open access

Vol 79, No 2 (2020)
REVIEW ARTICLES
Published online: 2020-02-13
Submitted: 2019-09-30
Accepted: 2020-02-03
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Pyruvate dehydrogenase deficiency: morphological and metabolic effects, creation of animal model to search for curative treatment

A. Ebertowska, B. Ludkiewicz, I. Klejbor, N. Melka, J. Moryś
DOI: 10.5603/FM.a2020.0020
·
Pubmed: 32073132
·
Folia Morphol 2020;79(2):191-197.

open access

Vol 79, No 2 (2020)
REVIEW ARTICLES
Published online: 2020-02-13
Submitted: 2019-09-30
Accepted: 2020-02-03

Abstract

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.

Abstract

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.

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Keywords

pyruvate dehydrogenase deficiency, metabolic disorders, Leigh syndrome, phenylbutyrate, ketogenic diet

About this article
Title

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

Journal

Folia Morphologica

Issue

Vol 79, No 2 (2020)

Pages

191-197

Published online

2020-02-13

DOI

10.5603/FM.a2020.0020

Pubmed

32073132

Bibliographic record

Folia Morphol 2020;79(2):191-197.

Keywords

pyruvate dehydrogenase deficiency
metabolic disorders
Leigh syndrome
phenylbutyrate
ketogenic diet

Authors

A. Ebertowska
B. Ludkiewicz
I. Klejbor
N. Melka
J. Moryś

References (57)
  1. Acharya MM, Hattiangady B, Shetty AK. Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol. 2008; 84(4): 363–404.
  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.
  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.
  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.
  5. Berendzen K, Theriaque DW, Shuster J, et al. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion. 2006; 6(3): 126–135.
  6. Brown GK, Otero LJ, LeGris M, et al. Pyruvate dehydrogenase deficiency. J Med Genet. 1994; 31(11): 875–879.
  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.
  8. Dahl HH, Brown RM, Hutchison WM, et al. A testis-specific form of the human pyruvate dehydrogenase E1α subunit is coded for by an intronless gene on chromosome 4. Genomics. 1990; 8(2): 225–232.
  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.
  10. Dienel GA. Brain glucose metabolism: integration of energetics with function. Physiol Rev. 2019; 99(1): 949–1045.
  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.
  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.
  13. Finsterer J. Leigh and leigh-like syndrome in children and adults. Pediatr Neurol. 2008; 39(4): 223–235.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  25. Lee HF, Tsai CR, Chi CS, et al. Leigh syndrome: clinical and neuroimaging follow-up. Pediatr Neurol. 2009; 40(2): 88–93.
  26. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951; 14(3): 216–221.
  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::aid-humu1>3.0.co;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.
  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.
  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::aid-gene1>3.0.co;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.
  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.
  34. Ng F, Tang BL. Pyruvate dehydrogenase complex (PDC) export from the mitochondrial matrix. Mol Membr Biol. 2014; 31(7-8): 207–210.
  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.
  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.
  37. Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J. 1990; 4(14): 3224–3233.
  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.
  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.
  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 dehydrogenase complex deficiency. Mol Genet Metab Rep. 2016; 7: 78–86.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  50. Stafstrom C, Rho J. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders. Front Pharmacol. 2012; 3: 59.
  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.
  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.
  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.
  54. Wilbur DO, Patel MS. Development of mitochondrial pyruvate metabolism in rat brain. J Neurochem. 1974; 22(5): 709–715.
  55. Williams TJ, Cervenka MC. The role for ketogenic diets in epilepsy and status epilepticus in adults. Clin Neurophysiol Pract. 2017; 2: 154–160.
  56. Włodarek D. Role of ketogenic diets in neurodegenerative diseases (Alzheimer's disease and Parkinson's disease). Nutrients. 2019; 11(1).
  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.

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