Andersen-Tawil Syndrome

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What is Andersen-Tawil syndrome?

Anderson-Tawil syndrome is a disorder that causes episodes of muscle weakness (periodic paralysis), changes in heart rhythm (arrhythmia), and developmental abnormalities. The most common changes affecting the heart are ventricular arrhythmia, which is a disruption in the rhythm of the heart's lower chambers, and long QT syndrome. Long QT syndrome is a heart condition that causes the heart (cardiac) muscle to take longer than usual to recharge between beats. If untreated, the irregular heartbeats can lead to discomfort, fainting (syncope), or cardiac arrest.

Physical abnormalities associated with Andersen-Tawil syndrome typically affect the head, face, and limbs. These features often include a very small lower jaw (micrognathia), dental abnormalities, low-set ears, widely spaced eyes, and unusual curving of the fingers or toes (clinodactyly). Some affected people also have short stature and an abnormal curvature of the spine (scoliosis).

Two types of Andersen-Tawil syndrome are distinguished by their genetic causes. Type 1, which accounts for about 60 percent of all cases of the disorder, is caused by mutations in the KCNJ2 gene. The remaining 40 percent of cases are designated as type 2; the cause of these cases is unknown.

How common is Andersen-Tawil syndrome?

Andersen-Tawil syndrome is a rare genetic disorder; its incidence is unknown. About 100 people with this condition have been reported worldwide.

What genes are related to Andersen-Tawil syndrome?

Mutations in the KCNJ2 gene cause Andersen-Tawil syndrome.

The KCNJ2 gene provides instructions for making a protein that forms a channel across cell membranes. This channel transports positively charged atoms (ions) of potassium into muscle cells. The movement of potassium ions through these channels is critical for maintaining the normal functions of muscles used for movement (skeletal muscles) 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 in skeletal and cardiac muscle, leading to the periodic paralysis and irregular heart rhythm characteristic of Andersen-Tawil syndrome.

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 developmental abnormalities often found in Andersen-Tawil syndrome.

How do people inherit Andersen-Tawil syndrome?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, a person with Andersen-Tawil syndrome inherits the mutation from one affected parent. Other cases result from new mutations in the KCNJ2 gene. These cases occur in people with no history of the disorder in their family.

Source: National Institutes of Health

New andersen-tawil syndrome findings from University of Maryland, Department of Physiology published

"Val-302 is located in the G-loop, a structure that is believed to form a flexible barrier for potassium permeation at the apex of the cytoplasmic pore. Consistent with a role in stabilizing the G-loop in an open conformation, we found the V302M mutation specifically renders the channel unable to conduct potassium without altering subunit assembly or attenuating cell surface expression. As predicted by the position of the Val-302 side chain in the crystal structure, amino acid substitution analysis revealed that channel activity and phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity are profoundly sensitive to alterations in the size, shape, and hydrophobicity of side chains at the Val-302 position. The observations establish that the Val-302 side chain is a critical determinant of potassium conduction through the G-loop," wrote D. Ma and colleagues, University of Maryland, Department of Physiology.

The researchers concluded: "Based on our functional studies and the cytoplasmic domain crystal structure, we suggest that Val-302 may influence PIP2 gating indirectly by translating PIP2 binding to conformational changes in the G-loop pore."

Ma and colleagues published their study in the Journal of Biological Chemistry (An andersen-Tawil syndrome mutation in Kir2.1 (V302M) alters the G-loop cytoplasmic K+ conduction pathway. Journal of Biological Chemistry, 2007;282(8):5781-9).

For additional information, contact D. Ma, University of Maryland School of Medicine, Dept. of Physiology, Baltimore, Maryland 21201 USA.

Publisher contact information for the Journal of Biological Chemistry is: American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA.

Keywords: United States, Baltimore, Andersen-Tawil Syndrome, Biological Chemistry, Neurology.

This article was prepared by Pain & Central Nervous System Week editors from staff and other reports. Copyright 2007, Pain & Central Nervous System Week via NewsRx.com.