the SCN4A sodium channel. 1276 26

Critical illness myopathy (CIM) is the most common caused of acquired weakness in critically ill patients. While atrophy of muscle fibers causes weakness, the primary cause of acute weakness is loss of muscle excitability. Studies in an animal model of CIM suggest that both depolarization of the resting potential and a hyperpolarized shift in the voltage dependence of sodium channel gating combine to cause inexcitability. In active adult skeletal muscle the only sodium channel isoform expressed is Nav1.4. In the animal model of CIM the Nav1.5 sodium channel isoform is upregulated, but the majority of sodium current is still carried by Nav1.4 sodium channels. Experiments using toxins to selectively bock the Nav1.4 isoform demonstrated that the cause of the hyperpolarized shift in sodium channel inactivation is a hyperpolarized shift in inactivation of the Nav1.4 isoform. These data suggest that CIM represents a new type of ion channel disease in which altered gating of sodium channels is due to improper regulation of the channels rather than mutation of channels or changes in isoform expression. The hypothesis that dysregulation of sodium channel gating underlies inexcitability of skeletal muscle in CIM raises the possibility that there maybe dysregulation of sodium channel gating in other tissues in critically ill patients. We propose that there is a syndrome of reduced electrical excitability in critically ill patients that affects skeletal muscle, peripheral nerve, the heart and central nervous system. This syndrome manifests as CIM, critical illness polyneuropathy, reduced cardiac contractility and septic encephalopathy.
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PMID:Dysregulation of sodium channel gating in critical illness myopathy. 1687 52

Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed. Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.
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PMID:Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis. 1739 31

S4 voltage-sensor mutations in CaV1.1 and NaV1.4 channels cause the human muscle disorder hypokalemic periodic paralysis (HypoPP). The mechanism whereby these mutations predispose affected sarcolemma to attacks of sustained depolarization and loss of excitability is poorly understood. Recently, three HypoPP mutations in the domain II S4 segment of NaV1.4 were shown to create accessory ionic permeation pathways, presumably extending through the aqueous gating pore in which the S4 segment resides. However, there are several disparities between reported gating pore currents from different investigators, including differences in ionic selectivity and estimates of current amplitude, which in turn have important implications for the pathological relevance of these aberrant currents. To clarify the features of gating pore currents arising from different DIIS4 mutants, we recorded gating pore currents created by HypoPP missense mutations at position R666 in the rat isoform of Nav1.4 (the second arginine from the outside, at R672 in human NaV1.4). Extensive measurements were made for the index mutation, R666G, which created a gating pore that was permeable to K(+) and Na(+). This current had a markedly shallow slope conductance at hyperpolarized voltages and robust inward rectification, even when the ionic gradient strongly favored outward ionic flow. These characteristics were accounted for by a barrier model incorporating a voltage-gated permeation pathway with a single cation binding site oriented near the external surface of the electrical field. The amplitude of the R666G gating pore current was similar to the amplitude of a previously described proton-selective current flowing through the gating pore in rNaV1.4-R663H mutant channels. Currents with similar amplitude and cation selectivity were also observed in R666S and R666C mutant channels, while a proton-selective current was observed in R666H mutant channels. These results add support to the notion that HypoPP mutations share a common biophysical profile comprised of a low-amplitude inward current at the resting potential that may contribute to the pathological depolarization during attacks of weakness.
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PMID:Gating pore currents in DIIS4 mutations of NaV1.4 associated with periodic paralysis: saturation of ion flux and implications for disease pathogenesis. 1882 91


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