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

Hypokalaemic periodic paralysis (hypoPP) is a dominantly inherited muscle disorder characterized by episodes of flaccid weakness. Previous genetic studies revealed mutations in the voltage-gated calcium channel alpha1-subunit (CACNA1S gene) in families with hypoPP (type I). Electrophysiological studies on these mutants in different expression systems could not explain the pathophysiology of the disease. In addition, several mutations (Arg669His, Arg672His, Arg672Gly and Arg672Ser) in the voltage sensor of the skeletal muscle sodium channel alpha-subunit (SCN4A gene) have been found in families with hypoPP (type II). For Arg672Gly/His a fast inactivation defect was described, and for Arg669His an impairment of slow inactivation was reported. Except for the substitution for serine, we have now expressed all mutants in a human cell-line and studied them electrophysiologically. Patch-clamp recordings show an enhanced fast inactivation for all three mutations, whereas two of them reveal enhanced slow inactivation. This may reduce the number of functional sodium channels at resting membrane potential and contribute to the long-lasting periods of paralysis experienced by hypoPP patients. The gating of both histidine mutants (Arg669His, Arg672His) can be modulated by changes of extra- or intracellular pH. The inactivation defects of Arg669His and Arg672His can be alleviated by low pH to a significant degree, suggesting that the decrease of pH in muscle cells (e.g. during muscle work) might lead to an auto-compensation of functional defects. This may explain a delay or prevention of paralytic attacks in patients by slight physical activity. Moreover, the histidine residues may be the target for a potential therapeutic action by acetazolamide.
 ...
PMID:Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type II. 1191 16

Hypokalaemic periodic paralysis is an autosomal, dominantly inherited disorder, characterised by attacks of partial or total muscle weakness and serum hypokalaemia. the mutations responsible are located in the CACNA1S gene (type 1) and in the SCN4A gene (type 2), and are all missense mutations where arginine is mostly replaced by histidine or sometimes glycine. The mutation has been localised in the voltage sensor of the transmembrane segment of calcium channel (type 1) and sodium channel (type 2) respectively. How muscle weakness develops is not known. Oral or intravenous administration of potassium is helpful in treating partial or complete attacks. Acetazolamide can reduce the frequency of attacks in type-1 hypokalaemic periodic paralysis.
 ...
PMID:[From gene to diseases; hypokalemic periodic paralysis]. 1518 39

Thyrotoxic hypokalemic periodic paralysis (THPP) is a medical emergency characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis that resolve with the treatment of hyperthyroidism. Attacks are transient, self-limited, associated with hypokalemia and resemble those of familial hypokalemic periodic paralysis (FHPP), an autosomal dominant neurological channelopathy. This study reviews the clinical features and genetic findings of THPP in 25 Brazilian patients. Most patients had weight loss, taquicardia, goiter, tremor, and ophthalmopathy. Most often attacks arose during the night and recovered spontaneously but some patients evolved to total quadriplegia, and few experienced cardiac arrhythmias. All patients had suppressed TSH and elevated T4 and most had positive anti-thyroid antibodies, indicating autoimmunity thyrotoxic etiology. Potassium was low in all patients during the crisis. Prophylactic potassium therapy has not been shown to prevent attacks; however it was useful for curbing the paralysis during the crisis. We identified the mutation R83H in the KCNE3 gene in one sporadic case, and M58V in the KCNE4 gene in one case with family history. Furthermore, we identified other genetic polymorphisms in the CACNA1S, SCN4A, KCNE1, KCNE2, KCNE1L, KCNJ2, KCNJ8 e KCNJ11 genes. We conclude that THPP is the most common treatable cause of acquired periodic paralysis; therefore, it must be included in the differential diagnosis of acute muscle weakness.
 ...
PMID:[Thyrotoxic hypokalemic periodic paralysis, an endocrine emergency: clinical and genetic features in 25 patients]. 1561 33

Hypokalemic periodic paralysis (HOPP) is a rare disease characterized by reversible attacks of muscle weakness accompanied by episodic hypokalemia. Recent molecular work has revealed that the majority of familial HOPP is due to mutations in a skeletal muscle voltage-dependent calcium-channel: the dihydropyridine receptor. We report a 13-yr old boy with HOPP from a family in which 6 members are affected in three generations. Genetic examination identified a nucleotide 3705 C to G mutation in exon 30 of the calcium channel gene, CACNA1S. This mutation predicts a codon change from arginine to glycine at the amino acid position #1239 (R1239G). Among the three known mutations of the CACNA1S gene, the R1239G mutation was rarely reported. This boy and the other family members who did not respond to acetazolamide, showed a marked improvement of the paralytic symptoms after spironolactone treatment.
 ...
PMID:A Korean family of hypokalemic periodic paralysis with mutation in a voltage-gated calcium channel (R1239G). 1571 25

Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. The skeletal muscle calcium channel alpha-subunit gene CACNA1S is a major disease-causing gene for HypoPP, however, only three specific HypoPP-causing mutations, Arg528His, Arg1,239His and Arg1,239Gly, have been identified in CACNA1S to date. In this study, we studied a four-generation Chinese family with HypoPP with 43 living members and 19 affected individuals. Linkage analysis showed that the causative mutation in the family is linked to the CACNA1S gene with a LOD score of 6.7. DNA sequence analysis revealed a heterozygous C to G transition at nucleotide 1,582, resulting in a novel 1,582C-->G (Arg528Gly) mutation. The Arg528Gly mutation co-segregated with all affected individuals in the family, and was not present in 200 matched normal controls. The penetrance of the Arg528Gly mutation was complete in male mutation carriers, however, a reduced penetrance of 83% (10/12) was observed in female carriers. No differences were detected for age-at-onset and severity of the disease (frequency of symptomatic attacks per year) between male and female patients. Oral intake of KCl is effective in blocking the symptomatic attacks. This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease.
 ...
PMID:Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. 1572 7

