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)

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

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases involving the abnormal function of ion channels. This group of muscle diseases also comprises hyperkalemic periodic paralysis and paramyotonia congenita, both sodium-channel diseases, and myotonia congenita, a chloride-channel disorder. HypoPP is characterized by acute attacks of muscle weakness concomitant with a fall in blood potassium levels. We recently localized the hypoPP locus (hypoPP1) to chromosome 1q31-32, in an interval where the alpha 1 subunit of the dihydropyridine receptor calcium channel (CACNL1A3) also maps. Subsequently, deleterious mutations in the voltage-sensor segment S4 were found, establishing the dihydropyridine receptor CACNL1A3 as the causative gene for hypoPP. In this paper, we report the study of 16 hypoPP families of Caucasian origin. We found only two mutations--Arg528His and Arg1239His--that cosegregated with hypoPP, each in half of the families. Analysis of the clinical characteristics of both groups of families demonstrated that incomplete penetrance is a distinctive feature of the Arg528His mutation. Using dinucleotide repeats contained within or close to the dihydropyridine receptor gene, in conjunction with evidence of a de novo Arg1239His mutation, we show that a founder effect is unlikely to account for the two predominant mutations.
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PMID:Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. 784 70

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant or sporadic disorder characterized by periodic, reversible attacks of muscle weakness. Mutations in the skeletal muscle dihydropyridine receptor alpha 1-subunit that functions as a calcium channel (CACNL1A3) cause hypoKPP. We studied a group of 45 hypoKPP probands and demonstrated mutations in 30 of them. When compared with patients in whom CACNL1A3 mutations were not identified, those with mutations had an earlier age of onset and more often had a family history of hypoKPP. To date, three mutations have been identified. The R1239G mutation has only been found in one family. Of the 30 probands with recognized mutations, R528H accounted for 43% and R1239H was seen in 53%. Age of onset and potassium levels during attacks were lower in patients with the R1239H mutation than those with R528H. Cardiac dysrhythmias co-segregated with hypoKPP in one small kindred with the R528H mutation. No mutations were identified in exons of the gene encoding the S4 segments of domains one and three or the cytoplasmic loop between domains two and three. In addition to the 45 hypoKPP probands, an additional 11 probands with clinical variants of hypoKPP (three thyrotoxic hypoKPP and eight Andersen syndrome patients) were examined for CACNL1A3 mutations and none were found.
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PMID:Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis. 913 38

Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant muscle disorder characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels. Mutations in the gene encoding the skeletal muscle voltage-gated calcium channel alpha-1 subunit (CACNL1A3) account for the majority of cases. Recently, mutations in the gene coding for the skeletal muscle voltage-gated sodium channel alpha subunit (SCN4A) have been reported in a small number of hypoPP families. In order to determine the relative frequency of the CANCL1A3 and SCN4A mutations in a large population of hypoPP patients, and to specify the clinical and pathological features associated with each of them, we searched for mutations in 58 independent hypoPP index cases. We detected the causative mutation in 45 cases: 40 were linked to the CACNL1A3 gene and five to the SCN4A gene. One mutation has not been described before. Some remarkable clinical features were observed in a large hypoPP family carrying an SCN4A mutation: a complete penetrance in men and women, an early age at onset, postcritic myalgias and an increased number and severity of attacks induced by acetazolamide. A muscle biopsy, performed in two members of this family, revealed a peculiar myopathy characterized by tubular aggregates. In contrast, vacuoles were predominant in muscles from hypoPP patients carrying CACNL1A3 mutations. Our findings point to the usefulness of a molecular characterization of hypoPP patients in clinical practice. They also provide new clues for understanding the mechanisms behind functional and structural alterations of the skeletal muscle in hypoPP.
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PMID:Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. 1135 25

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

Periodic paralyses (PP) are characterized by episodic muscle weakness and are classified into the distinct hyperkalaemic (hyperPP) and hypokalaemic (hypoPP) forms. The dominantly-inherited form of hyperPP is caused by overactivity of Nav1.4 - the skeletal muscle voltage-gated sodium channel. Familial hypoPP results from a leaking gating pore current induced by dominant mutations in Nav1.4 or Cav1.1, the skeletal muscle voltage-gated calcium channel. Here, we report an individual with clinical signs of hyperPP and hypokalaemic episodes of muscle paralysis who was heterozygous for the novel p.Ala204Glu (A204E) substitution located in one region of Nav1.4 poor in disease-related variations. A204E induced a significant decrease of sodium current density, increased the window current, enhanced fast and slow inactivation of Nav1.4, and did not cause gating pore current in functional analyses. Interestingly, the negative impact of A204E on Nav1.4 activation was strengthened in low concentration of extracellular K+. Our data prove the existence of a phenotype combining signs of hyperPP and hypoPP due to dominant Nav1.4 mutations. The hyperPP component would result from gain-of-function effects on Nav1.4 and the hypokalemic episodes of paralysis from loss-of-function effects strengthened by low K+. Our data argue for a non-negligible role of Nav1.4 loss-of-function in familial hypoPP.
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PMID:A204E mutation in Nav1.4 DIS3 exerts gain- and loss-of-function effects that lead to periodic paralysis combining hyper- with hypo-kalaemic signs. 3042 Jul 13

Familial hypokalemic periodic paralysis (f-hypoPP) is a rare neuromuscular disorder causing intermittent muscle paralysis. Pregnancy can exacerbate f-hypoPP, yet obstetric management is not well documented. We present a case of a nulliparous woman with f-hypoPP, outlining a complete prenatal care plan generalizable to other women with known f-hypoPP. To our knowledge, this is the first obstetric f-hypoPP case to prioritize intrapartum oral potassium over intravenous potassium, as well as to outline the importance of multidisciplinary care. The patient had a spontaneous vaginal delivery at term with an uneventful postpartum period. Muscle weakness and episodes of relative hypokalemia in the second trimester and during labor were effectively treated with oral potassium supplementation. Care was provided by a multidisciplinary team, and caution was taken to avoid known triggers of paralytic episodes.
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PMID:Familial hypokalemic periodic paralysis in pregnancy: A case report. 3121 37