Authors' recommendations: Mitochondrial disorders result from abnormalities in mitochondrial function. Mitochondria are specialized structures in the cell that produce energy through a reaction called oxidative phosphorylation (OXPHOS; also referred to as the respiratory chain reaction or the electron transport chain reaction). Mitochondria contain a circular DNA molecule of 16,569 base pairs, referred to as mitochondrial DNA (mtDNA) or the mitochondrial genome. While the mtDNA encodes proteins involved in OXPHOS, the vast majority of proteins with a role in mitochondrial structure and function are encoded by the DNA found in the nucleus of the cell (i.e., nuclear genes). POLGrelated disorders, which represent the most common group of mitochondrial conditions, are caused by variants in the nuclear gene encoding DNA polymerase gamma (POLG), which is located on chromosome 15 at band q26.1. Deleterious variants in the POLG gene, which encodes an enzyme required for replication and repair of the mtDNA, result in several clinically defined syndromes, including Alpers-Huttenlocher syndrome (AHS; also known as Alpers syndrome), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), autosomal recessive progressive external ophthalmoplegia (arPEO), and autosomal dominant PEO (adPEO). Most POLG-related disorders are autosomal recessive conditions (i.e., both copies of the POLG gene need to be altered in order to develop the condition), with the exception of adPEO, which is inherited in an autosomal dominant fashion (i.e., only 1 copy of the POLG gene needs to be altered in order to develop the condition). In general, POLG-related disorders represent a broad spectrum of disease with overlapping clinical manifestations, including ataxia (an inability to control voluntary muscle movements), myoclonus (rapid jerking movement), neuropathy (dysfunction of the peripheral nervous system), myopathy (disorder of muscle tissue), seizures, progressive external ophthalmoplegia (PEO; weakness or paralysis of muscles controlling eye movement), and progressive intellectual disability. In addition, hepatopathy (liver dysfunction) may occur in affected individuals. Importantly, the use of valproic acid (sodium valproate) in the treatment of seizures is known to precipitate liver failure (often rapidly and with fatal consequences) in those with POLG gene variants. Liver dysfunction may also occur in the absence of an exposure to valproic acid. With regard to the diagnosis of POLG-related disorders, affected individuals may demonstrate mtDNA depletion in muscle or liver, multiple mtDNA deletions, abnormal activity of respiratory chain complexes, abnormal muscle or liver pathology, and changes on neuroimaging (e.g., cerebellar atrophy, white matter changes, and hyperintense lesions in various regions of the brain) or electrophysiological testing. However, there are no biochemical, histopathologic, or radiologic findings that are sensitive and specific for POLGrelated disorders, as none are uniformly present in all POLG-positive patients, particularly in the early stages of the disease. In addition, each of these findings may be evident in individuals with other mitochondrial conditions. At the present time, the care for patients with POLG gene variants is symptom specific and primarily supportive in nature, with the goals of managing symptoms and preventing secondary complications (e.g., medication-induced liver toxicity).

Project Status: Completed

Year Published: 2013

URL for published report: The report may be purchased from: http://www.hayesinc.com/hayes/crd/?crd=15070

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: HAYES, Inc.

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Contact Email: saleinfo@hayesinc.com

Copyright: 2013 Winifred S. Hayes, Inc