Timothy syndrome ... (Timothy syndrome) - Gen CACNA1C.
Timothy syndrome is a rare disorder that affects many parts of the body, including the heart, fingers and nervous system. This disease is characterized by a cardiac condition called long QT syndrome, which causes the heart muscle requires more time than usual to recharge between beats. This anomaly in the electrical system of the heart can cause arrhythmia, which can lead to sudden death. Many people with Timothy syndrome are also born with structural heart defects that affect the heart's ability to pump blood effectively. As a result of these serious heart problems, many people with Timothy syndrome live only in childhood. The most frequent cause of death is ventricular tachyarrhythmia, in which the ventricles beat abnormally fast and lead to cardiac arrest.
Other associated signs and symptoms may include cutaneous syndactyly, flattened nasal bridge, low - set ears, a small upper jaw, a thin upper lip and small teeth and out of place, with dental caries. Additional signs and symptoms of Timothy syndrome may include baldness at birth, frequent infections, hypoglycemia and hypothermia. Cases have been reported where children affected have features of autism or autism spectrum disorders. Affected children often have impaired communication skills and socialization, and delayed development of speech and language. Other abnormalities of the nervous system, including mental retardation and seizures, may also occur in children with Timothy syndrome.
They have identified two forms of Timothy syndrome. Type 1, also known as the conventional type, includes all the characteristics described above. Type 2, or atypical type, causes more serious long QT syndrome and increased risk of arrhythmia and sudden death is. Unlike the classical type, atypical type does not seem to cause skin syndactyly.
This process is due to mutations in the gene CACNA1C, located on the short arm of chromosome 12 (12p13.3). This gene belongs to a family of genes encoding calcium channels. These channels, which transport of calcium ions into cells, play a key role in the ability of a cell to generate and transmit electrical signals. Calcium ions are involved in many different cellular functions, including cell-cell communication, muscle contraction and regulation of certain genes. The calcium channel formed from CACNA1C gene known as Cav1.2. These channels are found in many cell types, although they appear to be particularly important for the normal function of heart cells and brain. In the heart, Cav1.2 channels control the flow of calcium ions into cardiac muscle cells. By changing the electrical properties of these cells, calcium channel signal the heart muscle to contract and help keep the heart normal rhythm. The role of channels in the brain and other tissues is less clear.
Many different versions of Cav1.2 channel can be encoded from CACNA1C gene by a mechanism known as alternative splicing. This mechanism produces different versions of the channel by cutting and rearranging the genetic instructions in different ways. Some versions of Cav1.2 channel are more common than others in certain parts of the body. For example, in the heart and brain, about 80% of Cav1.2 channels are formed with a particular segment known as exon 8. The other 20% of Cav1.2 channels contains a slightly different version of this segment known as exon 8A. This difference is important in studying the effects of mutations in various tissues CACNA1C.
We have identified a mutation in all people diagnosed with classic Timothy syndrome or type 1. This mutation replaces the amino acid glycine with the amino acid arginine at position 406 (Gly406Arg or G406R). This genetic change occurs in exon 8A, and is present only in the version of Cav1.2 channel formed with this segment. Therefore, in the brain and heart, the mutation affects about 20% of all Cav1.2 channels. Two mutations in the gene CACNA1C are responsible for more intense called atypical Timothy syndrome or type 2. These mutations occur in Cav1.2 channel version incorporated exon 8. One of these genetic changes, G406R, is the same mutation causing classical Timothy syndrome when it occurs in exon 8A. The other mutation replaces the amino acid glycine with serine at amino acid position 402 (Gly402Ser or G402S).
Because the mutations responsible for atypical Timothy syndrome occurring in exon 8 of the gene, are present only in versions Cav1.2 containing this segment. In the brain and heart, this version represents about 80% of all Cav1.2 channels. It is believed that the strongest characteristics of atypical Timothy syndrome are due to a higher percentage of mutated genes in heart cells and brain channels. Mutations in the gene CACNA1C change the structure of Cav1.2 channels throughout the body. The altered channels remain open longer than usual, allowing calcium ions continue to flow into abnormal cells. This overload of calcium ions inside the heart muscle cells changes how the heart beats, which can cause arrhythmia. Work is being done to determine how an increase in the transport of calcium ions in other tissues, including cells in the brain, behind the other features of Timothy syndrome.
It is considered that Timothy syndrome is an autosomal dominant inheritance, which means that a copy of the altered gene in each cell CACNA1C is sufficient to express the disease. Most cases are due to new mutations in the gene and occur in people with no history of disease in your family. Less often, people with Timothy syndrome inherit the altered gene from an affected parent is the mosaic of a CACNA1C mutation. Mosaicism means that the parent has the mutation in some cells but not others.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Timothy syndrome, by complete PCR amplification of exons CACNA1C l gene, and subsequent sequencing. The most common mutation found in exon 8, so we offer the possibility of starting the test with this exon and, if found, would not have to continue studying the other exons, thus reducing time implementation and cost.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).