Pyruvate dehydrogenase deficiency explained

Pyruvate dehydrogenase complex deficiency

Pyruvate dehydrogenase deficiency (also known as pyruvate dehydrogenase complex deficiency or PDCD or PDH deficiency) is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC).[1] The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria.[2] The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.[3]

Signs and symptoms

PDCD is generally presented in one of two forms. The metabolic form appears as lactic acidosis. The neurological form of PDCD contributes to hypotonia, poor feeding, lethargy and structural abnormalities in the brain.[4] Patients may develop seizures and/or neuropathological spasms. These presentations of the disease usually progress to mental retardation, microcephaly, blindness, and spasticity.[5]

Females with residual pyruvate dehydrogenase activity will have no uncontrollable systemic lactic acidosis and few, if any, neurological symptoms. Conversely, females with little to no enzyme activity will have major structural brain abnormalities and atrophy. Males with mutations that abolish, or almost abolish, enzyme activity presumably die in utero because brain cells are not able to generate enough ATP to be functionally viable. It is expected that most cases will be of mild severity and have a clinical presentation involving lactic acidosis. Male infants that reach full term display more severe symptoms than females, and exhibit high mortality within the first few years of life [6]

Prenatal onset may present with non-specific signs such as low Apgar scores and small for gestational age. These cases display hydrocephalus, and thinning of the cerebral tissue. Metabolic disturbances may also be considered with poor feeding and lethargy out of proportion to a mild viral illness, and especially after bacterial infection has been ruled out. PDH activity may be enhanced by exercise, phenylbutyrate and dichloroacetate.

The clinical presentation of congenital PDH deficiency is typically characterized by heterogenous neurological features that usually appear within the first year of life. In addition, patients usually show severe hyperventillation due to profound metabolic acidosis mostly related to lactic acidosis. Metabolic acidosis in these patients is usually refractory to correction with bicarbonate.[7]

The following table lists common symptoms of pyruvate dehydrogenase deficiency.

Notes and References

  1. Brown. G K. Otero. L J. LeGris. M. Brown. R M. November 1994. Pyruvate dehydrogenase deficiency.. Journal of Medical Genetics. 31. 11. 875–879. 10.1136/jmg.31.11.875. 0022-2593. 1016663. 7853374.
  2. Patel. Mulchand S.. Nemeria. Natalia S.. Furey. William. Jordan. Frank. 2014-06-13. The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation. Journal of Biological Chemistry. en. 289. 24. 16615–16623. 10.1074/jbc.R114.563148. 0021-9258. 4059105. 24798336. free.
  3. Web site: pyruvate dehydrogenase deficiency. Reference. Genetics Home. Genetics Home Reference. 2016-11-08.
  4. Web site: Cassandra L. Kniffin . 28 October 2014 . pyruvate dehydrogenase E1-alpha deficiency; PDHAD . Online Mendelian Inheritance in Man . Johns Hopkins University . Entry # 312170 . 2016-11-09.
  5. Patel. Kavi P.. O'Brien. Thomas W.. Subramony. Sankarasubramon H.. Shuster. Jonathan. Stacpoole. Peter W.. January 2012. The Spectrum of Pyruvate Dehydrogenase Complex Deficiency: Clinical, Biochemical and Genetic Features in 371 Patients. Molecular Genetics and Metabolism. 105. 1. 34–43. 10.1016/j.ymgme.2011.09.032. 1096-7192. 3754811. 22079328.
  6. Natarajan. Niranjana. Tully. Hannah M.. Chapman. Teresa. 2016-08-01. Prenatal presentation of pyruvate dehydrogenase complex deficiency. Pediatric Radiology. en. 46. 9. 1354–1357. 10.1007/s00247-016-3585-z. 1432-1998. 6383724. 27026023.
  7. Book: Mitochondrion.
  8. Imbard. A.. Boutron. A.. Vequaud. C.. Zater. M.. de Lonlay. P.. de Baulny. H. Ogier. Barnerias. C.. Miné. M.. Marsac. C.. Saudubray. J.-M.. Brivet. M.. December 2011. Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein. Molecular Genetics and Metabolism. 104. 4. 507–516. 10.1016/j.ymgme.2011.08.008. 1096-7206. 21914562.
  9. G K Brown. L J Otero. M LeGris. R M Brown. November 1994. Pyruvate dehydrogenase deficiency. J Med Genet. 31. 11. 875–879. 10.1136/jmg.31.11.875. 1016663. 7853374.
  10. H H Dahl. March 1995. Pyruvate dehydrogenase E1 alpha deficiency: males and females differ yet again.. Am J Hum Genet. 56. 3. 553–557. 1801181. 7887408.
  11. Web site: Phenotypic Series - PS312170 Pyruvate dehydrogenase complex deficiency - PS312170 - 6 Entries . OMIM - Online Mendelian Inheritance In Man.
  12. (GeneCards - Human Genes | Gene Database | Gene Search, n.d.)
  13. Web site: Pyruvate Dehydrogenase Complex Deficiency Workup: Laboratory Studies, Imaging Studies, Histologic Findings. emedicine.medscape.com. 8 November 2016.
  14. Web site: Garry Brown . Pyruvate dehydrogenase deficiency . Orphanet . ORPHA765 . April 2012 . 8 November 2016 .
  15. Sofou. Kalliopi. Dahlin. Maria. Hallböök. Tove. Lindefeldt. Marie. Viggedal. Gerd. Darin. Niklas. 2017. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. Journal of Inherited Metabolic Disease. en. 40. 2. 237–245. 10.1007/s10545-016-0011-5. 1573-2665. 5306430. 28101805.
  16. Web site: KetoCal family of ketogenic medical foods (ketogenic formulas). www.myketocal.com. 2020-05-06.
  17. 2019-11-11. Metabolic Acidosis Treatment & Management: Approach Considerations, Type 1 Renal Tubular Acidosis, Type 2 Renal Tubular Acidosis.
  18. Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies - Full Text View - ClinicalTrials.gov. clinicaltrials.gov. May 2020. en. 2020-05-06.
  19. Stacpoole . Peter W. . Owen . Renius . Flotte . Terence R. . June 2003 . The pyruvate dehydrogenase complex as a target for gene therapy . Current Gene Therapy . 3 . 3 . 239–245 . 10.2174/1566523034578320 . 1566-5232 . 12762482.
  20. Web site: Philadelphia . The Children's Hospital of . 2019-12-20 . Gene Therapy for Spinal Muscular Atrophy (SMA) . 2022-11-13 . www.chop.edu.
  21. Web site: Gene Therapy for PDHA1 . 2022-11-13 . Hope for PDCD Foundation . en-US.
  22. Shin. Ha Kyung. Grahame. George. McCandless. Shawn E.. Kerr. Douglas S.. Bedoyan. Jirair K.. 2017-11-01. Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. Molecular Genetics and Metabolism. en. 122. 3. 61–66. 10.1016/j.ymgme.2017.09.001. 1096-7192. 5722699. 28918066.

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