Acta Scientific Neurology (ASNE) (ISSN: 2582-1121)

Review Article Volume 3 Issue 2

POLG Related Neurological Disorders and Their Mimics

Rajib Dutta*

MD, Neurology, India

*Corresponding Author: Rajib Dutta, MD, Neurology, India.
E-mail: rajibdutta808@gmail.com

Received: January 17, 2020 Published: January 24, 2020

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Abstract

  The POLG gene is responsible for production of alpha subunit, of a protein called polymerase gamma (pol γ). Pol γ is a mitochondrial DNA polymerase, responsible for replication of the mitochondrial genome. POLG-related disorders comprise a continuum of broad and overlapping phenotypes that can be distinct clinical entities or consist of a spectrum of overlapping phenotypes. Presentations within a given family are usually similar. Although almost any organ system can be involved, evidence to date suggests that diabetes and cardiomyopathy are not very common in POLG-related disorders, distinguishing them from other multisystem mitochondrial diseases. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later- onset syndromes arising from mt DNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. Clinical features may include hypotonia, developmental delay, seizures, movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism), Myopathy(e.g., ptosis, ophthalmoplegia, proximal > distal limb weakness with fatigue and exercise intolerance), Ataxia, Peripheral neuropathy, Episodic psychomotor regression, Psychiatric illness (e.g., depression, mood disorder),Endocrinopathy (e.g., premature ovarian failure).Most common disorders caused by POLG mutations are Alpers-Hutten ocher syndrome (AHS),Childhood myocerebrohepatopathy spectrum(MCHS),Myoclonic epilepsy myopathy sensory ataxia (MEMSA),Ataxia neuropathy spectrum (ANS),Autosomal recessive progressive external ophthalmoplegia (arPEO), Autosomal dominant progressive external ophthalmoplegia (adPEO). This review will summarize POLG related disorders and their mimics focusing mainly on the neurological manifestations of these conditions.

