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)

DNA from seven unrelated patients with hyperkalemic periodic paralysis (HYPP) was examined for mutations in the adult skeletal muscle sodium channel gene (SCN4A) known to be genetically linked to the disorder. Single-strand conformation polymorphism analysis revealed aberrant bands that were unique to three of these seven patients. All three had prominent fixed muscle weakness, while the remaining four did not. Sequencing the aberrant bands demonstrated the same C to T transition in all three unrelated patients, predicting substitution of a highly conserved threonine residue with a methionine in a membrane-spanning segment of this sodium channel protein. The observation of a distinct mutation that cosegregates with HYPP in two families and appears as a de novo mutation in a third establishes SCN4A as the HYPP gene. Furthermore, this mutation is associated with a form of HYPP in which fixed muscle weakness is seen.
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PMID:Identification of a mutation in the gene causing hyperkalemic periodic paralysis. 165 48

Paramyotonia congenita (PC), an autosomal dominant non-progressive muscle disorder, is characterised by cold-induced stiffness followed by muscle weakness. The weakness is caused by a dysfunction of the sodium channel in muscle fibre. Parts of the gene coding for the alpha-subunit of the sodium channel of the adult human skeletal muscle (SCN4A) have been localised on chromosome 17. To investigate the role of this gene in the etiology of PC, a linkage analysis in 17 well-defined families was carried out. The results (zeta = 20.61, theta = 0.001) show that the mutant gene responsible for the disorder is indeed tightly linked to the SCN4A gene. The mutation causing hyperkalemic periodic paralysis (HyperPP) with myotonia has previously been mapped to this gene locus by the same candidate gene approach. Thus, our data suggest that PC and HyperPP are caused by allelic mutations at a single locus on chromosome 17.
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PMID:Linkage data suggesting allelic heterogeneity for paramyotonia congenita and hyperkalemic periodic paralysis on chromosome 17. 166 29

The periodic paralyses are a group of autosomal dominant muscle diseases sharing the common feature of episodic stiffness and weakness, usually occurring with muscle cooling (as in the case of paramyotonia congenita, PC phenotype) or changes in extracellular K+ levels resulting from various precipitating factors (hyperkalemic periodic paralysis, HYPP and hypokalemic periodic paralysis, HypoPP). It is now known that HYPP maps to chromosome 17q, and that PC and a form of myotonia congenita without periodic paralysis also map to the 17q locus, thus indicating that they derive from allelic variants. So far, these disorders have been described in various ethnic groups but, to our knowledge, have never been reported in Italy. We describe a mutation in an S4 segment of the adult skeletal muscle sodium channel in a clinically-defined Italian family that leads to the paramyotonia congenita (PC) phenotype with dominant autosomal inheritance and temperature-related symptoms (regional weakness following cooling and exercise), present since childhood in all of the affected family members.
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PMID:Mutation in the S4 segment of the adult skeletal sodium channel gene in an Italian paramyotonia congenita (PC) family. 772 50

In vitro twitch tests were performed on excised muscle bundles from 30 periodic paralysis (PP) patients in an attempt to verify the somatic origin of PP, and to differentiate between the hypokalemic (HypoPP) and the hyperkalemic forms (HyperPP). Seventeen PP patients with a definite diagnosis of familial HypoPP, familial HyperPP (subsequently confirmed by SCN4A mutations), or thyrotoxic PP entered the study, as well as 13 patients with a history of attacks of weakness but with negative clinical provocation tests and therefore ambiguous diagnosis; 15 normal subjects served as controls. In contrast to control, bundles from patients with clear diagnosis went into sustained paralysis on exposure to Cl-free solution. Exposure to K+ channel activators induced a large increase in force. Specifically for HypoPP muscle, low extracellular [K+] decreased twitch force which was further reduced by addition of insulin or adrenaline, whereas HyperPP bundles responded with an irreversible decrease in twitch force when extracellular [K+] was elevated. Out of the 13 patients with unclear diagnosis, the in vitro studies made it possible to classify 10 as HypoPP and one as HypePP (later confirmed by a M1592V mutation). In the remaining two patients who claimed to suffer from paralytic attacks, all in vitro tests were normal, questioning the occurrence of dyskalemic PP. The results demonstrate that in vitro tests can be used to ensure the proper diagnosis to a high percentage when clinical provocative tests have failed.
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PMID:Differential diagnosis of periodic paralysis aided by in vitro myography. 776 90

Hyperkalemic periodic paralysis (hyperPP), paramyotonia congenita (PC) and PC with myotonia permanens are closely related muscle disorders of genetic origin due to allelic mutations in the muscle sodium channel gene, SCN4A. Seven families of French origin with hyperPP were studied. Five of these had the Thr704Met mutation, but 2 families, genetically linked to SCN4A, failed to show any of the known mutations of SCN4A. Correlations between the phenotype and the genotype were made for patients with the Thr704Met mutation. All 12 patients over 30 years old with the Thr704Met mutation presented muscle weakness due to degeneration of muscle fibers in addition to periodic paralysis. Only approximately 12.5% of patients with the Thr704Met mutation presented with clinical myotonia and about 50% with hyperkalemia. One family with PC displayed the Gly1306Val mutation with a phenotype similar to the one already reported for this mutation. Five families with either PC or PC with myotonia permanens had the Thr1313Met mutation indicating that the severity of myotonia and its permanence were variable. Two mutations of SCN4A were found to be predominant in these 13 families: the Thr704Met and the Thr1313Met mutations. Only 2 families with the Thr704Met mutation and 3 families with the Thr1313Met shared the same SCN4A haplotype determined with intragenic dinucleotide repeats. Recurrent mutations of SCN4A may contribute to the predominance of these two mutations in the French population.
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PMID:Mutations in the muscle sodium channel gene (SCN4A) in 13 French families with hyperkalemic periodic paralysis and paramyotonia congenita: phenotype to genotype correlations and demonstration of the predominance of two mutations. 804 56

