A multicenter, prospective, cross-sectional, genotype-phenotype and longitudinal natural history study of Andersen-Tawil syndrome

Objective A multi-center, prospective, cross-sectional natural history study to define the clinical phenotype of Andersen-Tawil syndrome, validate its current diagnostic criteria, explore genotype-phenotype correlations, and establish clinically relevant endpoints for use in therapeutic trials. Methods Participants were followed at yearly intervals for two years. Outcome measures included attack frequency and duration, neurophysiological exercise testing and interictal muscle strength. Cardiac endpoints were QTc interval, presence of U-waves, frequency of ventricular ectopy and arrhythmias. Participants completed the SF-36 and underwent KCNJ2 gene analysis. Results 28 participants were enrolled. The age range was 17 to 82 years. 23 participants harbored mutations in KCNJ2 , including a new mutation, Y68D. All exhibited at least one skeletal feature with 26/28 exhibiting two or more. Common physical abnormalities were a small mandible (89%), low set ears (82%) and micromelia of hands or feet (71%). 26 participants reported periodic paralysis. The frequency of attacks varied from 12/week to 1/year, and duration from 12 minutes to 21 days. Common triggers for attacks were prolonged rest (85%) and exercise/exertion (73%). 20/25 had an abnormal long exercise test. A prolonged QTc interval was identified in 36% participants, U waves in 39% and ambulatory ECGs demonstrated runs of ventricular tachycardia in 32% and more than 10 000 ventricular couples in 14% of participants. Interpretation There is extensive heterogeneity in both the spectrum and severity of Andersen-Tawil syndrome. Overall, the symptoms result in a significant impairment in quality of life. The cardiac and neurophysiological data could serve as outcome measures in future treatment trials.