Ataxic neuropathy, spectrum ... (Ataxia neuropathy spectrum) - Genes POLG and C10orf2.
The spectrum ataxic neuropathy is part of a group of disorders called the POLG related disorders. Diseases of this group have a number of similar signs and symptoms related functions that affect the muscles, nerves and brain. Ataxic neuropathy spectrum includes diseases previously called recessive mitochondrial ataxia (MIRAS) and sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO) syndrome.
As the name suggests, people with ataxic neuropathy spectrum often have ataxia and neuropathy. The neuropathy can be classified as sensory, motor, or a combination of the two. Sensory neuropathy leads to numbness, tingling or pain in the arms and legs, and motor neuropathy refers to alterations in the nerves used for muscle movement. Most people with ataxic neuropathy spectrum also have encephalopathy and seizures. Some affected individuals have ophthalmoplegia, causing ptosis. Other signs and symptoms may include myoclonus, liver disease, depression, migraine headaches and blindness.
Ataxic neuropathy spectrum is due, in most cases, to mutations in the POLG gene and, rarely, mutations in the C10orf2 gene.
The POLG gene, located on the long arm of chromosome 15 (15q25), encoding the alpha subunit protein gamma polymerase (pol ?). L alpha subunit binds two copies of the beta subunit to form pol ?. Pol ? is a DNA polymerase, which "reads" DNA sequences and used as templates for encoding new DNA. These enzymes are important for copying genetic material into cells. Polymerases also play a critical role in DNA repair. Pol ? is the only DNA polymerase is active in the mitochondria and can copy mtDNA. Most mutations change the individual amino acids in the alpha subunit of pol ?, which decreases the efficiency copy of mtDNA. L more common mutation, is the same as in Alpers syndrome-Huttenlocher Ala467Thr. It is unclear how the same mutation can lead to different changes. And other disorders related to the POLG gene, individuals with ataxic neuropathy spectrum exhibiting reduced mtDNA in affected tissues such as the brain. This reduction in mtDNA decreases the amount of energy available to the cell due to reduced oxidative phosphorylation, which may explain the signs and symptoms of the disease.
The C10orf2 gene, located on the long arm of chromosome 10 (10q24), encoding two similar proteins called "Twinkle" and "Twinky" localized in mitochondria. Mitochondria contain mitochondrial DNA (mtDNA), essential for normal function. The "Twinkle" protein is involved in the production and maintenance of mtDNA, functioning as a helicase mitochondrial DNA. Function "Twinky" protein is unknown. Mutations in the gene C10orf2 disrupt the function of "Twinkle" and lead to large deletions of mtDNA in muscle tissue of affected individuals. It is unclear how mutations in the gene C10orf2 result in signs and symptoms of ataxic neuropathy spectrum.
Ataxic neuropathy spectrum can have different patterns depending on the associated gene inheritance. Mutations in the POLG gene lead to a form of inherited disease with 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. Mutations in the C10orf2 gene lead to a form of inherited disease with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to cause the alteration.
Tests in IVAMI: in IVAMI perform detection of mutations associated with spectrum ataxic neuropathy, by complete PCR amplification of the exons of POLG and C10orf2, 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).