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)

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.
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PMID:[Thyrotoxic hypokalemic periodic paralysis, an endocrine emergency: clinical and genetic features in 25 patients]. 1561 33

Periodic paralyses (PPs) are rare inherited channelopathies that manifest as abnormal, often potassium (K)-sensitive, muscle membrane excitability leading to episodic flaccid paralysis. Hypokalaemic (HypoPP) and hyperkalaemic PP and Andersen-Tawil syndrome are genetically heterogeneous. Over the past decade mutations in genes encoding three ion channels, CACN1AS, SCN4A and KCNJ2, have been identified and account for at least 70% of the identified cases of PP and several allelic disorders. No prospective clinical studies have followed sufficiently large cohorts with characterized molecular lesions to draw precise conclusions. We summarize current knowledge of the clinical diagnosis, molecular genetics, genotype-phenotype correlations, pathophysiology and treatment in the PPs. We focus on unresolved issues including (i) Are there additional ion channel defects in cases without defined mutations? (ii) What is the mechanism for depolarization-induced weakness in Hypo PP? and finally (iii) Will detailed electrophysiological studies be able to correctly identify specific channel mutations? Understanding the pathophysiology of the potassium-sensitive PPs ought to reduce genetic complexity, allow subjects to be stratified during future clinical trials and increase the likelihood of observing true clinical effects. Ideally, therapy for the PPs will prevent attacks, avoid permanent weakness and improve quality of life. Moreover, understanding the skeletal muscle channelopathies will hopefully lead to insights into the more common central nervous system channel diseases such as migraine and epilepsy.
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PMID:The primary periodic paralyses: diagnosis, pathogenesis and treatment. 1619 44

Thyrotoxic periodic paralysis (TPP), familial periodic paralysis (FPP), and sporadic periodic paralysis (SPP) are the most common causes of hypokalemic periodic paralysis (hypoKPP). The patients present with similar clinical features characterized by episodic attacks of muscle weakness and a decrease in blood potassium. Mutations in the gene encoding the voltage-sensor coding regions of the skeletal muscle sodium channel gene (SCN4A) and the alpha-1 subunit of the skeletal muscle calcium channel gene were analyzed in 23 Chinese hypoKPP patients, including 1 FPP pedigree, 14 TPP patients, and 8 SPP patients. In addition, R83H mutation of the potassium channel subunit gene which was originally published as periodic paralysis mutation was also analyzed. A heterozygous CGT-TGT mutation at codon 672 in SCN4A gene was identified to segregate with the disease in the FPP family. Mutations in these regions were excluded in those patients with SPP and TPP. The results suggest that a likely genetic basis for FPP does not contribute to TPP and SPP, despite close similarities among FPP, TPP, and SPP.
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PMID:Mutation screening in Chinese hypokalemic periodic paralysis patients. 1638 35

We report a phenotype associated with the Val1589Met substitution in SCN4A gene in a French family which would be better classified as paramyotonia congenita. The proband was a 48-year-old woman, who described muscle stiffness and occasional flaccid weakness, both symptoms being induced by exercise, cold and heat. Severe muscle stiffness affected facial, oropharyngeal and limb muscles leading to transient paralysis of these muscles. One sister, two nephews and the son of the proband had similar symptoms. Molecular analysis of the muscle sodium channel gene (SCN4A) by nucleotide sequencing revealed a G-to-A transition of cDNA nucleotide at position 4765 predicting a substitution of methionine for valine at position 1589. This shows that the Val1589Met mutation in the SCN4 gene may cause different phenotypes, either potassium-aggravated myotonia or paramyotonia congenita. Familial or individual factors other than the missense mutation per se influence the expression of the disease in sodium channel disorders.
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PMID:A new case of autosomal dominant myotonia associated with the V1589M missense mutation in the muscle sodium channel gene and its phenotypic classification. 1662 58

Paralysis periodica paramyotonica is an overlapping disease that shares the features of paramyotonia characteristic of paramyotonia congenita (PC) and periodic paralysis characteristic of hyperkalemic periodic paralysis. We report the case of a 23-year-old man with paralysis periodica paramyotonica. His father and a younger brother also exhibited a similar phenotype. A SCN4A Arg1448Cys mutation was detected in this family. The affected family members exhibited marked shifts in compound muscle action potential amplitudes on exercise test, and muscle weakness could be induced by potassium loading and cold exposure. This case demonstrates that SCN4A Arg1448Cys can produce paralysis periodica paramyotonica. Other genetic or environmental factors may modulate the manifestation of SCN4A Arg1448Cys mutation.
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PMID:Paralysis periodica paramyotonica caused by SCN4A Arg1448Cys mutation. 1680 Oct 39

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.
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PMID:Gene analysis of the calcium channel 1 subunit and clinical studies for two patients with hypokalemic periodic paralysis. 1718 4

Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.
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PMID:A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene. 1721 50

Toxic thyroid adenoma presenting as hypokalemic periodic paralysis is extraordinarily rare. We describe a 26-year-old Japanese man who suffered from acute and painful muscle weakness of extremity in the morning. Physical examination showed a left anterior neck mass and laboratory tests revealed hypokalemia during his paralysis, and thyrotoxicosis. Neck sonogram showed a solitary nodule in the left lobe of the thyroid. Thyroid scintigraphy revealed a hot nodule of the tumor region with suppressed uptake in the other thyroid area. The tumor was surgically removed and his paralytic attack ceased. No somatic mutation of TSH receptor was found in his thyroid adenoma and no known genetic mutations of ionic channel genes, such as calcium (CACN1S), sodium (SCN4A) and potassium (KCNE3), were found. Although thyrotoxic periodic paralysis is usually accompanied with Graves' disease, thyrotoxicosis of other conditions including Plummer's disease should be considered.
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PMID:Toxic thyroid adenoma presenting as hypokalemic periodic paralysis. 1791 8

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.
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PMID:The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. 1816 4

In Western countries, thyrotoxic periodic paralysis (TPP) is a rare condition with only sporadic cases described so far. Here, we describe a 29-year-old Italian man who presented with leg weakness and hypokalaemia. Treatment with intravenous potassium resulted in a rapid resolution of symptoms. TPP as the underlying cause was suggested by suppressed thyroid-stimulating hormone (TSH), elevated free T3 and free T4, and the presence of TSH-receptor antibodies (TRAB). Genetic analysis showed no mutations in the candidate exons of calcium (CACN1AS), potassium (KCNE3) and sodium (SCN4A) channel genes. However, we identified the presence of two single nucleotide polymorphisms (SNPs), 1491C > T and 1551 T > C, in exon 11 of the CACN1AS gene. Although the 1491C > T SNP is not apparently involved in the pathogenesis of the disease, the 1551 T > C SNP has been associated with TPP in Asians and reported in only one case in European Caucasians. Further investigations are needed to clarify whether such polymorphisms have a role in the disease pathogenesis in Caucasians.
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PMID:Thyrotoxic periodic paralysis in an Italian man: clinical manifestation and genetic analysis. 1832 91


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