CHANNELOPATHIES AND RELATED DISORDERS: EP.221 Diagnostic delay and atypical phenotypes in a French cohort of Andersen-Tawil syndrome

Abstract

Andersen- Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations and characterized by a triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The absence of the complete triad and/or the presence of atypical presentations can delay diagnosis. The muscle phenotype, particularly the atypical forms with permanent weakness or exercise intolerance, remains incompletely characterized. We report 33 patients from 26 unrelated families carrying 17 different missense KCJN2 mutations, 4 of them previously unreported. Only 14 patients (42.4%) present with the typical triad. 30 (90.9%) patients had muscle symptoms, 5 of them (15.2%) without cardiac or dysmorphic features. Periodic paralysis was noticed in 26 (78%), in most of them mirroring hypokalemic periodic paralysis. Ictal serum potassium concentrations were low in 13 (65%) and normal in 7 (35%). Sixteen (48.5%) had permanent weakness, 12 (36.4%) of them also had periodic paralysis. Seven (21.2%) patients presented with atypical muscle features. 4 of the latter had permanent weakness without periodic paralysis, 2 presented with mild proximal weakness and exercise intolerance and 1 with myalgia and raised CK levels. Weakness which usually affected scapular and pelvic girdles, was mild and slowly progressive. Only 1 patient needed walking aids (cane). Diagnostic delay was increased in patients presenting with atypical neuromuscular features or permanent weakness: 18.3 ±12.1 years vs 12±9.7 for those presenting with the classical triad. EMG with long exercise test was performed in 21 (63.6%), showing in all cases a decremental response up to >40%. Muscle biopsy was performed in 13, revealing no abnormalities in 5, dystrophic features in 5 and tubular aggregates in 3. No genotype-phenotype correlation was found. This work provides novel insights into the phenotypical characterization of muscular involvement in ATS and highlights the high diagnostic yield of the long exercise test.