ClinVar Genomic variation as it relates to human health

This variant, formerly titled HYPOKALEMIC PERIODIC PARALYSIS, HYPERKALEMIC PERIODIC PARALYSIS, and SUSCEPTIBILITY TO THYROTOXIC PERIODIC PARALYSIS based on the findings of Abbott et al. (2001) and Dias Da Silva et al. (2002), has been reclassified based on the findings of Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004). Abbott et al. (2001) identified a 340G-A transition in the KCNE3 gene, resulting in an arg83-to-his (R83H) substitution in 2 of 100 patients with atypical forms of hyperkalemic periodic paralysis (HYPP; 170500) and hypokalemic periodic paralysis (HOKPP; 170400), respectively. However, Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004) concluded that the R83H variant does not play a causative role in periodic paralysis and that it is a polymorphism. Abbott et al. (2001) reported a male proband with atypical HYPP who was negative for mutations in the SCN4A gene and who carried the R83H variant. He presented at 22 months of age with episodic weakness of the extremities. Most episodes came on during sleep and were brief (12 hours), although they occasionally lasted for days. Serum potassium levels during attacks were normal. High carbohydrate meals helped resolve attacks, and treatment with a carbonic anhydrase inhibitor prevented attacks. The age at onset, frequent nature of attacks, and improvement with carbohydrate loading were all consistent with HYPP; however, provocative testing with potassium had not been performed. Frequent attacks upon awakening and absence of myotonia were considered atypical for this diagnosis. Abbott et al. (2001) reported a male proband with atypical HOKPP who was negative for mutations in the SCN4A and CACNA1S genes and who carried the R83H variant. He had onset of episodic paralytic weakness at the age of 14 years. Episodes were characterized by weakness primarily affecting the lower extremities and lasting hours to days, and were usually precipitated by strenuous exercise followed by rest or after prolonged sitting. Carbohydrate ingestion did not precipitate attacks, alcohol intake appeared to facilitate recovery from an attack, and potassium had no effect. He was classified as having hypokalemic periodic paralysis because of the typical age of onset, paralytic attacks that most often occurred after exercise, a low potassium level during a spontaneous attack, and the ability to precipitate an attack with insulin and glucose on 1 occasion. Atypical for this diagnosis was that a second provocative test was negative and that attacks usually occurred while awake. The variant was not found in DNA from a control population of 120 unaffected individuals, suggesting to them that it does not represent a polymorphism. Abbott et al. (2001) reported functional expression studies that showed that the mutant R83H KCNE3-Kv3.4 complexes exhibited reduced current density and diminished capacity to set resting membrane potential as a dominant-negative effect compared to wildtype. In in vitro studies, Abbott et al. (2006) found that the R83H variant shifts the voltage-dependence of channel activation in response to pH change. The current through the mutant channel decreased compared to wildtype as intracellular pH was lowered. The authors suggested that R83H acts as a regulatory domain, and concluded that the variation may predispose to the development of periodic paralysis. In contrast, Sternberg et al. (2003) did not identify the R83H mutation in 64 probands with either HYPP or HOKPP in whom mutations in the SCN4A and CACNA1S genes had been excluded. One patient with HOKPP had the R83H change, but he also had a mutation in the SCN4A gene (R672H; 603967.0016). His father, who had the same clinical phenotype and the SCN4A mutation, did not carry the R83H mutation, whereas the asymptomatic mother carried the R83H variant. The findings yielded a frequency of 0.0096 in patients with periodic paralysis (1 in 104) and 0.0158 (8 of 506) in healthy controls. Likewise, Jurkat-Rott and Lehmann-Horn (2004) identified the R83H mutation in 1 of 76 patients with HYPP, in 1 of 61 patients with paramyotonia congenita (608390), in 5 unaffected relatives, in 0 of 8 patients with TTPP, and in 3 of 321 healthy controls, suggesting that it is a polymorphism. Provocation of an unaffected carrier with glucose or potassium administration did not induce weakness. The authors offered a formula for determining causality of a mutation based on reduced penetrance, but concluded that the R83H mutation does not cause these muscle disorders. Dias Da Silva et al. (2002) identified the R83H substitution in 1 of 15 patients with thyrotoxic hypokalemic periodic paralysis (188580). The patient was a 44-year-old Caucasian man of Portuguese descent who experienced episodic paralysis for 2 years before developing thyrotoxicosis caused by Graves disease (275000). Two of his 3 offspring, all asymptomatic, were found to have the same variant. Tang et al. (2004) did not identify the R83H substitution, or any mutations in the KCNE3 gene, among 79 Chinese patients with thyrotoxic hypokalemic periodic paralysis. Jurkat-Rott and Lehmann-Horn (2007) again refuted the pathogenicity of the R83H variant, noting that it had been identified in 1.17% of patients and 1.16% of healthy controls, which does not support disease causality. (less)