Preferencje help
Widoczny [Schowaj] Abstrakt
Liczba wyników
2020 | 79 | 2 |
Tytuł artykułu

Pyruvate dehydrogenase deficiency: morphological and metabolic effects, creation of animal model to search for curative treatment

Warianty tytułu
Języki publikacji
The main source of energy for brain and other organs is glucose. To obtain energy for all tissue, glucose has to come through glycolysis; then as pyruvate it is converted to acetyl-CoA by pyruvate dehydrogenase complex (PDC) and finally enters citric acid cycle. What happens when one of these stages become disturb? Mutation in genes encoding subunits of PDC leads to pyruvate dehydrogenase deficiency. Abnormalities in PDC activity result in severe metabolic and brain malformations. For better understanding the development and mechanism of pyruvate dehydrogenase deficiency the murine model of this disease has been created. Studies on a murine model showed similar malformation in brain structures as in the patients suffered from pyruvate dehydrogenase deficiency such as reduced neuronal density, heterotopias of grey matter, reduced size of corpus callosum and pyramids. There is still no effective cure for PDC-deficiency. Promising therapy seemed to be ketogenic diet, which substitutes glucose to ketone bodies as a source of energy. Studies have shown that ketogenic diet decreases lactic acidosis and inhibits brain malformations, but not the mortality in early childhood. The newest reports say that phenylbutyrate increases the level of PDC in the brain, because it reduces the level of inactive form of PDH. Experiments on human fibroblast and zebra fish PDC-deficiency model showed that phenylbutyrate is promising cure to PDC-deficiency. This review summarizes the most important findings on the metabolic and morphological effects of PDC-deficiency and research for treatment therapy. (Folia Morphol 2020; 79, 2: 191–197)
Słowa kluczowe
Opis fizyczny
  • Department of Anatomy and Neurobiology, Medical University of Gdansk, Poland
  • Department of Anatomy and Neurobiology, Medical University of Gdansk, Poland
  • Department of Anatomy and Neurobiology, Medical University of Gdansk, Poland
  • Department of Clinical Anatomy, Pomeranian University in Slupsk, Poland
  • Department of Anatomy and Neurobiology, Medical University of Gdansk, Poland
  • Department of Anatomy and Neurobiology, Medical University of Gdansk, Poland
  • 1. Acharya MM, Hattiangady B, Shetty AK. Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol. 2008; 84(4): 363–404, doi: 10.1016/j.pneurobio.2007.10.010, indexed in Pubmed: 18207302.
  • 2. Ambrus A, Adam-Vizi V. Human dihydrolipoamide dehydrogenase (E3) deficiency: Novel insights into the structural basis and molecular pathomechanism. Neurochem Int. 2018; 117: 5–14, doi: 10.1016/j.neuint.2017.05.018, indexed in Pubmed: 28579060.
  • 3. Barnerias C, Saudubray JM, Touati G, et al. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol. 2010; 52(2): e1–e9, doi: 10.1111/j.1469-8749.2009.03541.x, indexed in Pubmed: 20002125.
  • 4. Barzegar M, Afghan M, Tarmahi V, et al. Ketogenic diet: overview, types, and possible anti-seizure mechanisms. Nutr Neurosci. 2019 [Epub ahead of print]: 1–10, doi: 10.1080/1028415X.2019.1627769, indexed in Pubmed: 31241011.
  • 5. Berendzen K, Theriaque DW, Shuster J, et al. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion. 2006; 6(3): 126–135, doi: 10.1016/j.mito.2006.04.001, indexed in Pubmed: 16725381.
  • 6. Brown GK, Otero LJ, LeGris M, et al. Pyruvate dehydrogenase deficiency. J Med Genet. 1994; 31(11): 875–879, doi: 10.1136/jmg.31.11.875, indexed in Pubmed: 7853374.
  • 7. Choi CS, Ghoshal P, Srinivasan M, et al. Liver-specific pyruvate dehydrogenase complex deficiency upregulates lipogenesis in adipose tissue and improves peripheral insulin sensitivity. Lipids. 2010; 45(11): 987–995, doi: 10.1007/s11745-010-3470-8, indexed in Pubmed: 20835892.
