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Andersen-Tawil syndrome is a neurological channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel. The syndrome is characterized by episodic weakness, cardiac arrythmias and dysmorphic features. However, the full extent of the multisystem phenotype is not well described. In-depth, multisystem phenotyping is required to inform diagnosis and guide management. We report our findings following deep multimodal phenotyping across all systems in a large case series of 69 total patients, with comprehensive data for 52. As a national referral centre, we assessed point prevalence and showed it is higher than previously reported, at 0.105 per 100 000 population in England. While the classical phenotype of episodic weakness is recognized, we found that a quarter of our cohort have fixed myopathy and 13.5% required a wheelchair or gait aid. We identified frequent fat accumulation on MRI and tubular aggregates on muscle biopsy, emphasizing the active myopathic process underpinning the potential for severe neuromuscular disability. Long exercise testing was not reliable in predicting neuromuscular symptoms. A normal long exercise test was seen in five patients, of whom four had episodic weakness. Sixty-seven per cent of patients treated with acetazolamide reported a good neuromuscular response. Thirteen per cent of the cohort required cardiac defibrillator or pacemaker insertion. An additional 23% reported syncope. Baseline electrocardiograms were not helpful in stratifying cardiac risk, but Holter monitoring was. A subset of patients had no cardiac symptoms, but had abnormal Holter monitor recordings which prompted medication treatment. We describe the utility of loop recorders to guide management in two such asymptomatic patients. Micrognathia was the most commonly reported skeletal feature; however, 8% of patients did not have dysmorphic features and one-third of patients had only mild dysmorphic features. We describe novel phenotypic features including abnormal echocardiogram in nine patients, prominent pain, fatigue and fasciculations. Five patients exhibited executive dysfunction and slowed processing which may be linked to central expression of KCNJ2. We report eight new KCNJ2 variants with in vitro functional data. Our series illustrates that Andersen-Tawil syndrome is not benign. We report marked neuromuscular morbidity and cardiac risk with multisystem involvement. Our key recommendations include proactive genetic screening of all family members of a proband. This is required, given the risk of cardiac arrhythmias among asymptomatic individuals, and a significant subset of Andersen-Tawil syndrome patients have no (or few) dysmorphic features or negative long exercise test. We discuss recommendations for increased cardiac surveillance and neuropsychometry testing., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Andersen-Tawil syndrome (ATS) is an uncommon form of channelopathy linked to mutations in the KCNJ2 gene. Currently, little is known about the long-term arrhythmic prognosis of this disease., Methods and Results: We conducted a retrospective multicentre study in nine French hospitals. Patients were recruited only if they were KCNJ2 mutation carriers. Thirty-six patients (female n = 22, 61%) from 20 unrelated kindred were included with a mean follow-up of 9.5 ± 8.2 years. We found 12 distinct KCNJ2 mutations in the 20 probands. Three of them were novel. Thirteen patients (36%) experienced syncope and one patient was resuscitated from cardiac arrest before diagnosis. The mean QTc interval was 439 ± 57 ms and QUc was 642 ± 64 ms. All patients had normal ejection fraction. Holter recordings in 33 patients found 11 272 premature ventricular complexes (PVCs) per day on average, 25 patients had episodes of bigeminy, and 25 patients had polymorphic PVCs. Twenty-three patients (70%) had non-sustained polymorphic ventricular tachycardia (VT), and six sustained polymorphic VT. Only one patient presented with torsades de pointes. Patients were treated with beta-blocker (n = 20), beta-blocker and amiodarone (n = 2), beta-blocker and flecainide (n = 6), or acetazolamide (n = 6). Radiofrequency ablation was attempted in five patients without clinical success. An implantable cardiac defibrillator was implanted in three patients. During follow-up, none of the patients died, four patients experienced syncope under treatment, and one patient had non-fatal cardiac arrest., Conclusion: Despite a severe clinical presentation with a very high rate of ventricular arrhythmias, the arrhythmic prognosis of the ATS patients is relatively good under treatment.

Andersen-Tawil syndrome (ATS) is an autosomal dominant or sporadic disorder characterized by periodic paralysis, dysmorphic features, and ventricular arrhythmias. Although ventricular tachycardia burden is quite high sudden cardiac death in ATS is rare. We describe a case with sudden cardiac death due to electrical storm a few days after ICD implantation in KCNJ2 mutation-negative ATS.