Progressive external ophthalmoplegia (Progressive external ophthalmoplegia) - Genes POLG, C10orf2, rrm2b, SLC25A4 and
The progressive external ftalmoplejia or is a disease characterized by weakness of the eye muscles. The alteration usually occurs in adults between 18 and 40 years. The most common signs and symptoms of progressive external ophthalmoplegia include ptosis that can affect one or both eyelids, ophthalmoplegia and myopathy, especially in the neck, arms or legs. Muscle weakness may also cause dysphagia. Although muscle weakness is the main symptom of progressive external ophthalmoplegia, the disease may be accompanied by other signs and symptoms. In these cases, the disease is known as progressive external ophthalmoplegia + (PEO +). Additional signs and symptoms may include sensorineural hearing loss, weakness and loss of sensation in the limbs, hearing loss due to neuropathy, ataxia, parkinsonism and depression.
Progressive external ophthalmoplegia is the part of a spectrum of disorders with signs and symptoms overlap. Similar diseases include other alterations due to mutations in the POLG gene, such as neuropathy-ataxia spectrum and other disorders mtDNA deletion, such as Kearns -Sayre. As progressive external ophthalmoplegia the, other diseases in this spectrum may involve weakness of the eye muscles. However, these changes have many additional features that do not match the signs and symptoms of most people with progressive external ophthalmoplegia.
This may be due to mutations in one of several different genes. In some cases, mutations in nuclear DNA are responsible for disease, including mutations in the POLG gene (Polymerase (DNA) gamma, catalytic subunit), C10orf2 (chromosome 10 open reading frame 2), rrm2b (ribonucleotide reductase regulatory TP53 inducible subunit M2B) and SLC25A4 (solute carrier family 25 member 4), among others. These genes are critical to the production and maintenance of mitochondrial DNA (mtDNA). Although the mechanism is unclear, mutations in these genes cause the removal of large segments of mtDNA in muscle cells. The size of the deleted region may vary from 2,000 to 10,000 nucleotides.
In other cases, the disease is due to a mtDNA deletion that is not associated with a mutation in a gene of nuclear DNA. Less often, mutations that change individual nucleotides in genes found in mtDNA, such as MT-TL1 gene (mitochondrially encoded tRNA Leucine 1 UUA / G), cause progressive external ophthalmoplegia. These mutations occur in genes encoding transfer RNA. Transfer RNA helps assemble amino acids in functional proteins. RNAs associated with progressive external ophthalmoplegia transfer are present in mitochondria and help assemble the proteins that carry out the steps of oxidative phosphorylation. It has not been determined how mtDNA deletions or mutations in mtDNA genes give rise to specific signs and symptoms of progressive external ophthalmoplegia, although the characteristics of the disease are probably related to impaired oxidative phosphorylation. It has been suggested that the eye muscles are frequently affected by mitochondrial defects, as they are especially dependent on oxidative phosphorylation to produce energy.
The POLG gene (Polymerase (DNA) gamma, catalytic subunit), located on the long arm of chromosome 15 (15q25), encoding the alpha subunit of the polymerase protein gamma (pol ?). L alpha subunit binds two copies of the beta subunit to form ? Pol. The Pol ? is a DNA polymerase that synthesizes new DNA on a previous strand, but also play a critical role in DNA repair. Pol ? is the only DNA polymerase is active in the mitochondria and can copy mtDNA. They have identified at least 67 POLG mutations in the gene cause the disease. Most mutations change individual amino acids in the alpha subunit of pol-?, which decreases the efficiency copy of mtDNA. L more common mutation is Ala467Thr. Mutations in the POLG gene lead to large deletions of genetic material mtDNA in muscle tissue. It has not been determined how mtDNA deletions lead to signs and symptoms of progressive external ophthalmoplegia, although the characteristics of alteration are probably related to an impairment of oxidative phosphorylation. L os eye muscles are often affected by mitochondrial defects because they are especially dependent on oxidative phosphorylation for energy.