A literature review of the clinical syndrome HYPP (Hyperkalemic periodic paralysis) affecting Quarter Horses is given. HYPP is characterized by sporadic attacks of muscle tremors, weakness and/or collapse, lasting for variable periods of time. Diagnosis is based on physical findings in association with hyperkalemia. In horses with HYPP, the regulation of ion transport through the sodium channels in the muscle cells occasionally fails, causing uncontrollable muscle twitching. Further investigations into molecular genetics reveals a mutation in the gene responsible for sodium and potassium regulation. The identification of this gene mutation is the basis for the blood test used to diagnose HYPP. HYPP is inherited as an autosomal dominant trait. Treatment of HYPP attacks by intravenous application of calcium gluconate, bicarbonate and glucose results in rapid recovery. Consequent dietary management and daily administration of acetazolamide effectively controls the disease.
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PMID:[HYPP--hyperkalemic periodic paralysis in horses]. 812 39

The single strand conformation polymorphism (SSCP) technique was used to screen genomic DNA of a family with myotonia aggravated by cold, potassium loading and suxamethonium, but without muscle weakness. An aberrant band was found in exon 24 of SCN4A, the gene encoding the adult skeletal muscle sodium channel alpha-subunit. DNA sequencing led to the detection of a G-to-A transition of cDNA nucleotide 4765 predicting a substitution of methionine for valine at position 1589 of the protein sequence. This amino acid is located within transmembrane segment S6 of channel repeat IV close to the cytoplasmic surface, a region which is supposed to act as acceptor of the inactivation gate of the channel. Four lines of evidence indicate that this mutation causes the disease: (i) the transition was only found for affected family members; (ii) no mutations were found in all other SCN4A exons; (iii) the affected gene region is conserved among various species; and (iv) an increase in the number of non-inactivating sodium channels had been revealed in earlier electrophysiological studies on an excised muscle specimen from the index patient. In addition, the close-by occurring substitution of valine for methionine at position 1592 known to cause hyperkalemic periodic paralysis was deduced for six families with the myotonic, non-dystrophic form of this disease.
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PMID:A novel SCN4A mutation causing myotonia aggravated by cold and potassium. 824 56

We report here a Japanese family with paramyotonia congenita. The proband was a 42-year-old woman (case 1), who noticed muscle stiffness and weakness in the cold since the age of 7 years. These symptoms were alleviated by warming. Her eldest son (case 2) also experienced similar symptoms, while her younger son and daughter were healthy. Neurological examination in case 1 revealed mild weakness in facial and neck muscles. Cold-induced muscle stiffness and weakness were present. Electromyography showed myotonic discharges, intensified by cooling or repetitive exercise. The amplitude of the compound muscle action potentials was also reduced by the repetitive exercise and cooling. Serum chemistry including potassium and CK was normal. Molecular analysis of SCN4A (exon22-24) by SSCP and nucleotide sequencing revealed a C-to-T transition at nucleotide 3,938, causing a substitution of 1313methionine of threonine in case 1. This mutation was confirmed by PCR-RFLP with a mismatched primer; the proband (case 1) and her eldest son (case 2) had a heterozygous mutation, while the other family members did not. This is the first report that a mutation in SCN4A was identified in a Japanese family with paramyotonia congenita.
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PMID:[A Japanese family with paramyotonia congenita which has a mutation in the muscle sodium channel gene]. 866 33

Linkage studies and mutation analysis were performed in two Swedish families with hyperkalemic periodic paralysis (HYPP), an autosomal dominant inherited disorder characterized by episodic muscle weakness associated with increasing or high levels of serum potassium. The gene for HYPP is the gene encoding the alpha-subunit of the sodium channel of adult human skeletal muscle (SCN4A). SCN4A has been localized on chromosome 17 q closely linked to the human growth hormone gene. Linkage between a microsatellite polymorphism in the SCN4A gene and the disease was shown in two Swedish families (Z = 12.10 theta = 0). Sequence analysis revealed that the two Swedish families have got a C to T transition at position 2188 in the cDNA. At the protein level this Thr 704 to Met mutation is located in the fifth membrane spanning segment of domain II of the protein, as previously described (28). The mutation was linked to different microsatellite alleles regarding both a (GT)n and a (GA)n repeat in the gene. Either the families are related and new mutations have occurred in both microsatellites when the pedigrees were separated or the mutation has arisen independently in the two families analysed. From the mutant alleles characterized so far it seems as if a limited number of mutations is present in this gene.
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PMID:Hyperkalemic periodic paralysis caused by recurring mutation in the adult muscle sodium channel alpha-subunit gene. 898 30

We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed in medical records. Molecular examination of genomic DNA showed no expansion of the unstable (CTG)n trinucleotide repeat on chromosome 19q13.3 associated with myotonic dystrophy (DM). Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCN1) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded. The clinical findings differ from those described in proximal myotonic myopathy (PROMM), in terms of the more severe muscle involvement with atrophy of affected muscles and the hearing loss. These findings suggest phenotypic and probably genetic heterogeneity among the proximal myotonic syndromes.
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PMID:Proximal myotonic dystrophy--a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? 919 2


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