  • 8. Dahl HH, Brown RM, Hutchison WM, et al. A testis-specific form of the human pyruvate dehydrogenase E1a subunit is coded for by an intronless gene on chromosome 4. Genomics. 1990; 8(2): 225–232, doi: 10.1016/0888-7543(90)90275-y.
  • 9. Dahl HH, Hansen LL, Brown RM, et al. X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis. 1992; 15(6): 835–847, doi: 10.1007/bf01800219, indexed in Pubmed: 1293379.
  • 10. Dienel GA. Brain glucose metabolism: integration of energetics with function. Physiol Rev. 2019; 99(1): 949–1045, doi: 10.1152/physrev.00062.2017, indexed in Pubmed: 30565508.
  • 11. Ferriero R, Iannuzzi C, Manco G, et al. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis. 2015; 38(5): 895–904, doi: 10.1007/s10545-014-9808-2, indexed in Pubmed: 25601413.
  • 12. Ferriero R, Manco G, Lamantea E, et al. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013; 5(175): 175ra31, doi: 10.1126/scitranslmed.3004986, indexed in Pubmed: 23467562.
  • 13. Finsterer J. Leigh and leigh-like syndrome in children and adults. Pediatr Neurol. 2008; 39(4): 223–235, doi: 10.1016/j.pediatrneurol.2008.07.013, indexed in Pubmed: 18805359.
  • 14. Friedman J, Feigenbaum A, Chuang N, et al. Pyruvate dehydrogenase complex-E2 deficiency causes paroxysmal exercise-induced dyskinesia. Neurology. 2017; 89(22): 2297–2298, doi: 10.1212/WNL.0000000000004689, indexed in Pubmed: 29093066.
  • 15. Gerards M, Sallevelt SC, Smeets HJM. Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options. Mol Genet Metab. 2016; 117(3): 300–312, doi: 10.1016/j.ymgme.2015.12.004, indexed in Pubmed: 26725255.
  • 16. Giribaldi G, Doria-Lamba L, Biancheri R, et al. Intermittent-relapsing pyruvate dehydrogenase complex deficiency: a case with clinical, biochemical, and neuroradiological reversibility. Dev Med Child Neurol. 2012; 54(5): 472–476, doi: 10.1111/j.1469-8749.2011.04151.x, indexed in Pubmed: 22142326.
  • 17. Gu H, Zou YR, Rajewsky K. Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell. 1993; 73(6): 1155–1164, doi: 10.1016/0092-8674(93)90644-6.
  • 18. Gzielo K, Soltys Z, Rajfur Z, et al. The impact of the ketogenic diet on glial cells morphology. A quantitative morphological analysis. Neuroscience. 2019; 413: 239–251, doi: 10.1016/j.neuroscience.2019.06.009, indexed in Pubmed: 31220541.
  • 19. Harris R, Bowker-Kinley M, Huang B, et al. Regulation of the activity of the pyruvate dehydrogenase complex. Adv Enzyme Regul. 2002; 42: 249–259, doi: 10.1016/s0065-2571(01)00061-9.
  • 20. Hawkins RA, Williamson DH, Krebs HA. Ketone-body utilization by adult and suckling rat brain in vivo. Biochem J. 1971; 122(1): 13–18, doi: 10.1042/bj1220013, indexed in Pubmed: 5124783.
  • 21. Imbard A, Boutron A, Vequaud C, et al. Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein. Mol Genet Metab. 2011; 104(4): 507–516, doi: 10.1016/j.ymgme.2011.08.008, indexed in Pubmed: 21914562.
  • 22. Johnson MT, Mahmood S, Hyatt SL, et al. Inactivation of the murine pyruvate dehydrogenase (Pdha1) gene and its effect on early embryonic development. Mol Genet Metab. 2001; 74(3): 293–302, doi: 10.1006/mgme.2001.3249, indexed in Pubmed: 11708858.
  • 23. Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006; 66(3): 324–330, doi: 10.1212/01.wnl.0000196641.05913.27, indexed in Pubmed: 16476929.