The C10orf2 gene (chromosome 10 open reading frame 2), located on the long arm of chromosome 10 (10q24), encoding two similar proteins called Scintillation and Twinky, localized in mitochondria. Mitochondria contain mitochondrial DNA (mtDNA), essential for normal function of these structures. Scintillation protein is involved in the production and maintenance of mtDNA, functioning as a helicase mitochondrial DNA. Twinky function protein is unknown. They have identified at least 40 mutations in the gene C10orf2 in people with the disease. It is believed that these changes affect the helicase activity, which hinders the process of DNA replication. Although the mechanism is unclear, this stagnation seems to lead to large deletions of genetic material from mtDNA in muscle tissue. It is believed that the eye muscles are affected by mitochondrial defects because they are particularly dependent on oxidative phosphorylation for energy.
The rrm2b gene (ribonucleotide reductase TP53 inducible regulatory subunit M2B) situated on the long arm of chromosome 8 (8q23.1), encodes the synthesis of a subunit termed p53R2, ribonucleotide reductase protein (RNR). Two copies of the p53R2 subunit are attached to two copies of another protein called R1 to form RNR. R1 can also be linked to another small subunit, designated R2 to represent another form of RNR. The RNR protein performs a reaction that produces nucleotides. RNR containing p53R2 creates nucleotides used for the formation of mtDNA. MtDNA contains genes essential for oxidative phosphorylation process. Production nucleotides p53R2 also helps to maintain a normal amount of mtDNA in cells. At least 17 mutations in the gene have been identified rrm2b in people with progressive external ophthalmoplegia. These mutations result in large deletions of genetic material mtDNA in muscle tissue, possibly due to the deterioration of RNR activity causes a deficiency nucleotide, although the mechanism is unclear.
The SLC25A4 gene (solute carrier family 25 member 4), located on the long arm of chromosome 4 (4q35), encoding the translocase enzyme adenine nucleotide type 1 (ANT1). ANT1, forms a channel in the inner membrane of mitochondria, allowing the ADP and ATP mitochondria can be used as energy for the cell. This enzyme ANT1 may also form part of the mitochondrial transition pore. This structure allows multiple molecules access the mitochondria where it is thought to play a role in apoptosis. They have identified at least five mutations in the gene responsible for the development SLC25A4 progressive external ophthalmoplegia of. Mutations in the gene give rise to large deletions of genetic material mtDNA in muscle tissue.
The gene MT- TL1 (mitochondrially encoded tRNA Leucine 1 (UUA / G)), located in mitochondrial DNA, encoding a transfer RNA (tRNA) molecule, which is involved in the assembly of amino acids for the synthesis of l as proteins. MT- TL1 gene, encoding a tRNA specifically called tRNALeu (UUR). During protein synthesis, this molecule binds to the amino acid leucine (Leu) and inserts it in the appropriate positions the growing protein. The tRNALeu (UUR) molecule is present in the mitochondria, where it is involved in the assembly of proteins that carry out oxidative phosphorylation. This process uses oxygen, simple sugars and fatty acids to create adenosine triphosphate (ATP), the main energy source of the cell. In beta cells in the pancreas, mitochondria play a role in controlling blood glucose. Some cases of progressive external ophthalmoplegia are due to the A3243G mutation.
Progressive external ophthalmoplegia the can have different inheritance patterns depending on the gene involved. When the disease is due to mutations in the gene MT- TL1, it inherited with a mitochondrial pattern, also known as maternal inheritance. Mitochondrial disorders can appear in each generation of a family and can affect both men and women, but parents do not pass mitochondrial traits to their children. When POLG are involved, C10orf2, rrm2b or SLC25A4 gene, usually inherited disease with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the disease. Certain mutations in the POLG gene or rrm2b can also cause a form that is inherited in an autosomal recessive pattern, which means that 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. MtDNA large deletions generally not inherited, but occur during the formation of reproductive cells or early embryonic development. Individuals with these mutations often have no history of the disease in your family.
Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with progressive external ophthalmoplegia, by complete PCR amplification of exons of the POLG, C10orf2, rrm2b, SLC25A4 and MT-TL1 respectively, genes 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).