Andersen-Tawil syndrome -: Definition of a neurocognitive phenotype

Background: The Andersen-Tawil syndrome ( ATS) is a potassium ion channelopathy caused by mutations in the KCNJ2 gene. It is characterized by periodic paralysis, cardiac arrhythmias, and distinctive features; the effect of KCNJ2 mutations on the CNS has never been studied. Objective: To define a potential CNS phenotype in ATS using standardized methods. Methods: Ten subjects with KCNJ2 mutations and their unaffected siblings were evaluated at the University of California San Francisco General Clinical Research Center. A comprehensive battery of neurocognitive tests was administered to ATS subjects and their unaffected siblings, followed by pairwise analysis of the resultant differences in scores. An EEG was obtained for all ATS subjects. Results: There was no EEG evidence of subclinical seizure activity in any subject. ATS subjects universally had more school difficulties than their siblings, despite similar IQ between the two groups. On formal neurocognitive testing, there was no difference between ATS subjects and their siblings on tests of verbal and visual memory. Assessment of executive functioning revealed ATS subjects scored 1.93 points lower than their siblings on tests of Design Fluency ( 95% CI -3.46, 0.01; p = 0.052) and made 1.9 more errors ( 95% CI 0.46, 2.54; p = 0.005). Subjects with ATS scored an average of 5 points lower than their siblings on tests of matrix reasoning ( 95% CI - 8.67, - 1.33; p = 0.008). On tests of general ability, ATS subjects achieved much lower scores than their siblings, with an average difference of 9.13 points for reading ( 95% CI - 12.46, 3.21; p = 0.056) and 23.4 points for mathematics ( 95% CI - 42.53, - 4.22; p = 0.017). Conclusion: Mutations in KCNJ2 are associated with a distinct neurocognitive phenotype, characterized by deficits in executive function and abstract reasoning.