Hypokalemic periodic paralysis (HypoPP) is a skeletal muscle disorder in which episodic attacks of muscle weakness occur; they are associated with decreased serum potassium (K+) levels. Recent molecular approaches have clarified that the condition is caused by mutations in the skeletal muscle voltage-gated calcium channel 1 subunit (CACNA1S). We describe two unrelated patients with HypoPP, followed by their relevant clinical studies and gene analysis. Clinical studies included an oral glucose tolerance test (OGTT), food-loading and insulin tolerance tests (ITT). For Case 1, serum K+ levels were extremely decreased following insulin tolerance testing compared with levels for controls. These results support the hypothesis that no efflux of K+ ion occurs in patients because of low activity of adenosine triphosphate (ATP)-sensitive K+ channel (KATP) channels. Mutational analysis of the CACNA1S gene showed a duplicate insertion of 14 base pairs (bp) from 52 to 65 in intron 26, present in the heterozygous state in both patients. No other mutations were detected in the CACNA1S gene, the muscle sodium channel gene (SCN4A) or the voltage-gated K+ channel gene (KCN3) of either patient. Further analysis showed that this duplicate insertion of 14 bp in intron 26 of the CACNA1S gene was found in 23.7% of healthy subjects. K+ dynamics studies are useful for confirming this syndrome, while further gene analysis for various ion channels using amplification and direct sequencing are required to evaluate the molecular basis of the disorder in the individual patient.
 ...
PMID:Gene analysis of the calcium channel 1 subunit and clinical studies for two patients with hypokalemic periodic paralysis. 1718 4

Familial hypokalemic periodic paralysis (HOPP) is a rare autosomal-dominant disease characterized by reversible attacks of muscle weakness occurring with episodic hypokalemia. Mutations in the skeletal muscle calcium (CACNA1S) and sodium channel (SCN4A) genes have been reported to be responsible for familial HOPP. Fifty-one HOPP patients from 20 Korean families were studied to determine the relative frequency of the known mutations and to specify the clinical features associated with the identified mutations. DNA analysis identified known mutations in 12 families: 9 (75%) were linked to the CACNA1S gene and 3 (25%) to the SCN4A gene. The Arg528His mutation in the CACNA1S gene was found to be predominant in these 12 families. Additionally, we have detected one novel silent exonic mutation (1950C>T) in the SCN4A gene. As for a SCN4A Arg669His mutation, incomplete penetrance in a woman was observed. Characteristic clinical features were observed both in patients with and without mutations. This study presents comprehensive data on the genotype and phenotype of Korean families with HOPP.
 ...
PMID:The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. 1816 4

Familial hypokalemic periodic paralysis is an autosomal dominant muscle disorder characterized by episodic attacks of muscle weakness, accompanied by a decrease in blood potassium levels. It is based on genetic mutations in the genes CACNA1S (most frequent, encoding the skeletal muscle calcium channel) and SCN4A (10% of cases, encoding the sodium channel). Few cases have been reported with cardiac dysrhythmia. We report a rare case of a patient with a novel SCN4A mutation who presented, on ECG, extreme bradycardia and syncopal sinus arrest that required a temporary pacemaker implant
 ...
PMID:Atypical arrhythmic complications in familial hypokalemic periodic paralysis. 1970 31

Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant disorder, which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. A major disease-causing gene for HypoPP has been identified as CACNA1S, which encodes the skeletal muscle calcium channel alpha-subunit with four transmembrane domains (I-IV), each with six transmembrane segments (S1-S6). To date, all CACNA1S mutations identified in HypoPP patients are located within the voltage-sensor S4 segment. In this study we report a novel CACNA1S mutation in a new region of the protein, the S3 segment of domain III. We characterized a four-generation South American family with HypoPP. Genetic analysis identified a novel V876E mutation in all HypoPP patients in the family, but not in normal family members or 160 control people. Clinical analysis indicates that mutation V876E is associated with a severe outcome as characterized by a very early age of onset, complete penetrance and a severe prognosis including death. These results identify a new mutation in CACNA1S and expand the spectrum of CACNA1S mutations associated with HypoPP.
 ...
PMID:Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family. 1977 99

Hypokalemic periodic paralysis (HOKPP) is a rare disorder characterized by episodic muscle weakness with hypokalemia. Mutations in the CACNA1S gene, which encodes the alpha 1-subunit of the skeletal muscle L-type voltage-dependent calcium channel, have been reported to be mainly responsible for HOKPP. The paralytic attacks generally spare the respiratory muscles and the heart. Here, we report the case of a 16-year-old boy who presented with frequent respiratory insufficiency during the severe attacks. Mutational analysis revealed a heterozygous c.1582C>G substitution in the CACNA1S gene, leading to an Arg528Gly mutation in the protein sequence. The parents were clinically unaffected and did not show a mutation in the CACNA1S gene. A de novo Arg528Gly mutation has not previously been reported. The patient described here presents the unique clinical characteristics, including a severe respiratory phenotype and a reduced susceptibility to cold exposure. The patient did not respond to acetazolamide and showed a marked improvement of the paralytic symptoms on treatment with a combination of spironolactone, amiloride, and potassium supplements.
 ...
PMID:Severe respiratory phenotype caused by a de novo Arg528Gly mutation in the CACNA1S gene in a patient with hypokalemic periodic paralysis. 1982 48


1 2 3 Next >>