National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Andersen-Tawil Syndrome is not the name you expected.
Andersen-Tawil syndrome is a rare genetic disorder characterized by episodes of muscle weakness and paralysis (periodic paralysis); abnormalities affecting the electrical system of the heart that can cause abnormal heart rhythms (arrhythmias); and a variety of distinctive facial and skeletal features. The specific symptoms and severity can vary greatly from one person to another, even among members of the same family. Some individuals will not develop all of the characteristic findings. Distinctive facial features may be so mild as to go unnoticed. In some cases, Andersen-Tawil syndrome is caused by mutations in the KCNJ2 gene; in other cases, the associated gene is unknown. The KCNJ2 gene mutation can occur randomly for unknown reasons (sporadically) or be inherited in an autosomal dominant manner.
Andersen-Tawil syndrome is sometimes referred to as long QT syndrome 7 because some individuals in early reports of the disorder had a prolonged QT interval, which is measured on an electrocardiogram and indicates that the heart muscle is taking longer than usual to recharge between beats. However, subsequent clinical reports have shown the QT interval is not prolonged or only mildly prolonged in most cases. Instead, the T-U wave pattern is markedly prolonged. In addition, unlike most forms of long QT syndrome, Andersen-Tawil syndrome is associated with symptoms in addition to disturbances of the electrical system of the heart. Although still sub-classified as a form of long QT syndrome, the disorder is recognized as separate from traditional long QT syndromes.
Andersen-Tawil syndrome can also be classified as a form of periodic paralysis, a group of rare neuromuscular disorders characterized by episodes of weakness or paralysis. The terms Andersen-Tawil syndrome type 1 or type 2 are also used in the medical literature. Type 1 refers to cases caused by a known KCNJ2 gene mutation; type 2 refers to cases without an identified KCNJ2 mutation.
Andersen-Tawil syndrome is defined by three main features (i.e. a clinical triad), specifically periodic paralysis, arrhythmias and heart abnormalities, and distinctive physical features. However, the disorder is highly variable and not all affected individuals will develop all three of these characteristic symptoms. Andersen-Tawil syndrome can vary greatly in expression and severity from one person to another, even among members of the same family.
Although researchers have been able to establish a clear syndrome with characteristic or "core" symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children's physician and medical team about their specific case, associated symptoms and overall prognosis.
Affected individuals may experience temporary episodes of flaccid, muscle weakness or paralysis, known as periodic paralysis. The legs are most often affected and the severity of muscle weakness can range from mild weakness to an inability to walk unassisted. The arms, hands, legs and feet are also commonly affected. The frequency and duration of episodes varies from one person to another, and from one episode to the next for the same person. Some episodes may last only minutes to hours; others can go on for days. Episodes can occur without warning (spontaneously), but can also occur following prolonged exercise, prolonged rest (e.g. upon awaking in the morning), rest after exercise, going too long without eating, eating a large meal, or emotional stress. Episodes can range in frequency from once per day to once per year. In some cases, a mild, but permanent weakness that is present even between episodes can develop with age and progress slowly over time.
In most cases, periodic paralysis may be associated with low levels of potassium in the blood (hypokalemia), a common finding with other forms of periodic paralysis. However, some individuals who experience periodic paralysis have had normal potassium levels or even elevated levels (hyperkalemia). Low potassium levels can also impact the function of heart muscle cells.
Affected individuals may experience disturbances of the normal rhythm of the heartbeat (arrhythmias), which can include abnormally fast heartbeats that originate in the lower chamber of the heart (ventricular tachycardia). Generally, this may not cause any symptoms (asymptomatic) or may cause shortness of breath or palpitations. In some cases, these arrhythmias may degenerate to cause episodes of fainting or loss of consciousness (syncope). In severe cases, the possibility of cardiac arrest and sudden death exists. Although sudden death due to the cardiac abnormalities has occurred in Andersen-Tawil syndrome, it is extremely rare.
Some affected individuals also have characteristic physical features including distinctive facial features, which are often mild in expression. Such features include a broad forehead, low-set ears, eyes that are spaced apart wider than usual (hypertelorism), and a small jaw (micrognathia). Additional facial features include a round (bulbous) nose, a thin upper lip, a triangular-shaped face, highly-arched roof of the mouth (palate), a cleft palate, and underdevelopment of the cheek bones (malar hypoplasia). Common physical features include webbing (syndactyly) of the second and/or third toes, pinkies that are fixed in a bent or crooked position (clinodactyly), and disproportionately small fingers and toes (brachydactyly). Additional findings include small hands and feet, loose joints, and abnormal sideways curvature of the spine (scoliosis). Dental anomalies have also been reported including delayed loss of primary or 'baby' teeth (persistent primary dentition), multiple missing teeth (oligodontia), and teeth that are abnormally crowed together.
As affected children grow into adulthood, short stature may become evident. Short stature refers to an individual whose height is much shorter than would otherwise be expected based upon age and gender.
Some individuals with Andersen-Tawil syndrome have experienced neuropsychiatric abnormalities including mild learning disabilities, depression, and deficits in executive functioning and abstract reasoning. Some infants experience seizures without fever (afebrile seizures).
