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Andersen–Tawil syndrome: deep phenotyping reveals significant cardiac and neuromuscular morbidity

医学 离子通道病 队列 肌肉活检 人口 弱点 动态心电图监护仪 心脏病学 内科学 肌病 周期性麻痹 心电图 外科 活检 环境卫生 麻痹
作者
Vinojini Vivekanandam,Roope Männikkö,Iwona Skorupinska,Louise Germain,Belinda Gray,Sarah Wedderburn,Damian Kozyra,Richa Sud,Natalie James,Sarah Holmes,Konstantinos Savvatis,Doreen Fialho,Ashirwad Merve,J. Pattni,Maria Elena Farrugia,Elijah R. Behr,Chiara Marini‐Bettolo,Michael G. Hanna,Emma Matthews
出处
期刊:Brain [Oxford University Press]
卷期号:145 (6): 2108-2120 被引量:16
标识
DOI:10.1093/brain/awab445
摘要

Abstract 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.
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