Andersen-Tawil Syndrome

Andersen-Tawil syndrome is a rare genetic disorder that affects the muscles, heart, and physical development, causing episodes of muscle weakness, abnormal heart rhythms, and distinctive physical features in those affected.

Table of contents

• What is Andersen-Tawil syndrome
• Signs and symptoms
• How common is the condition
• What causes Andersen-Tawil syndrome
• How the condition is inherited
• Diagnosis and testing
• Treatment and management

Long QT Syndrome Type 7, Andersen Syndrome, Cardiodysrhythmic potassium-sensitive periodic paralysis

What is Andersen-Tawil syndrome

Andersen-Tawil syndrome is a disorder that causes episodes of muscle weakness, changes in heart rhythm, and developmental abnormalities. The condition is characterized by three main groups of features that can appear together or separately in affected individuals.^[1]

The condition typically presents in the first or second decade of life with either heart symptoms such as palpitations (the feeling that the heart is skipping beats) and fainting or weakness that occurs after rest or following rest after physical activity. About 60 percent of affected individuals have all three major features of the condition.^[1][2]

The signs and symptoms of Andersen-Tawil syndrome vary widely, and they can be different even among affected members of the same family. Some people with the condition may also experience mild learning difficulties and specific problems with thinking skills, including deficits in planning and abstract reasoning.^[2]

Signs and symptoms

Andersen-Tawil syndrome classically involves three groups of features: abnormal electrical function of the heart, periodic paralysis (episodes of temporary muscle weakness), and characteristic physical features, although some affected people will not show all aspects of the condition.^[2][3]

Periodic paralysis begins early in life, and episodes last from hours to days. These episodes may occur after exercise or long periods of rest, but they often have no obvious trigger. Muscle strength usually returns to normal between episodes. However, mild muscle weakness may eventually become permanent.^[1]

In people with Andersen-Tawil syndrome, the most common changes affecting the heart are ventricular arrhythmia, which is a disruption in the rhythm of the heart’s lower chambers (the ventricles), and long QT syndrome. Long QT syndrome is a heart condition that causes the heart muscle to take longer than usual to recharge between beats. The irregular heartbeats can lead to discomfort, such as palpitations. Uncommonly, the irregular heartbeats can cause fainting, and even more rarely, sudden death.^[1]

The heart rhythm disturbances seen in Andersen-Tawil syndrome often take a form known as bidirectional ventricular tachycardia. While these arrhythmias can cause sudden cardiac death, the risk of this is lower than in other forms of long QT syndrome.^[3]

Physical abnormalities associated with Andersen-Tawil syndrome typically affect the face, other parts of the head, and the limbs. These features often include a very small lower jaw (micrognathia), dental abnormalities such as crowded teeth, low-set ears, widely spaced eyes, fusion of the second and third toes (syndactyly), and unusual curving of the fingers or toes (clinodactyly). Some affected people also have short stature and an abnormal side-to-side curvature of the spine (scoliosis).^[1]

Other facial features may include a broad forehead, a broad nasal root, a high arched or cleft palate, and a long narrow head.^[3]

How common is the condition

Andersen-Tawil syndrome is a rare genetic disorder. Its exact prevalence is unknown, although it is estimated to affect 1 in 1 million people worldwide. About 200 affected individuals have been described in the medical literature.^[1]

Researchers believe that Andersen-Tawil syndrome accounts for less than 10 percent of all cases of periodic paralysis.^[1]

What causes Andersen-Tawil syndrome

Mutations in the KCNJ2 gene cause about 60 percent of all cases of Andersen-Tawil syndrome. When the disorder is caused by mutations in this gene, it is classified as type 1, also called ATS1.^[1]

The KCNJ2 gene provides instructions for making channels that transport positively charged potassium ions across the membrane of muscle cells. The movement of potassium ions through these channels is critical for maintaining the normal function of muscles used for movement and cardiac muscle. Mutations in the KCNJ2 gene alter the usual structure and function of these potassium channels. These changes disrupt the flow of potassium ions in skeletal and cardiac muscle, leading to the periodic paralysis and irregular heart rhythm characteristic of Andersen-Tawil syndrome.^[1]

