The Clinical And Genetic Features Of Thyrotoxic Periodic Paralysis

Objective:Thyrotoxic periodic paralysis(TPP) is a life-threatening channelopathy manifesting as recurrent episodes of hypokalemia and muscle weakness in the presence of hyperthyroidism. Recent findings indicate defects of inward rectifying K+(Kir) channels are associated with some TPP patients. The associations are not only found in Caucasian population(mainly Brazilian), but also in Singaporean population. However, potential genetic risk factors for mainland Chinese patients, the largest group of TPP cases in the world, have been largely unexplored. This study collecte and analyze the clinical dates of TPP patients in order to know the clinical characteristics of TPP patients in mainland Chinese patients. In this study, we investigate the genetic features of TPP patients by testing the mutations in KCNJ18,KCNJ2 and loci polymorphisms(rs623011and rs312691). Furthemore, we discuss the genotype/phenotype correlations and investigate potential pathogenic mechanism of TPP.Methods:127 cases of TPP from 5 clinical centers from Jan 2011 to Jan 2014 were clinically diagnosed and collected according to the diagnostic criteria. Samples of DNA from 127 individuals with TPP and 102 hyperthyroidism male controls self-reported as mainland Chinese were collected. Polymerase chain reaction(PCR)was performed to amplify the exons of KCNJ2 gene, KCNJ18 gene, as well as loci polymorphisms(rs623011and rs312691). PCR products were detected by agarosegel electrophoresis and purified, then gene mutations were analysed by DNA directly sequencing in TPP patients and controls. According to the results of the gene screening, we retrospectively summarized and analyzed the clinical features of KCNJ18 patients and non-KCNJ18 patients, and the genotype/phenotype correlations.At the same time, genetic characteristics of loci polymorphisms(rs623011and rs312691) in TPP patients and controls were researched.Results:1、Genotype features:(1) 4 cases in 127 TPP patients were genetically identified by the detection of KCNJ18 mutations. 3 novel heterogeneous mutations(p.Q126 X, p.K360 T, p. E388K)and 1 reported heterogeneous mutation(p.A200P) were found in the KCNJ18 gene.Blast software revealed that 4 mutations in Kir2.6 had highly evolutional conservation in Kir2.x protein family in different species, p.K360 T and p.E388 Kmutation had highly evolutional conservation in Kir2.x protein family in human. 3.1% of TPP cases harbored KCNJ18 gene mutations in mainland Chinese patients.(2) In rs623011, the allele frequency of A was 0.772 in 127 individuals with TPP,while A allele frequency was 0.461 in 102 hyperthyroidism male controls, AA was significant risk factors for TPP(odds ratio, 11.94). In rs312691, the allele frequency of C was 0.799 in TPP patients, while C allele frequency was 0.471 in hyperthyroid controls. CC was significant risk factors for TPP(odds ratio, 10.57).2、Phenotype features:4 patients with KCNJ18 mutation were male with onset age of 19-25 years old. The attack duration of patients with KCNJ18 mutation was2-4 hours, and all patients with KCNJ18 mutation suffered from severe limbs weakness. The diagnosis of hyperthyroidism was not made before weakness attacking.The symptom recurred in 3 patients during the treatment, however, weakness did not occur again after remission of hyperthyroidism. 123 patients without KCNJ18 mutation were male with onset age of 16-62 years old. The attack duration of patients with KCNJ18 mutation ranged from 1 hour to 6 days, and half of the patients without KCNJ18 mutation had severe limbs weakness. The symptom recurred in 36 patients without KCNJ18 mutation during the treatment, however, weakness did not occur again after remission of hyperthyroidism. All the 127 TPP patients had hypokalaemia,hyperthyroidism and elevated CK.3、genotype/phenotype correlations: The 4 heterogeneous mutations(p.Q126 X,p.K360 T, p. E388 K, p.A200P) in KCNJ18 were responsible for TPP, and caused much severer manifestation than patients without KCNJ18 mutation. However,p.A200 P also caused hypokalaemic periodic paralysis and was correlated with bothTPP and hypokalaemic periodic paralysis. The rs623011 and rs312691 loci were associated with TPP, but had no significantly correlation with the phenotype of TPP.Conclusions:This study demonstrates that the KCNJ18 variants are only responsible for a small proportion of TPP patients in mainland China. There are significant clinical differences between patients with KCNJ18 mutations and patients without KCNJ18 mutations. TPP patients with KCNJ18 mutations had shorter attack duration, higher prevalence of muscle soreness and weakness recurrence than patients without KCNJ18 mutation. In addition, the rs623011 and rs312691 loci are significantly associated with TPP patients in mainland China, and highlight the Kir2.1 channel as a causative target in TPP.