Keywords: POLG; Mimics; Mitochondrial DNA; mtDNA polymerase; Syndromes

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References

  1. Rangaraju Vidhya Nathaniel Calloway and Timothy A. Ryan”. Activity-driven local ATP synthesis is required for synaptic function”. Cell 156.4 (2014): 825-835.
  2. Chaban YuriyEgbert J., et al. “Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation”. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1837.4 (2014): 418-426.
  3. Kukat C., et al. “Super- resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA”. Proceedings of the National Academy of Sciences of the United States of America 108 (2011): 13534-13539.
  4. Zullo SJ., et al. “Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase gamma (POLG) to human chromosome band 15q24-->q26 and of mouse mitochondrial polymerase gamma (Polg) to mouse chromosome band 7E with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs)". Cytogenetics and Cell Genetics 78.3-4 (1998): 281-284.
  5. Longley MJ., et al. “Characterization of the native and recombinant catalytic subunit of human DNA polymerase gamma: identification of residues critical for exonuclease activity and dideoxynucleotide sensitivity”. Biochemistry 37 (1998): 10529-10539.
  6. Lim SE., et al. “The mitochondrial p55 accessory subunit of human DNA polymerase gamma enhances DNA binding promotes processive DNA synthesis and confers N-ethylmaleimide resistance”. Journal of Biological Chemistry 274 (1999): 38197-38203.
  7. Longley MJ., et al. “Identification of 5′-deoxyribose phosphate lyase activity in human DNA polymerase gamma and its role in mitochondrial base excision repair in vitro”. Proceedings of the National Academy of Sciences of the United States of America 95 (1998): 12244-12248.
  8. Kunkel TA and Soni A “Exonucleolytic proofreading enhances the fidelity of DNA synthesis by chick embryo DNA polymerase-gamma”. Journal of Biological Chemistry 263 (1988): 4450-4459.
  9. Larsson NG., et al. “Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice”. Nature Genetics 18 (1998) 231-236.
  10. Ghivizzani SC., et al. “In organello footprint analysis of human mitochondrial DNA: human mitochondrial transcription factor A interactions at the origin of replication”. Molecular and Cellular Biology 14 (1994): 7717-7730.
  11. Scarpulla RC. “Nuclear control of respiratory gene expression in mammalian cells”. Journal of Cellular Biochemistry 97 (2006): 673-683.
  12. Graziewicz MA., et al. “DNA polymerase gamma in mitochondrial DNA replication and repair”. Chemical Reviews 106 (2006): 383-405.
  13. Van Goethem G., et al. “Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions”. Nature Genetics 28 (2001): 211-212.
  14. Hakonen AH., et al. “Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin”. American Journal of Human Genetics 77 (2005): 430-441.
  15. Winterthun S., et al. “Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations”. Neurology 64 (2005): 1204-1208.
  16. Woodbridge P., et al. “POLG mutations in Australian patients with mitochondrial disease”. Journal of Internal Medicine 43 (2013): 150-156. 
  17. Rahman S. “Mitochondrial disease and epilepsy”. Developmental Medicine and Child Neurology 54 (2012): 397-406. 
  18. Bugiardini E., et al. “Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease”. Neurology Genetics 3 (2017): e149. 
  19. Schicks J., et al. “POLG but not PEO1 is a frequent cause of cerebellar ataxia in Central Europe”. Movement Disorders 25 (2010): 2678-2682.
  20. Wong LJ., et al. “Molecular and clinical genetics of mitochondrial diseases due to POLG mutations”. Human Mutation 29 (2008): E150-E172.
  21. Horvath R., et al. “Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene”. Brain 129 (2006): 1674-1684.
  22. Tzoulis C., et al. “The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases”. Brain 169 (2006): 1685-1692.
  23. Mancuso M., et al. “A novel polymerase gamma mutation in a family with ophthalmoplegia neuropathy and Parkinsonism”. Archives of Neurology.61 (2004): 1777-1779.
  24. Hakonen AH., et al. “Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin”. American Journal of Human Genetics 77 (2005): 430-441.
  25. Van Goethem G., et al. “Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia”. Neuromuscular Disorders 13 (2003b): 133-142.
  26. Luoma PT., et al. “Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome”. Human Molecular Genetics 14 (2005): 1907-1920.
  27. Cohen BH and Naviaux RK. “The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders”. Methods 51 (2010): 364-373.
  28. Saneto RP., et al. “Alpers-Huttenlocher syndrome”. Pediatric Neurology 48 (2013): 167-178.
  29. Nguyen KV., et al. “Molecular diagnosis of Alpers syndrome”. Journal of Hepatology 45 (2006): 108-116.
  30. Montassir Hesham., et al. “Myocerebrohepatopathy spectrum disorder due to POLG mutations: a clinicopathological report”. Brain and Development 37.7 (2015): 719-724.
  31. Pfeffer Gerald and Patrick F Chinnery. "Diagnosis and treatment of mitochondrial myopathies”. Annals of Medicine 45.1 (2013): 4-16.
  32. Fadic R., et al. “Sensory ataxic neuropathy as the presenting feature of a novel mitochondrial disease”. Neurology 49 (1997): 239-45.
  33. Henao Adriana I., et al. “Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation”. The Neuroradiology Journal 29.1 (2016): 46-48.
  34. Takata Atsushi., et al. “Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia”. Genome Biology 12.9 (2011): R92.
  35. Tyynismaa Henna., et al. “Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions”. Human Molecular Genetics 21.1 (2011): 66-75.
  36. Van Goethem., et al. “Progressive external ophthalmoplegia and multiple mitochondrial DNA deletions”. Acta Neurologica Belgica 102.1 (2002): 39-42.
  37. Van Goethem G., et al. “Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions”. Nature Genetics 28 (2001): 211-212.
  38. Luoma P., et al. “Parkinsonism premature menopause and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study”. Lancet 364 (2004): 875-882.
  39. Pagnamenta AT., et al. “Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma”. Human Reproduction 21 (2006): 2467-2473.
  40. Li F. Y., et al. “Mapping of autosomal dominant progressive external ophthalmoplegia to a 7-cM critical region on 10q24”. Neurology 53.6 (1999): 1265-1265.
  41. Wanrooij Sjoerd., et al. “Twinkle and POLG defects enhance age‐dependent accumulation of mutations in the control region of mtDNA”. Nucleic Acids Research 32.10 (2004): 3053-3064.
  42. Fontanesi Flavia., et al. “Mutations in AAC2 equivalent to human adPEO-associated ANT1 mutations lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stability”. Human Molecular Genetics 13.9 (2004): 923-934.
  43. Huang Hongyan., et al. “Leukoencephalopathy in mitochondrial neurogastrointestinal encephalomyopathy-like syndrome with polymerase-gamma mutations”. Annals of Indian Academy of Neurology 22.3 (2019): 325.
  44. Tang Sha., et al. “Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations”. Journal of Neurology 259.5 (2012): 862-868.
  45. Prasun Pankaj and Dwight D Koeberl. "Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype in a patient with a novel heterozygous POLG mutation”. Journal of Neurology 261.9 (2014): 1818.
  46. Van Goethem G., et al. “Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy”. European Journal of Human Genetics 11 (2003): 547-549. 
  47. Martikainen MH., et al. “Clinical genetic and radiological features of extrapyramidal movement disorders in mitochondrial disease”. Journal of the American Medical Association 73 (2016): 668-674. 
  48. Davidzon G., et al. “Early- onset familial parkinsonism due to POLG mutations”. Annals of Neurology 59 (2006): 859-862. 
  49. Nicastro Nicolas., et al. “Pure progressive ataxia and palatal tremor (PAPT) associated with a new polymerase gamma (POLG) mutation”. The Cerebellum 15.6 (2016): 829-831.
  50. Gao Andrew F., et al. “Progressive ataxia and palatal tremor: two autopsy cases of a novel tauopathy”. Movement Disorders 32.10 (2017): 1465-1473.
  51. Synofzik M., et al. “Complex hyperkinetic movement disorders associated with POLG mutations”. Movement Disorders 25 (2010): 2472-2475.
  52. Hinnell C., et al. “Dystonia in mitochondrial spinocerebellar ataxia and epilepsy syndrome associated with novel recessive POLG mutations”. Movement Disorders 27 (2012): 162-163.
  53. Felczak Paulina., et al. “Diagnosing MERRF requires clinical and genetic evidence”. Polish Journal of Pathology: official Journal of the Polish Society of Pathologists 70.2 (2019): 144.
  54. Deschauer M., et al. “MELAS associated with mutations in the POLG1 gene”. Neurology 68 (2007): 1741-1742.
  55. Miyahara Hiroaki et al. "Autopsied case with MERRF/MELAS overlap syndrome accompanied by stroke‐like episodes localized to the precentral gyrus”. Neuropathology (2019).
  56. Isohanni P., et al. “POLG1 manifestations in childhood”. Neurology 76 (2011): 811-815.
  57. Harris MO., et al. “Is it ADEM POLG or both?”. Archives of Neurology 67 (2010): 493-496.
  58. Echaniz- Laguna A., et al. “POLG1 variations presenting as multiple sclerosis”. Archives of Neurology 67 (2010): 1140-1143.
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Citation

Citation: Rajib Dutta. “POLG Related Neurological Disorders and Their Mimics".Acta Scientific Neurology 3.2 (2020): 54-59.




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