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Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Mitochondrial disorders associated with chorea: POLG mutations.MELAS (A351G mutation).Costeff's syndrome.ELAC2 mutations.33TSFM mutations.34Beta-ketothiolase deficiency.
The mitochondrial DNA depletion syndromes: mitochondrial DNA polymerase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The first evidence for depletion of mitochondrial DNA in human disease was reported by Moraes and colleagues in 1991 [1]. Three hepatic (newborn, infantile, and toddler) and two nonhepatic, myopathic (infantile and toddler) forms are now recognized. The hepatic forms are more appropriately called hepatocerebral [2]. Both hepatic and myopathic phenotypes have been reported in the products of both consanguineous [3] and nonconsanguineous unions [4]. Each of the three hepatic forms is characterized by episodes of acute liver failure, fasting hypoglycemia, and mitochondrial DNA depletion. The two nonhepatic forms are characterized by nonepisodic myopathy, ragged red fibers, elevated serum creatine kinase (CK), and mitochondrial DNA depletion. An enzymatic diagnosis was established for the hepatic toddler form (Alper syndrome), in which mitochondria are deficient in the enzyme responsible for replicating mitochondrial DNA, DNA polymerase γ [5]. Mutations in the POLG gene have now been recognized [6, 7].
Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Polymerase gamma, the only replicative DNA polymerase in human mitochondria, is a heterotrimer composed of one catalytic subunit encoded by the POLG gene (15q26.1) and two accessory subunits encoded by the POLG2 gene (17q23.3). The catalytic subunit is responsible not only for polymerase and exonuclease activities but also have the properties of reverse transcriptase. Accessory subunits increase the processivity of the enzyme.
The impact of mitochondria-related POLG and TFAM variants on breast cancer pathomorphological characteristics and patient outcomes
Published in Biomarkers, 2021
Ieva Golubickaite, Rasa Ugenskiene, Erika Korobeinikova, Jurgita Gudaitiene, Domas Vaitiekus, Lina Poskiene, Elona Juozaityte
The variation analysis in POLG and TFAM genes was chosen for this study based on their functional significance in mitochondrion. The POLG gene encodes the alpha subunit of polymerase gamma (pol γ). This polymerase functions in mitochondria and it is the only polymerase that is involved in mtDNA replication. It also plays an important role in mtDNA repair. Furthermore, POLG gene was found to be frequently mutated in breast and colorectal cancer tissue (Linkowska et al.2015, Singh et al.2009). The TFAM gene encodes an essential mitochondrial transcription factor A. It is also involved in mtDNA replication, repair and it is required for the maintenance of normal mitochondrial DNA levels. Mutations in TFAM were reported in prostate cancer (Granados et al.2017). The SNVs for this study were selected from the 1000 Genomes Project (The 1000 Genomes Project Consortium 2015).
Novel POLG mutation in a patient with early-onset parkinsonism, progressive external ophthalmoplegia and optic atrophy
Published in International Journal of Neuroscience, 2020
Lin Ma, Wei Mao, Erhe Xu, Yanning Cai, Chaodong Wang, Jagadish K. Chhetri, Piu Chan
Polymerase gamma (POLG) is a nuclear gene that encodes mitochondrial DNA polymerase gamma (pol γ). It is the only polymerase for mitochondrial DNA(mtDNA) replication and repair [1]. Dysfunction of pol γ results in impaired integrity of mtDNA, including to depletion or deletion, eventually leading to diminution of mitochondrial energy with disorders of oxidative phosphorylation [2]. The spectrum of phenotypes caused by the mutation of POLG is broad, which include Alpers syndrome, progressive external ophthalmoplegia (PEO), limb myopathy, parkinsonism, epilepsy and other multi-systemic features [3]. The first 2 cases of parkinsonism with POLG mutation were reported in 2004, by Michelangelo Mancuso [4]. Here, we report another case of a female patient carrying a novel compound heterozygotic missense mutation in POLG.
An update on Alpers-Huttenlocher syndrome: pathophysiology of disease and rational treatment designs
Published in Expert Opinion on Orphan Drugs, 2018
Although AHS represents a defined syndrome with specific neurohistological, biochemical, electroclinical, genetic, and phenotypic characteristics, there are no known treatments to correct the disorder. Although, logically it seems that correction of the deficit created by pathological variants in POLG1, would be to increase mtDNA synthesis and mtDNA content. What has yet to be reconciled is that early in the course of the disorder, neither quantitative mtDNA levels nor respiratory chain activities are consistently abnormal yet significant symptoms are present. Furthermore, although POLG enzyme activity is significantly altered in all cells, the disease burden resides in brain, liver, and muscle. Thus, the mechanism of disease must be more complex than just POLG1 altering mtDNA replication and repair. One thought is that the rate of decline of mtDNA might be, in part, responsible. So, although correction of mtDNA synthesis, repair and hence mtDNA content normalization can occur, the other mechanism(s) of POLG1 deficits inducing disease must be explored before real treatments are more than supportive.