  • 24. Lee EH, Ahn MS, Hwang JS, et al. A Korean female patient with thiamine-responsive pyruvate dehydrogenase complex deficiency due to a novel point mutation (Y161C) in the PDHA1 gene. J Korean Med Sci. 2006; 21(5): 800–804, doi: 10.3346/jkms.2006.21.5.800, indexed in Pubmed: 17043409.
  • 25. Lee HF, Tsai CR, Chi CS, et al. Leigh syndrome: clinical and neuroimaging follow-up. Pediatr Neurol. 2009; 40(2): 88–93, doi: 10.1016/j.pediatrneurol.2008.09.020, indexed in Pubmed: 19135620.
  • 26. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951; 14(3): 216–221, doi: 10.1136/jnnp.14.3.216, indexed in Pubmed: 14874135.
  • 27. Lissens W, Meirleir LDe, Seneca S, et al. Mutations in the X-linked pyruvate dehydrogenase (E1) ? subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Human Mutation. 2000; 15(3): 209–219, doi: 10.1002/(sici)1098-1004(200003)15:3<209::aidhumu1>;2-k.
  • 28. Lissens W, Vreken P, Barth PG, et al. Cerebral palsy and pyruvate dehydrogenase deficiency: identification of two new mutations in the E1alpha gene. Eur J Pediatr. 1999; 158(10): 853–857, doi: 10.1007/s004310051222, indexed in Pubmed: 10486093.
  • 29. Maragos C, Hutchison WM, Hayasaka K, et al. Structural organization of the gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex. J Biol Chem. 1989; 264(21): 12294–12298, indexed in Pubmed: 2745444.
  • 30. Masino SA, Rho JM. Mechanisms of Ketogenic Diet Action. National Center for Biotechnology Information. (US): 2012.
  • 31. Nagy A. Cre recombinase: The universal reagent for genome tailoring. Genesis. 2000; 26(2): 99–109, doi: 10.1002/(sici)1526-968x(200002)26:2<99::aidgene1>;2-b.
  • 32. Naito E, Kuroda Y, Takeda E, et al. Detection of pyruvate metabolism disorders by culture of skin fibroblasts with dichloroacetate. Pediatr Res. 1988; 23(6): 561–564, doi: 10.1203/00006450-198806000-00005, indexed in Pubmed: 2839811.
  • 33. Neal E, Chaffe H, Schwartz R, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008; 7(6): 500–506, doi: 10.1016/s1474-4422(08)70092-9.
  • 34. Ng F, Tang BL. Pyruvate dehydrogenase complex (PDC) export from the mitochondrial matrix. Mol Membr Biol. 2014; 31(7-8): 207–210, doi: 10.3109/09687688.2014.987183, indexed in Pubmed: 25495576.
  • 35. Patel KP, O’Brien TW, Subramony SH, et al. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012; 105(1): 34–43, doi: 10.1016/j.ymgme.2011.09.032, indexed in Pubmed: 22079328.
  • 36. Patel MS, Nemeria NS, Furey W, et al. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem. 2014; 289(24): 16615–16623, doi: 10.1074/jbc.R114.563148, indexed in Pubmed: 24798336.
  • 37. Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J. 1990; 4(14): 3224–3233, doi: 10.1096/fasebj.4.14.2227213, indexed in Pubmed: 2227213.
  • 38. Di Pisa V, Cecconi I, Gentile V, et al. Case report of pyruvate dehydrogenase deficiency with unusual increase of fats during ketogenic diet treatment. J Child Neurol. 2012; 27(12): 1593–1596, doi: 10.1177/0883073812436424, indexed in Pubmed: 22378660.
  • 39. Pliss L, Hausknecht KA, Stachowiak MK, et al. Cerebral developmental abnormalities in a mouse with systemic pyruvate dehydrogenase deficiency. PLoS One. 2013; 8(6): e67473, doi: 10.1371/journal.pone.0067473, indexed in Pubmed: 23840713.
  • 40. Pliss L, Jatania U, Patel MS. Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydro genase complex deficiency. Mol Genet Metab Rep. 2016; 7: 78–86, doi: 10.1016/j.ymgmr.2016.03.012, indexed in Pubmed: 27331005.