The majority of patients with Andersen-Tawil syndrome have specific changes in the KCNJ2 gene that result in a dominant negative effect on potassium channel current, resulting in prolonged electrical activity in the muscle cells.^[6]

Researchers have not determined the role of the KCNJ2 gene in bone development, and it is not known how mutations in the gene lead to the skeletal changes and other physical abnormalities often found in Andersen-Tawil syndrome.^[1]

In the 40 percent of cases not caused by KCNJ2 gene mutations, the cause of Andersen-Tawil syndrome is usually unknown. These cases are classified as type 2, also called ATS2. Studies suggest that variations in at least one other potassium channel gene may underlie the disorder in some of these affected individuals.^[1]

How the condition is inherited

This condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. When the condition results from a mutation in the KCNJ2 gene, an affected individual may inherit the mutation from one affected parent. In other cases, the condition results from a new mutation in the KCNJ2 gene. About 50 percent of children will not have a parent with the condition.^[1]

The parents of a child with Andersen-Tawil syndrome should have an evaluation by a heart specialist and specialist in nervous system disorders. Parents should meet with a medical geneticist or genetic counselor to discuss genetic testing for Andersen-Tawil syndrome. If parents do not have the condition, then the siblings of the child with Andersen-Tawil syndrome have a low risk to have the condition.^[10]

Diagnosis and testing

The diagnosis of Andersen-Tawil syndrome is established in an individual with characteristic clinical findings and results from heart electrical testing, and by identification of a disease-causing change in the KCNJ2 gene.^[2]

Obtaining an accurate diagnosis involves obtaining a blood test for potassium levels during an episode of weakness. High values suggest one form of periodic paralysis and low values suggest another form, but normal values do not rule out the diagnosis.^[2]

Genetic testing is a simple next step. Testing can help identify the specific mutation in the KCNJ2 gene. Short or long exercise electromyography (EMG), a test that measures muscle electrical activity, is helpful. Similar episodes in family members support the diagnosis.^[2]

Most importantly is the patient’s medical history. Triggers of rest after exercise, cold, or illness can suggest the diagnosis. Improvement with oral potassium supplementation can also provide diagnostic clues. The presence of facial features and skeletal abnormalities such as curved fingers, fused toes, and low-set ears help support the diagnosis of Andersen-Tawil syndrome.^[2][13]

It is important to rule out thyroid problems in cases where low potassium causes periodic paralysis, as thyroid hormone excess can produce similar symptoms.^[2]

Annual screening of individuals with a KCNJ2 gene mutation who do not have symptoms should include a 12-lead electrocardiogram (EKG) and 24-hour continuous heart monitoring.^[2]

Treatment and management

For episodes of weakness when blood potassium concentration is low (less than 3.0 millimoles per liter), treatment involves giving oral potassium every 15 to 30 minutes until blood levels normalize. The dose should not exceed 200 milliequivalents in a 12-hour period. If a relative drop in blood potassium within the normal range causes episodes of paralysis, an individual potassium replacement plan with a goal of maintaining blood potassium levels in the high range of normal can be considered.^[2]

If blood potassium concentration is high during an attack, eating carbohydrates may lower blood potassium levels. Mild exercise may shorten or reduce the severity of the attack.^[2]

Prevention of attacks can be achieved through lifestyle and dietary changes to avoid known triggers. Medications called carbonic anhydrase inhibitors can reduce the frequency and severity of episodes of weakness. Daily use of slow-release potassium supplements may also help.^[2]

For heart rhythm problems, an implantable cardioverter-defibrillator may be placed for those who experience fainting due to rapid heart rhythms. Treatment with the medication flecainide should be considered for significant, frequent abnormal heart rhythms, especially when heart pumping function is reduced.^[2]

Certain medications and substances should be avoided, including medications known to prolong heart electrical activity (QT intervals), salbutamol inhalers (which may worsen heart arrhythmias), and certain diuretics that can cause potassium loss.^[2]

Cautious use of heart rhythm medications is needed, particularly certain classes of drugs that may paradoxically worsen the muscle symptoms.^[2]