Unique post-exercise electrophysiological test results in a new Andersen-Tawil syndrome mutation

Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology (Impact Factor: 3.1). 06/2011; 122(12):2537-9. DOI: 10.1016/j.clinph.2011.04.025
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    • "occurring only in infancy were reported in 4 out of 23 (17%) patients of a Japanese cohort with ATS [8] and in Spain, one patient was reported with an isolated episode of seizures when he was 18-years-old [9]. Seizure activity and long QT interval may be both due to the dysfunction of K ir 2.1 or an association to other subunits of the K ir family channels. "
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    ABSTRACT: Andersen-Tawil syndrome Sudden cardiac death Long QT syndrome Ventricular tachycardia Epilepsy Mitral valve prolapse Congenital heart disease Andersen–Tawil Syndrome (ATS) is type 7 of congenital LQTS and is caused by mutations in the gene KCNJ2 that encodes a protein that forms the rectifier potassium channel K ir 2.1 [1,2]. ATS is characterized by periodic paralysis, ventricular arrhythmias, prolonged Q–U interval, and mild facial or skeletal abnormalities [3–5]. Sudden cardiac death (SCD) has been increasingly reported [6]. A very small number of ATS cases with seizures have been previously reported [7–9]. A case of ATS with aborted SCD, molecular confirmation, and two relevant associa-tions: epilepsy and congenital heart disease (mitral valve prolapse) is presented. The association of severe congenital mitral valve disease re-quiring surgery has not been reported before in ATS. A 7-year-old Mexican mestizo girl was evaluated due to her twin sister's sudden death. She had history of 6 episodes of syncope. Physical examination showed triangular facies and micrognatia (Fig. 1A, B), ar-rhythmic heart sounds and murmur of mitral insufficiency. Laboratory exams showed hypokalemia. Her 12-lead ECG (Fig. 1C) showed sinus rhythm, prominent U wave, QT/QTc 409/510 ms, and ventricular pre-mature beats (VPB). Holter monitoring confirmed very frequent VPB (41,192/24 h), with multiple morphologies, couplets, bigeminy, and several episodes of non-sustained ventricular tachycardia. Severe mitral regurgitation secondary to prolapse of the anterior leaflet was con-firmed (Fig. 2A, B). She underwent uncomplicated mitral valvuloplasty and was discharged with potassium supplementation. After surgery, the number of fainting episodes was substantially decreased. Initially, the diagnosis of ATS was not suspected and she was given amiodarone and later sotalol without effect on VPB. Four years later, when the diag-nosis of ATS was suspected, a detailed clinical examination revealed short stature, slow weight gain, large forehead, abundant eyebrows, downward slanting palpebral fissures, flat nasal bridge, bulbous nose, malar and mandibular hypoplasia, dental crowding, low set ears, clinodactyly of the fifth fingers of both hands, and cutaneous syndactyly. Using massive sequencing sponsored by Sistemas Genómicos® (Valen-cia, Spain) in three different genes for LQTS, it was identified a patho-genic mutation in the KCNJ2 gene, which changes an arginine by tryptophan at residue 218 in the protein, affecting interaction between K ir 2.1 and phosphatidylinositol-4,5-bisphosphate (PIP2), which makes K ir 2.1 enters an extra-long closed state [1]. A variant of unknown signif-icance (rs201861473) in the CACNA1C gene was also identified. Once the diagnosis was confirmed, she was given flecainide (up to 5 mg/kg/ day) without any relevant decrease in VPB. Under this treatment, she presents syncope suggestive of a vasovagal origin as it was preceded by dizziness and blurred vision, with no palpitations or cyanosis. When she arrived to the Emergency Department, 5 min later, she was found in sinus rhythm and was hospitalized. Twelve days later, still hos-pitalized, another syncope occurred. This time with generalized sei-zures. Due to the seizures, an electroencephalogram (EEG) was performed and considered frankly abnormal (Fig. 3), the brain MRI was normal. Instructions were given to take diphenylhydantoin and flecainide but the relatives never give it to her, she only received potas-sium supplementation. One year later she had another syncope, without premonitory symptoms and with facial traumatism. Therefore she underwent EP study. No VT/FV could be induced and the burden of PVB was so low that they could not be mapped; interestingly PVB di-minished with isoproterenol infusion. An implantable loop recorder
    Full-text · Article · Feb 2015 · International Journal of Cardiology
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    ABSTRACT: Andersen–Tawil syndrome (ATS) is a rare hereditary multisystem disorder. Ventricular arrhythmias, periodic paralysis and dysmorphic features constitute the classic triad of ATS symptoms. The expressivity of these symptoms is, however, extremely variable, even within single ATS affected families, and not all ATS patients present with the full triad of symptoms. ATS patients may show a prolongation of the QT interval, which explains the classification as long QT syndrome type 7 (LQT7), and specific neurological or neurocognitive defects. In ATS type 1 (ATS1), the syndrome is associated with a loss-of-function mutation in the KCNJ2 gene, which encodes the Kir2.1 inward rectifier potassium channel. In ATS type 2 (ATS2), which does not differ from ATS1 in its clinical symptoms, the genetic defect is unknown. Consequently, ATS2 comprises all cases of ATS in which genetic testing did not reveal a mutation in KCNJ2. The loss-of-function mutations in KCNJ2 in ATS1 affect the excitability of both skeletal and cardiac muscle, which underlies the cardiac arrhythmias and periodic paralysis associated with ATS. Thus far, the molecular mechanism of the dysmorphic features is only poorly understood. In this review, we summarize the clinical symptoms, the underlying genetic and molecular defects, and the management and treatment of ATS.
    No preview · Article · Dec 2013 · International journal of cardiology
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    ABSTRACT: Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism characterized by episodes of weakness. Although TPP has been described in patients all over the world, it is especially frequent in Asiatic patients. Recently, two genomewide association studies have found a susceptibility locus on chromosome 17q24.3 near the KCNJ2 gene, which is responsible for another cause of periodic paralysis, the Andersen-Tawil syndrome (ATS). We report the first patient diagnosed with ATS with a de novo c.G899C mutation in the KCNJ2 gene in 2010 who developed an autoimmune hyperthyroidism and TPP in 2013. At the time of the ATS diagnosis other causes of periodic paralysis, including thyroid dysfunction, were ruled out. The condition of the patient, who had mild episodes of proximal weakness at follow-up, deteriorated dramatically in 2013, presenting continuous episodes of severe generalized weakness associated with low levels of potassium requiring frequent admissions to the hospital. After a few months, he also presented signs of hyperthyroidism, and a diagnosis of Grave's disease was made. In our opinion, this case clearly demonstrates that a dysfunction of the Kir2.1 potassium channel encoded by the KCNJ2 gene is a risk factor to develop TPP, and can be a useful tool to identify patients at risk in daily clinics.Journal of Human Genetics advance online publication, 22 May 2014; doi:10.1038/jhg.2014.43.
    No preview · Article · May 2014 · Journal of Human Genetics
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