Severe infantile myoclonic epilepsy; Dravet syndrome ... (Severe myoclonic epilepsy of infancy, Dravet syndrome) - Gen SCN1A

Dravet syndrome (DS), formerly known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy that usually occurs during the first year of life. It is characterized by severe epilepsy that does not respond adequately to treatment. Clonic seizure or tonic-clonic seizures are usually associated with fever and usually begin before the first birthday of the affected patient. As more recurrences, fever is increasingly discreet. From the second or third year of life other episodes, usually afebrile, including myoclonic seizures, atypical absence seizures and complex partial seizures may occur. Slowing the disease progresses psychomotor development and often also by the appearance of behavioral disorders and ataxia.

This process is due in 80% of cases with mutations in the gene SCN1A, located on the long arm of chromosome 2 (2q24.3). This gene consists of 26 exons that span over 82 kb of genomic DNA and encoding ? subunit of the sodium channel Nav1.1 voltage - dependent. These channels are in the brain and muscles, which control the flow of sodium ions into cells. In the brain, Nav1.1 channels are involved in the transmission of signals from one neuron to another. Communication between neurons depends on neurotransmitters, which are released from one neuron and are captured by neighboring neurons. The flow of sodium ions through Nav1.1 channels helps determine when the neurotransmitters are released.

We found over 150 mutations in the gene SCN1A with various types of seizures that begin in childhood or childhood. Several of these abnormalities are relatively mild and include simple febrile seizures that begin in childhood and others that may persist beyond childhood. Other alterations cause more severe seizures that last longer and can be difficult to control. These recurrent seizures can worsen over time and lead to a decline in brain function. These severe convulsive disorders include severe infantile myoclonic epilepsy (SMEI) and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). The underlying mutations SCN1A convulsive disorders have a variety of effects on the function of Nav1.1 channel. Milder processes are due to mutations changing the individual amino acids in the channel, which alters the channel structure. The most serious processes may be due to several different changes in the gene SCN1A. Some mutations result encoding a non - functional version of Nav1.1 channel or reduce the number of these channels in each cell produced. Other mutations change individual amino acids in critical regions of the channel. All these genetic changes affect the ability of Nav1.1 channels for transporting sodium ions in neurons. It is unclear, however, why these genetic changes result in a wide range of convulsive disorders.

Most of these genetic alterations are detectable by sequencing the exons 26 comprising SCN1A gene. However, a small percentage of cases (10-12%) may lack mutations and are caused by deletions or duplications requiring another detection method. To detect these deletions or duplications the procedure MLPA (Multiplex Ligation-dependent Probe Amplification) is commonly used. This procedure uses a commercial kit (kit) and is based on the use of labeled probes that provide greater or lesser depending on the number of copies of the genomic sequence signal. The detected signal depends on the hybridization of the probes, which depends on several factors. The same manufacturers indicate these problems, and recommend to confirm the results obtained by the MLPA test by another procedure. Therefore in IVAMI, used to detect deletions or duplications the method of quantitative PCR in real time, based on comparison of the amount of amplicons generated, which is related to the number of existing copies of a genomic sequence as they are increased if (duplication) will be detected more amplicons more genomic copies exist, and conversely, if they are decreased (deletions) less amplicons will be detected at a specific number of cycles.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed. However, most cases are due to new mutations in the SCN1A gene and occur in people with no family history of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Dravet syndrome, by complete PCR amplification of the exons of the gene SCN1A, and subsequent sequencing. However, no cases have been reported in which point mutations are deletions or genetic duplication. These deletions or duplications can be detected by the MLPA technique, but due to the large number of factors which may affect the results of the test MLPA in IVAMI test performed quantitative real time PCR. This test determines the proportion of the genomic sequences of each exon relative to a genomic pattern of another gene of the same individual.

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).