Lafora progressive myoclonus epilepsy (Lafora progressive myoclonus epilepsy) - Genes EPM2A and NHLRC1
The Lafora progressive myoclonus epilepsy is a brain disorder characterized by epilepsy and decreased intellectual function. Signs and symptoms of the disease usually appear in late childhood or adolescence and worsen over time. Myoclonus can occur when an affected person is at rest and worsens with movement, emotions, or photonic stimulation. Often in the later stages of the disease, myoclonus occur continuously and affect the entire body.
There are several types of seizures that occur frequently in people with Lafora progressive myoclonus epilepsy. On the one hand, tonic-clonic seizures, also known as episodes of epilepsy, affect the entire body causing muscle stiffness, seizures and loss of consciousness. On the other hand, those affected may also have occipital seizures that can cause temporary blindness and visual hallucinations. Eventually, seizures worsen and become more difficult to treat. You can also have a life - threatening condition called status epilepticus. Almost simultaneously starting seizures, intellectual function begins to decline. Behavioral changes, depression, confusion and dysarthria are among the first signs and symptoms of the disease. As the disease progresses, dementia affects memory, judgment and thinking. Affected individuals lose the ability to perform activities of daily life around twenty years and ultimately require comprehensive care. People with Lafora progressive myoclonus epilepsy usually survive until 10 years after the first symptoms appear.
The Lafora progressive myoclonus epilepsy is due to mutations in EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease -laforin-) and NHLRC1 genes (NHL repeat container containing E3 ubiquitin protein ligase 1). These genes encode proteins that play a critical role in the survival of neurons in the brain.
The EPM2A gene, located on the long arm of chromosome 6 (6q24), encoding the protein laforina. Although this protein is active in cells throughout the body, it appears to play a critical role in the survival of neurons in the brain. It is believed that laforina has multiple functions within cells. To perform these functions, the laforina interacts with other proteins, including malin (from NHLRC1 encoded gene). These proteins are part of complex networks transmitting chemical signals and decompose unnecessary or abnormal proteins. Furthermore, laforina can act as a tumor suppressor protein. Laforina and Malina likely play a critical role in the regulation of glycogen coding. The body stores this polysaccharide in the liver and muscles, and breaks it when needed as an energy source. It is likely that laforina and malin can prevent potentially harmful accumulation of glycogen in tissues not normally this molecule is stored, such as the nervous system.
There are more than 50 mutations in the gene EPM2A in people with Lafora progressive myoclonus epilepsy. Many of these mutations change the amino acids in protein laforina. Other mutations deleted or inserted genetic material into the EPM2A gene. Almost all mutations in this gene encoding laforina inhibit or result encoding a non - functional version of the protein. Although it is unclear how mutations in the gene result EPM2A the main features of the disease, it is believed that a loss of laforina prevents cells regulate glycogen production. Consequently, Lafora bodies are formed within many cell types. Lafora bodies are composed of an abnormal form called glycogen polyglucosan that can not be broken down and used as energy source. Therefore, polyglucosans accumulate and can damage cells. Although Lafora bodies are found in many tissues of the body, signs and symptoms of Lafora progressive myoclonus epilepsy are limited to the nervous system. It is unclear how a loss of functional laforina contributes to the formation of Lafora bodies. However, the lack of this protein ultimately kills neurons, interfering with normal brain function. Degeneration of neurons probably underlies seizures, abnormal movements, intellectual impairment and other neurological problems observed.
The NHLRC1 gene, located on the short arm of chromosome 6 (6p22.3), encodes a protein called malina. Although this protein is active in cells throughout the body, it appears to play a critical role in the survival of neurons in the brain. Malin is part of cellular process that degrades unwanted inside cell proteins. This process, known as ubiquitin-system proteasome acts as a system of quality control of the cell by removing excess proteins damaged or deformed. This system also regulates levels of proteins involved in several critical cellular activities, such as the time of cell division and growth. Malin belongs to a group of proteins in the ubiquitin system proteasome protein called ubiquitin E3 ligases. The interaction between malina and laforina encoded from EPM2A gene probably plays a critical role in the regulation of glycogen production. Probably malin and laforina can prevent potentially harmful accumulation of glycogen in tissues that do not normally store this molecule, such as the nervous system.
They have identified at least 62 mutations in the gene NHLRC1 in people with Lafora progressive myoclonus epilepsy. These mutations correspond to: missense mutations (40), small deletions (11), small insertions (6), insertions / deletions small (1) and larger deletions (4). Almost all mutations in this gene encoding malina inhibit or result encoding a non - functional version of the protein. The most frequent mutation replaces the amino acid proline the amino acid alanine at position 69 in the protein malina (Pro69Ala or P69A). The second most common mutation replaces the amino acid glycine by a premature stop signal in coding malina (Gly158Ter or G158X). Although it is unclear how mutations in the gene result NHLRC1 the main features of the disease, is likely to prevent loss malina cells regulate glycogen production. Consequently, Lafora bodies are formed within many cell types. It is unclear how a loss of functional Malina contributes to the formation of Lafora bodies. However, the lack of this protein ultimately kills neurons, interfering with normal brain function. Degeneration of neurons probably underlies seizures, abnormal movements, intellectual impairment and other neurological problems observed.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with progressive myoclonus epilepsy Lafora, by complete PCR amplification of the exons of EPM2A and NHLRC1 genes, respectively, and subsequent sequencing.
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).