In approximately 60% of cases, Andersen-Tawil syndrome is caused by a mutation in the KCNJ2 gene. In the other 40% of cases, the underlying genetic mutation is unknown, suggesting that additional as-yet-unidentified genes also cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
In approximately 50% of cases, the KCNJ2 gene mutation occurs sporadically, which means that in those specific cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or "carried" by a healthy parent. When the disorder runs in families, the mutations are inherited in an autosomal dominant manner.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
The KCNJ2 gene produces (encodes) a protein essential for the proper development and function of certain ion channels. These channels are pores in cell membranes that regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium ions) into muscle cells, including heart muscle and limb muscle cells and tissue. These ions carry electrical impulses necessary for the normal function of the cells involved. Mutations in the KCNJ2 gene results in abnormal functioning of the ion channels and, in turn, affect the proper function and development of skeletal muscle and the heart's electrical system. The exact manner this mutation affects bone development and cause the distinctive facial and other skeletal features associated with Andersen-Tawil syndrome is not known.
Andersen-Tawil syndrome affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown. More than 100 cases have been reported in the medical literature. Because many cases go undiagnosed or misdiagnosed, determining the true frequency of Andersen-Tawil syndrome in the general population is difficult.
Symptoms of the following disorders can be similar to those of Andersen-Tawil syndrome. Comparisons may be useful for a differential diagnosis.
Andersen-Tawil syndrome needs to be distinguished from other forms of periodic paralysis including hypokalemic periodic paralysis, hyperkalemic period paralysis, and thyrotoxic periodic paralysis. Other conditions that cause a prolonged QT interval or syncope should be ruled out as well including vasovagal syncope, orthostatic hypotension, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and catecholamingergic polymorphic ventricular tachycardia (CPVT). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of Andersen-Tawil syndrome is based upon identification of characteristic symptoms (e.g. periodic paralysis, symptomatic arrhythmias, and/or distinctive facial and skeletal features), a detailed family and patient history, a thorough clinical evaluation and a variety of specialized tests.
Clinical Testing and Workup
Because potassium levels may be reduced during an episode of periodic paralysis, a blood test to determine the serum potassium levels during an episode can be helpful in diagnosing the disorder in some cases.
Long exercise nerve conduction studies have been used to help diagnose individuals with Andersen-Tawil syndrome. During this test, an affected individual will perform voluntary muscle contractions of a small muscle on the ulnar side of the palm of the hand for approximately 2-5 minutes. This test allows physician to evaluate muscle function and specific results can be indicative of periodic paralysis.
An electrocardiogram or EKG records the heart's electrical impulses and may reveal abnormal electrical patterns or activity commonly associated with Andersen-Tawil syndrome including prominent U waves, prolonged QU intervals, prolonged QT intervals, premature ventricular contractions, or polymorphic ventricular tachycardia.
Some individuals may undergo 24-Holter monitoring, during which an affected individual wears a small device for 24 hours. Through electrodes attached to the chest, this device continuously records the rhythm of the heart in order to detect the presence, frequency and duration of ventricular tachycardia and other symptoms.
Molecular genetic testing can confirm a diagnosis of Andersen-Tawil syndrome in some cases. Molecular genetic testing can detect mutations in the KCNJ2 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
The treatment of Andersen-Tawil syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists experienced in the treatment of periodic paralysis, cardiologists experienced in the treatment of long QT syndrome, and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment. Genetic counseling may be of benefit for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Andersen-Tawil syndrome.
Affected individuals are encouraged to avoid potential triggers of periodic paralysis (e.g. rest following exercise or prolonged exercise). Avoidance of drugs that can prolong the QT interval is also recommended.
When periodic paralysis is associated with low potassium levels, treatment with oral supplemental potassium can be beneficial. In individuals prone to low potassium levels, daily potassium supplementation can be considered. Potassium supplementation may also shorten the QT interval, which can be of benefit for individuals who also experience a long QT interval.
A periodic paralysis episode that occurs when potassium levels are high usually resolve on their own within 60 minutes. However, eating carbohydrates or continuing mild exercise can shorten the duration of the episode.
Specific drugs known as carbonic anhydrase inhibitors, such as acetazolamide and dichlorpenamide, have been used successfully to treat periodic paralysis in individuals with Andersen-Tawil syndrome. These drugs have also been shown to be effective in other forms of periodic paralysis.
Despite a high rate of ventricular arrhythmias, the prognosis regarding arrhythmias is generally very good. Many arrhythmias do not cause symptoms and go away on their own with problems (self-terminate). Various different drugs have been used, but no standard, effective therapy has been established. Beta-adrenergic blocking drugs (beta blockers), drugs that suppress abnormal heart rhythms (anti-arrhythmics) such as flecainide or amiodarone, or calcium-channel blocking drugs such as verapamil have all shown some effect. Beta blockers are commonly used to treat abnormal heart rhythms. These drugs, which include propranolol, atenolol, metroprolol, and nadolol, reduce the workload of the heart by decreasing the electrical stimulation of the heart, thereby slowing the heartbeat and preventing symptoms. Beta blockers have been used in conjunction with flecainide. Some anti-arrhythmic drugs can worsen neuromuscular symptoms and should only be used in individuals with Andersen-Tawil syndrome with caution.
Treatment with an implantable automatic cardioverter-defibrillator or ICD has been used in rare cases. ICDs are considered for individuals in whom cardiac arrhythmias are severe and symptomatic. These small devices are implanted under the skin of the chest. The device detects the abnormal heartbeat automatically and selectively delivers an electrical impulse to restore the proper heartbeat. Opting for an ICD is a lifelong therapy that carries significant implications including the potential for complications, especially in younger individuals, and should be undertaken only after consultation with appropriate medical personnel and a careful risk vs. benefit evaluation.
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