Pyruvate Dehydrogenase Complex Deficiency Follow-up

  • Author: Richard E Frye, MD, PhD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Nov 6, 2009
 

Further Inpatient Care

Acute decompensation during acute pyruvate dehydrogenase complex (PDC) deficiency (PDCD) requires admission and management of acidosis with intravenous bicarbonate.

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Further Outpatient Care

Provide close follow-up for children with pyruvate dehydrogenase complex deficiency. Closely monitor lactate levels.

To help evaluate dietary manipulations and to ensure compliance, have caregivers of children with pyruvate dehydrogenase complex deficiency complete a dietary log.

Advise caregivers of individuals with pyruvate dehydrogenase complex deficiency to always carry an informational statement that describes pyruvate dehydrogenase complex deficiency and the appropriate medical treatment for the disorder in an emergency setting.

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Prognosis

Individuals with mild deficiencies in the E1 enzyme of the pyruvate dehydrogenase complex have a better prognosis than those with deficiencies in the E2 and E3 pyruvate dehydrogenase complex enzymes.

Prediction of prognosis is unclear because of the small number of children with pyruvate dehydrogenase complex deficiency studied and the large number of mutations involved.

In most cases of neonatal-onset and infantile-onset of pyruvate dehydrogenase complex deficiency, a poor prognosis remains, even when the lactic acidosis is treated successfully. Although lactic acidosis appears to be controlled by thiamine supplementation in individuals who respond to thiamine, the neurological outcome may be poor.

One case report describes cessation of neurological demyelination with the ketogenic diet; however, the ketogenic diet has not been reported to be of significant neurologic benefit to other patients with pyruvate dehydrogenase complex deficiency.[5]

Dichloroacetate appears to produce biochemical correction of pyruvate dehydrogenase complex deficiency in many cases, but resolution of neurologic symptoms is exceptional. Structural CNS abnormalities likely cannot be reversed with successful biochemical treatment.

Dichloroacetate may have greater efficacy with particular mutations of the E1 subunit.

In general, treatment of individuals with pyruvate dehydrogenase complex deficiency is most beneficial if started early. Although successful treatment is rare, some cases have been reported.

Although the recurrence rate for subsequent pregnancies is low, test future gestations for pyruvate dehydrogenase complex deficiency because of the possibility of germline mosaicism. Enzyme activity of cultured chorionic villus cells can be determined in time to make an early diagnosis. Inaccuracies in the diagnosis of the female fetus arise from X chromosome inactivation.

Individuals with an E2 subunit deficiency may have a mild phenotype.

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Patient Education

Educate the patient with pyruvate dehydrogenase complex deficiency and the caregivers regarding the factors that may elicit a crisis and the early signs of decompensation.

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Contributor Information and Disclosures
Author

Richard E Frye, MD, PhD  Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston

Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and International Neuropsychological Society

Disclosure: Nothing to disclose.

Coauthor(s)

Paul J Benke, MD, PhD  Director of Clinical Genetics, Joe DiMaggio Children's Hospital

Paul J Benke, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Ian Krantz, MD  Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia

Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center

Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Ostergaard E, Moller LB, Kalkanoglu-Sivri HS, et al. Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency. J Inherit Metab Dis. Jun 11 2009;[Medline].

  2. Han Z, Zhong L, Srivastava A, Stacpoole PW. Pyruvate dehydrogenase complex deficiency due ubiquitination and proteasome-mediated degradation of the E1beta subunit. J Biol Chem. Oct 8 2007;[Medline].

  3. Debray FG, Mitchell GA, Allard P, Robinson BH, Hanley JA, Lambert M. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem. May 2007;53(5):916-21. [Medline].

  4. [Best Evidence] Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. May 2006;117(5):1519-31. [Medline].

  5. Weber TA, Antognetti MR, Stacpoole PW. Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. J Pediatr. Mar 2001;138(3):390-5. [Medline].

  6. Al-Essa MA, Ozand PT. Manual of Metabolic Diseases. Saudi Arabia: King Faisal Specialist Hospital and Research Centre, Riyadh; 1998.

  7. Brown GK, Otero LJ, LeGris M, Brown RM. Pyruvate dehydrogenase deficiency. J Med Genet. Nov 1994;31(11):875-9. [Medline].

  8. Byrd DJ, Krohn HP, Winkler L, et al. Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia. Eur J Pediatr. Apr 1989;148(6):543-7. [Medline].

  9. De Meirleir L. Defects of pyruvate metabolism and the Krebs cycle. J Child Neurol. Dec 2002;17 Suppl 3:3S26-33; discussion 3S33-4. [Medline].

  10. Debray FG, Lambert M, Vanasse M, Decarie JC, Cameron J, Levandovskiy V. Intermittent peripheral weakness as the presenting feature of pyruvate dehydrogenase deficiency. Eur J Pediatr. Jul 2006;165(7):462-6. [Medline].

  11. Fouque F, Brivet M, Boutron A, et al. Differential effect of DCA treatment on the pyruvate dehydrogenase complex in patients with severe PDHC deficiency. Pediatr Res. May 2003;53(5):793-9. [Medline].

  12. Head RA, Brown RM, Zolkipli Z, et al. Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Ann Neurol. Aug 2005;58(2):234-41. [Medline].

  13. Head RA, de Goede CG, Newton RW, et al. Pyruvate dehydrogenase deficiency presenting as dystonia in childhood. Dev Med Child Neurol. Oct 2004;46(10):710-2. [Medline].

  14. Morris AA, Leonard JV. The treatment of congenital lactic acidoses. J Inherit Metab Dis. 1996;19(4):573-80. [Medline].

  15. Morten KJ, Beattie P, Brown GK, Matthews PM. Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency. Neurology. Aug 11 1999;53(3):612-6. [Medline].

  16. Naito E, Ito M, Yokota I, et al. Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci. Sep 15 2002;201(1-2):33-7. [Medline].

  17. Naito E, Ito M, Yokota I, et al. Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. Biochim Biophys Acta. Oct 9 2002;1588(1):79-84. [Medline].

  18. Pastoris O, Savasta S, Foppa P, et al. Pyruvate dehydrogenase deficiency in a child responsive to thiamine treatment. Acta Paediatr. May 1996;85(5):625-8. [Medline].

  19. Shevell MI, Matthews PM, Scriver CR, et al. Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol. Oct 1994;11(3):224-9. [Medline].

  20. Stacpoole PW, Barnes CL, Hurbanis MD, et al. Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child. Dec 1997;77(6):535-41. [Medline].

  21. Stacpoole PW, Bunch ST, Neiberger RE, et al. The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis. J Pediatr. Jan 1999;134(1):99-102. [Medline].

  22. Zand DJ, Simon EM, Pulitzer SB, et al. In vivo pyruvate detected by MR spectroscopy in neonatal pyruvate dehydrogenase deficiency. AJNR Am J Neuroradiol. Aug 2003;24(7):1471-4. [Medline].

 
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This diagram shows a simplified version of the citric acid cycle and shows the enzyme deficit. The dashed line indicates the blocked pathway and the size of the arrows indicates the relative flow of products. Because pyruvate does not proceed to acetyl-coenzyme A (CoA), it is shunted to other pathways that produce lactic acid and alanine.
 
 
 
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