eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Pyruvate Dehydrogenase Complex Deficiency: Treatment & Medication

Author: Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Coauthor(s): Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Contributor Information and Disclosures

Updated: Nov 6, 2009

Treatment

Medical Care

  • Direct treatment that stimulates the pyruvate dehydrogenase complex (PDC), provides alternative fuels, and prevents acute worsening of the syndrome. Correction of acidosis does not reverse all the symptoms. CNS damage is common and limits recovery of normal function.
  • Cofactor supplementation with thiamine, carnitine, and lipoic acid is the standard of care. The cases of pyruvate dehydrogenase complex deficiency (PDCD) that are responsive to these cofactors respond to supplementation, especially thiamine. Some evidence suggests that high doses of thiamine may be most effective in some mutations causing thiamine-responsive pyruvate dehydrogenase complex deficiency. However, administration of all of these cofactors to all patients with pyruvate dehydrogenase complex deficiency is typical in order to optimize pyruvate dehydrogenase complex function.
  • Ketogenic diets (with restricted carbohydrate intake) have been used to control lactic acidosis with minimal success.
  • Dichloroacetate reduces the inhibitory phosphorylation of pyruvate dehydrogenase complex. Resolution of lactic acidosis is observed in patients with E1 alpha enzyme subunit mutations that reduce enzyme stability.
    • Recently, oral dichloroacetate administered for 6 months was found to be well tolerated and blunted the postprandial increase in circulating lactate but did not improve neurologic or other clinical measures.4
    • Studies with human fibroblast have demonstrated that certain gene deletions are more response to dichloroacetate than others.
    • Other lactic acidemias have been treated successfully with this compound.
    • Long-term use is associated with reversible peripheral neuropathy and elevation in liver transaminases.
    • Coadministration of thiamine appears to protect against neuropathy in animals.
    • Because of the largely unknown benefit of this compound, it remains an investigational drug.
  • Oral citrate is often used to treat acidosis.

Consultations

  • Evaluation by an expert in metabolic and genetic disease is necessary to confirm the diagnosis, guide the appropriate treatment, and determine the prognosis.
  • Genetic counseling for the parents of the individual with pyruvate dehydrogenase complex deficiency is important in order to estimate the recurrence risk for future pregnancies.
  • Progressive renal failure is common in pyruvate dehydrogenase complex deficiency. A nephrologist should be consulted if signs of renal failure are evident.
  • Anesthesia can be complicated by pyruvate dehydrogenase complex deficiency. An anesthesiologist should be consulted prior to procedures that require anesthesia.

Diet

  • Limit carbohydrate administration to 3-4 mg/kg/min to prevent lactate buildup. The appropriate carbohydrate intake depends on the residual enzyme activity and must be individually treated.
  • A ketogenic diet may be indicated.
    • Ketogenic diets minimize the carbohydrate content and maximize the daily intake of fat content.
    • Fat intake should account for 65-80% of the caloric intake, with protein accounting for about 10% of the caloric intake and carbohydrate caloric intake making up the balance.
    • Manipulate the percent of dietary fat and carbohydrate calories to provide an appropriate lactic acid level.
    • Although the ketogenic diet may reduce the blood lactic acid level and extend lifespan, CNS metabolic abnormalities persist, as evidenced by high lactic acid levels in the cerebrospinal fluid and progressive neurological degeneration.
    • The vulnerability of the CNS is a result of its dependence on glucose as a fuel.

Medication

Cofactors

Organic substances required by the body in small amounts for various metabolic processes. They are essential for new cell growth and division. They are used clinically for the prevention and treatment of specific deficiency states.


Biotin

Essential cofactor for several important enzymes, including an alternative pathway for pyruvate. Vitamin H is a synonym.