  • 41. Pliss L, Mazurchuk R, Spernyak JA, et al. Brain MR imaging and proton MR spectroscopy in female mice with pyruvate dehydrogenase complex deficiency. Neurochem Res. 2007; 32(4-5): 645–654, doi: 10.1007/s11064-007-9295-z, indexed in Pubmed: 17342409.
  • 42. Pliss L, Pentney RJ, Johnson MT, et al. Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency. J Neurochem. 2004; 91(5): 1082–1091, doi: 10.1111/j.1471-4159.2004.02790.x, indexed in Pubmed: 15569252.
  • 43. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996; 39(3): 343–351, doi: 10.1002/ana.410390311, indexed in Pubmed: 8602753.
  • 44. Di Rocco M, Lamba LD, Minniti G, et al. Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency. Eur J Paediatr Neurol. 2000; 4(3): 115–117, doi: 10.1053/ejpn.2000.0278, indexed in Pubmed: 10872106.
  • 45. Siess E, Wittmann J, Wieland O. Interconversion and kinetic properties of pyruvate dehydrogenase from brain. Hoppe Seylers Z Physiol Chem. 1971; 352(3): 447–452, doi: 10.1515/bchm2.1971.352.1.447, indexed in Pubmed: 5550962.
  • 46. Sofou K, De Coo IFM, Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis. 2014; 9: 52, doi: 10.1186/1750-1172-9-52, indexed in Pubmed: 24731534.
  • 47. Sofou K, Dahlin M, Hallböök T, et al. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Dis. 2017; 40(2): 237–245, doi: 10.1007/s10545-016-0011-5, indexed in Pubmed: 28101805.
  • 48. Srinivasan M, Choi CS, Ghoshal P, et al. ß-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab. 2010; 299(6): E910–E917, doi: 10.1152/ajpendo.00339.2010, indexed in Pubmed: 20841503.
  • 49. Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006; 117(5): 1519–1531, doi: 10.1542/peds.2005-1226, indexed in Pubmed: 16651305.
  • 50. Stafstrom C, Rho J. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders. Front Pharmacol. 2012; 3: 59, doi: 10.3389/fphar.2012.00059.
  • 51. Takakubo F, Dahl HH. Analysis of pyruvate dehydrogenase expression in embryonic mouse brain: localization and developmental regulation. Dev Brain Res. 1994; 77(1): 63–76, doi: 10.1016/0165-3806(94)90214-3.
  • 52. Tuchman M, Lee B, Lichter-Konecki U, et al. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008; 94(4): 397–402, doi: 10.1016/j.ymgme.2008.05.004, indexed in Pubmed: 18562231.
  • 53. Wijburg FA, Barth PG, Bindoff LA, et al. Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet. Neuropediatrics. 1992; 23(3): 147–152, doi: 10.1055/s2008-1071331, indexed in Pubmed: 1641082.
  • 54. Wilbur DO, Patel MS. Development of mitochondrial pyruvate metabolism in rat brain. J Neurochem. 1974; 22(5): 709–715, doi: 10.1111/j.1471-4159.1974.tb04284.x, indexed in Pubmed: 4407094.
  • 55. Williams TJ, Cervenka MC. The role for ketogenic diets in epilepsy and status epilepticus in adults. Clin Neurophysiol Pract. 2017; 2: 154–160, doi: 10.1016/j.cnp.2017.06.001, indexed in Pubmed: 30214989.
  • 56. Włodarek D. Role of ketogenic diets in neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease). Nutrients. 2019; 11(1), doi: 10.3390/nu11010169, indexed in Pubmed: 30650523.
  • 57. Yoshida T, Kido J, Mitsubuchi H, et al. Clinical manifestations in two patients with pyruvate dehydrogenase deficiency and long-term survival. Hum Genome Var. 2017; 4: 17020, doi: 10.1038/hgv.2017.20, indexed in Pubmed: 28584645.
Typ dokumentu
Identyfikator YADDA
JavaScript jest wyłączony w Twojej przeglądarce internetowej. Włącz go, a następnie odśwież stronę, aby móc w pełni z niej korzystać.