Andersen–Tawil syndrome

Andersen–Tawil syndrome, also called Andersen syndrome and Long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The condition is associated with a disturbance of the electrical function of the heart, characterised by a feature of an electrocardiogram known as a long QT interval. This abnormality increases the risk of experiencing abnormal heart rhythms. Unlike those with other forms of Long QT syndrome, those with Andersen–Tawil syndrome often have characteristic physical features including low-set ears and a small lower jaw, and may experience intermittent periods of muscle weakness known as hypokalaemic periodic paralysis. Andersen–Tawil syndrome, also called Andersen syndrome and Long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The condition is associated with a disturbance of the electrical function of the heart, characterised by a feature of an electrocardiogram known as a long QT interval. This abnormality increases the risk of experiencing abnormal heart rhythms. Unlike those with other forms of Long QT syndrome, those with Andersen–Tawil syndrome often have characteristic physical features including low-set ears and a small lower jaw, and may experience intermittent periods of muscle weakness known as hypokalaemic periodic paralysis. Andersen–Tawil syndrome is inherited in an autosomal dominant pattern. It is caused in most cases by a mutation in the KCNJ2 gene which encodes an ion channel that transports potassium out of cardiac muscle cells. The arrhythmias seen in the condition can be treated with flecainide or beta-blockers, but an implantable defibrillator may sometimes be required. Periodic paralysis can be treated with carbonic anhydrase inhibitors such as acetazolamide. The condition is very rare and is estimated to affect one person in every million. The triad of features seen in this condition were first described in 1971 by Ellen Andersen, and significant contributions to its understanding were made by Rabi Tawil. Andersen-Tawil Syndrome classically comprises three groups of features: abnormal electrical function of the heart, hypokalemic periodic paralysis, and characteristic physical features, although some of those affected will not exhibit all aspects of the condition. Andersen-Tawil syndrome affects the heart by prolonging the QT interval, a measure of how long it takes the heart to relax after each heart beat. This, as in other forms of long QT syndrome, can lead to abnormal heart rhythms such as ventricular ectopy or ventricular tachycardia causing palpitations. The ventricular tachycardia seen in Andersen-Tawil syndrome often takes a form known as bidirectional ventricular tachycardia. The arrhythmias seen in association with the condition can cause sudden cardiac death, but the risk of this is lower than in other forms of Long QT syndrome. The physical abnormalities associated with Andersen–Tawil syndrome typically affect the head, face, limbs and spine. Abnormalities of the head and face include an unusually small lower jaw (micrognathia), low-set ears, widely spaced eyes (hypertelorism), a broad forehead and nasal root, a high arched or cleft palate, and a long narrow head (scaphocephaly). Abnormalities of the limbs and spine include an abnormal curvature of the fingers, particularly the fifth finger (clinodactyly), fused fingers or toes (syndactyly), short stature, and a curved spine (scoliosis). The third key feature of Andersen–Tawil syndrome is intermittent muscle weakness. This can last from seconds to minutes, but in some cases may last for days at a time. Weakness often occurs at times when the levels of potassium in the blood are lower than normal (hypokalaemia), and is referred to as hypokalaemic periodic paralysis. This weakness can however occur at times when potassium levels are normal, triggered by other factors including exercise, cold, or even menstruation. Andersen–Tawil syndrome is a genetic disorder which in the majority of cases is caused by a mutation in the KCNJ2 gene. The condition is often inherited from a parent in an autosomal dominant manner, but may occur due to a new genetic mutation in the affected person. Two types of Andersen–Tawil syndrome have been described, distinguished by the genetic abnormality that is detected. Type 1 Andersen-Tawil, accounting for about 60% of cases, is caused by mutations in the KCNJ2 gene. In type 2 Andersen–Tawil, accounting for about 40% of cases, a KCNJ2 mutation is not identified. Mutations in a related gene encoding a similar potassium ion channel, KCNJ5, have been identified in some of those with type 2 Andersen–Tawil, but in many cases a genetic variant is not found. The protein made by the KCNJ2 gene forms an ion channel that transports potassium ions into muscle cells. This specific channel (the inward rectifier potassium channel Kir2.1) carries a potassium current known as IK1 which is responsible for setting the resting membrane potential of muscle cells and is therefore critical for maintaining the normal functions of skeletal and cardiac muscle. Mutations in the KCNJ2 gene alter the usual structure and function of potassium channels or prevent the channels from being inserted correctly into the cell membrane. Many mutations prevent a molecule called PIP2 from binding to the channels and effectively regulating their activity. These changes disrupt the flow of potassium ions, leading to the periodic paralysis and abnormal heart rhythms characteristic of Andersen–Tawil syndrome.