Adult

Pediatric

1-5 mg/kg/d PO/IV divided bid

Anticonvulsants (eg, phenytoin, primidone, carbamazepine, phenobarbital) may decrease absorption, thus reducing blood levels of biotin

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

None reported


Thiamine (Thiamilate)

Important cofactor for the pyruvate dehydrogenase complex E1 enzyme. Some disorders are responsive to simple supplementation.

Adult

Pediatric

50-100 mg/kg/d PO/IV divided qid

Incompatible with alkaline or neutral solutions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Pregnancy category C for doses exceeding RDA; caution when administering thiamine IV (deaths have resulted from IV use); administer before or together with dextrose-containing fluids in suspected thiamine-deficiency; protect PO product from light

Enzyme activator

Dichloroacetate sodium is the only drug found to activate the enzyme complex.


Dichloroacetate sodium

A compound believed to activate the PDC by inhibiting the inactivating kinase. This decreases lactate production and promotes pyruvate oxidation.

Adult

30-100 mg/kg/d IV divided bid

Pediatric

Administer as in adults

Limited data are available; inhibits glucose synthesis, caution with coadministration of hypoglycemic agents

Pregnancy
Precautions

Polyneuropathy has been reported with long-term administration; urinary oxalate crystal formation has been reported and is a dose-related phenomenon; monitor for metabolic acidosis and hypoglycemia
Currently an investigational agent and is not commercially available; it is only available through an investigational protocol at this time

Alkalinizing agents

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs. Citric acid mixtures may also be used. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.


Bicarbonate sodium

Can be used to correct the acidosis in chronic and acute settings.

Adult

Acute: 1-2 mEq/kg IV over 20 min; infusion can be repeated up to q30min prn in an emergency setting; however, careful monitoring of blood pH must be obtained
Chronic: 1-3 mEq/kg/d PO divided qid

Pediatric

Acute: Administer as in adults
Chronic: 2-5 mEq/kg/d PO divided qid

Inactivates catecholamines, calcium salts, and atropine when mixed together; has been shown to decrease the therapeutic levels of methotrexate, tetracyclines, and salicylates because of urinary alkalinization

Alkalosis, hypernatremia, severe pulmonary edema, hypocalcemia, and unknown abdominal pain

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May precipitate hypernatremia, circulatory overload, and hypocalcemia; may cause a metabolic alkalosis; administer with extravasation precautions
Careful monitoring of arterial or venous blood pH must be obtained with IV infusion; check the response to bicarbonate 10-20 min after infusion; clinical change in the patient's condition along with laboratory values should guide repeat treatment with bicarbonate
Caution with neonates because of increased risk of intraventricular hemorrhage


Citrate mixtures (Bicitra, Oracit, Cytra-K)

Several mixtures of citrate with sodium or potassium or both are available as alkalinizing agents. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.

Adult

1-3 mEq/kg/d PO tid/qid to control chronic acidosis

Pediatric

2-5 mEq/kg/d PO tid/qid to control chronic acidosis

Severe renal impairment; acute dehydration

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause hypocalcemia, hypernatremia, and/or hyperkalemia, depending on the formulation used; individually base formulation with consideration of other supplementation and the ability of the patient to tolerate sodium or potassium loads

More on Pyruvate Dehydrogenase Complex Deficiency

Overview: Pyruvate Dehydrogenase Complex Deficiency
Differential Diagnoses & Workup: Pyruvate Dehydrogenase Complex Deficiency
Treatment & Medication: Pyruvate Dehydrogenase Complex Deficiency
Follow-up: Pyruvate Dehydrogenase Complex Deficiency
Multimedia: Pyruvate Dehydrogenase Complex Deficiency
References
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References

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  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].

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  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].

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  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].

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Further Reading

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Keywords

pyruvate dehydrogenase complex deficiency, PDCD, congenital infantile lactic acidosis, intermittent ataxia with lactic acidosis, developmental delay, X-linked Leigh syndrome, treatment, diagnosis

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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.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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.

CME Editor

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, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, 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.

 
 
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