Pyruvate Dehydrogenase Complex Deficiency Treatment & Management

Updated: Feb 18, 2016
  • Author: Richard E Frye, MD, PhD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Treatment

Medical Care

Consider pyruvate dehydrogenase complex deficiency in all patients with lactic acidosis and central nervous system (CNS) findings; failure to do so may lead to a second, similarly affected child.

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 thiamine and lipoic acid cofactors to all patients with pyruvate dehydrogenase complex deficiency is done to optimize pyruvate dehydrogenase complex function, and carnitine is given to facilitate fatty acid transport into mitochondria and to potentially increase cellular ATP production.

Thiamine-responsive cases are more likely in children who are diagnosed at older than 1 year, and high-dose thiamine (400 mg/day) should be continued in patients who are responsive clinically and chemically. [8]

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.

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. [9]

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.

Transfer the patient to a major medical center that takes care of complex metabolic cases is recommended if this specialized care cannot be provided.

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Consultations

Evaluation by an expert in metabolic and genetic disease is generally helpful 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.

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Diet

Limit carbohydrate administration to 3-4 mg/kg/min to prevent lactate buildup. The appropriate oral carbohydrate intake depends on the residual enzyme activity and must be individually treated. It may be as low as 10-20 carbohydrate calories per kg carbohydrate.

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. However, the brain will change glucose to lipid energy sources after a few days of a ketogenic diet.

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