BME 301 Group 2

Andersen’s syndrome, also known as Andersen-Tawil syndrome (ATS) is a rare inherited autosomal dominant disorder that affects reportedly 100 people worldwide. ATS is typically characterized by symptoms including irregular heart rhythms, brief episodes of localized muscle weakness or periodic paralysis in limbs, and developmental abnormalities.

ATS is categorized into two types: Type I accounts for about 60% of all cases of ATS and is caused by mutations in the KCNJ2 gene, which lead to abnormalities in the ion channels (potassium channels) of the muscle cell membranes. The causes, however, to Type II ATS, which account for the remaining 40% of all cases, have not been discovered yet.

Researchers and physicians do not fully understand the underlying genetics of this disorder. Type I is known to be caused by a mutation in the KCNJ2 gene; so far, there are over twenty known mutations in this gene that cause ATS [1]. The gene KCNJ2 contains the information necessary to produce a protein that forms an ion channel across the cell membrane, more specifically, the potassium ion channel [2]. While some mutations change the shape of the protein, others change the orientation of the protein within the membrane. About half of the mutations, however, prevent the binding of phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 acts as an intermediate in a cascade of reactions that affects the rest of the cell function, including Ca²⁺ channels in the endoplasmic reticulum [2]. The KCNJ2 gene encodes K⁺ channel component of the inward rectifier IK1 called Kir2.1 [2]. During the most terminal phase of repolarization, the inward rectifier IK1 produces a repolarizing current [2].

The KCNJ2 gene is located on chromosome 17q24.3, between base pairs 68,165,675 and 68,176,184 [1]. Specific mutations within this region cause the symptoms of ATS, although the pattern is not fully understood. A particular family with a T192A KCNJ2 mutation exhibits periodic paralysis and arrhythmias, but do not phenotypically present any form of dysmorphic features [2]. Scientists attribute this phenomenon to an assumption that there is a tetrameric combination of one wild-type and three T192A Kir2.1 subunits [2]. PIP2 is presumed to still bind to the one functional subunit, although the T192A Kir2.1 channels are nonfunctional, causing only partial suppression of Kir2.1 currents.

Symptoms such as periodic paralysis appear to have a trigger. Common triggers for paralysis are rest after activity, periods of inactivity (sleep, for example), starving and overeating, cold temperature, and sometimes hydrocarbon fumes. Triggers to paralysis can be avoided with proper management. Many patients still suffer from irregular heart rhythms, including ventricular arrhythmia and long QT syndrome. Ventricular arrhythmia disrupts the rhythm of the heart's lower chambers, while long QT syndrome, an electrophysiological disorder, causes the cardiac muscle to take longer than usual to recharge between beats. If the latter is left untreated, patients will often experience discomfort, syncope, or cardiac arrest.

Developmental abnormalities of ATS are exhibited as abnormal physical characteristics including large widely spaced eyes, a small jaw, low-set ears, crooked fingers or toes, webbed or fused 2nd and 3rd toes, and small stature. The severity of symptoms varies among patients; most are able to lead reasonably normal lives, while some are physically impaired and may require wheelchairs for transportation.

Due to the rarity of this disorder and the extremely small number of affected individuals diagnosed with Anderson-Tawil Syndrome (ATS), there are very few treatments today that help patients. The most common treatment for ATS is the oral intake of K⁺ ions to minimize the effect of low serum potassium concentrations. Since there are constant changes of potassium levels in cardiac and skeletal muscles, it is difficult to monitor the body’s response to drugs and overall refractoriness to anti-arrhythmic agents. Therefore, the treatments toward ATS have to be individualized for the best effect.

For the treatment of the syndrome’s manifestations, patients are required to take potassium supplements (20-30 mEq/L) orally in 15-30 minute intervals until the potassium concentration is normalized. During the treatment, ECG is used to monitoring the potassium concentration levels to ensure accurate control.

In order to prevent the reoccurrence of symptoms, patients need specific lifestyle and dietary changes to avoid triggering the manifestations of the disorder. In addition to lifestyle and diet changes, carbonic anhydrase inhibitors and potassium supplements could be taken by the patients on a daily basis to inhibit symptoms expression. Individuals with ATS should avoid the use of class I anti-arrhythmic drugs, as they may paradoxically exacerbate the neuromuscular symptoms.

Computer modeling:

Convert a template that simulates healthy cells into ill cells.

4 possible changes in ion channel functions: