AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

Pyruvate dehydrogenase complex deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The citric acid cycle is a major biochemical process that derives energy from carbohydrates. Malfunction of this cycle deprives the body of energy. An abnormal lactate buildup results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.

Progressive neurological symptoms usually start in infancy but may be evident at birth or in later childhood. These symptoms may include developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, or seizures. Childhood-onset forms of this disorder are often associated with intermittent periods of decompensation but normal neurological development. Therapies are suboptimal for other forms of PDCD; resolution of the lactic acidosis may occur, but cessation of the underlying progressive neurological damage is rare.

The key feature of this condition is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem. The group of disorders that result in this pathology are termed Leigh syndrome. Defects in one of many of the mitochondrial enzymes involved in energy metabolism may demonstrate similar brain pathology.

Pathophysiology

Pyruvate dehydrogenase complex (PDC) converts pyruvate to acetyl-coenzyme A (CoA), which is one of the two essential substrates needed to produce citrate (see Media file 1). A deficiency in this enzymatic complex limits the production of citrate. Because citrate is the first substrate in the citric acid cycle, the cycle cannot proceed. Alternate metabolic pathways are stimulated in an attempt to produce acetyl-CoA; however, an energy deficit remains, especially in the CNS. The magnitude of the energy deficit depends on the residual activity of the enzyme.

Severe enzyme deficiencies may lead to congenital brain malformation because of a lack of energy during neural development. Morphological abnormalities occur before 10 weeks' gestation. Maldevelopment of the corpus callosum is commonly observed in those with prenatal-onset types of PDCD.

Progressive neurological deterioration varies in neonates with an apparently healthy brain. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum, with gray matter degeneration or necrotizing encephalopathy, may occur in some individuals with PDCD, whereas a gliosis of the brainstem and basal ganglia with capillary proliferation occurs in those with Leigh syndrome. Underlying neuropathology is not usually observed in individuals whose onset of PDCD is in childhood.

The most common form of PDCD is caused by mutations in the X-linked E1 alpha gene; all other causes are due to alterations in recessive genes.

Frequency

International

PDCD is a rare disorder. Several hundred cases of PDCD have been reported. Most mutations are sporadic, and the recurrence rate is very low. The true occurrence of this disorder is unknown because mild mutations of the E1 alpha enzyme subunit gene on the X chromosome may be asymptomatic, especially in females.

Mortality/Morbidity

• Individuals with neonatal- and infantile-onset types of PDCD usually die during the first years of life. Later childhood onset of the disease is usually, but not always, associated with survival into adulthood.
• All children are born with some residual enzyme activity because a complete deficiency of PDC is incompatible with life. Infants with 15% or less PDC activity normally do not survive the newborn period. PDC activity greater than 25% is associated with less severe disease and is usually characterized by ataxia and mild psychomotor delay.
• Some therapies may extend the lives of individuals who are severely affected with PDCD; however, the progressive nature of the neurological deterioration results in significant morbidity.

Sex

• Gender differences appear for dysfunction of the E1 alpha enzyme subunit, which is coded by the X chromosome. Heterozygous females can manifest severe symptoms, though males are typically affected to a much greater extent.
• West syndrome is more common in females with PDCD.
• Severe lactic acidosis with early demise and Leigh syndrome are more commonly observed in males with PDCD.
• Progressive neurological degeneration is observed more commonly in females with PDCD.

Age

• Age of presentation varies from prenatal to early childhood and depends on the residual activity of the PDC.
• Individuals with severe disease have prenatal onset with structural brain abnormalities.
• Moderate disease presents in infants as psychomotor delay.
• Individuals with less severe disease usually present in early childhood with intermittent lethargy or ataxia.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

The presentation and progression of this disorder is highly variable.

• Nonspecific but common symptoms of metabolic illnesses include the following:
• • Poor feeding
  • Lethargy
  • Rapid breathing (ie, tachypnea)
• Developmental nonspecific signs of metabolic disease include the following:
• • Mental delays
  • Psychomotor delays
  • Growth retardation
• Progressive neurologic symptoms of pyruvate dehydrogenase complex deficiency (PDCD) usually start in infancy but may be evident at birth or in later childhood. The following are signs of poor neurological development or degenerative lesions:
• • Poor acquisition or loss of motor milestones
  • Poor muscle tone
  • New onset seizures
  • Periods of incoordination (ie, ataxia)
  • Abnormal eye movements
  • Poor response to visual stimuli
  • Episodic dystonia: This is associated with a deficiency of the E2 subunit, whereas progressive dystonia appears to be associated with a deficiency in the E1-alpha subunit.
• Early childhood-onset PDCD typically presents with intermittent periods of incoordination, especially during mild illnesses.
• The following respiratory symptoms are consistent with neurological disease and severe lactic acidosis:
• • Apnea
  • Dyspnea
  • Respiratory depression
• An acute form resembling Guillain-Barré syndrome with limb weakness has recently been described.

Physical

Low Apgar scores and small for gestational age are nonspecific signs of prenatal onset. With poor feeding and lethargy out of proportion to a mild viral illness, consider metabolic disturbances, especially after bacterial infection has been ruled out.

• Neurologic
• • Hypotonia, ataxia, choreoathetosis, and progressive encephalopathy are found in children with lactic acidosis.
  • Loss of cortical material can result in a positive Babinski reflex, absent deep tendon reflexes, tremors, or spastic diplegia or quadriplegia.
  • Prenatal or postnatal microcephaly may be found.
  • Ophthalmological examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary responses, and blindness.
  • Seizures vary in type from clonic-tonic to infantile spasms.
  • Episodic or progressive dystonia
• Respiratory: Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.
• Dysmorphology
• • A characteristic but uncommon dysmorphology has been described for infantile-onset PDCD. Features include narrow forehead, frontal bossing, wide nasal bridge, long philtrum, and anteverted nostrils. Structural brain lesions have also been reported.
  • In addition, a case of X-component deficiency has been described with trigonocephaly, supranasal lipoma, hypertelorism, thin upper lip, bilateral epicanthus, upward slant of the eyes, high palate, and pectus excavatum.

Causes

• The intramitochondrial PDC is composed of 3 basic substrate-processing enzymes: a protein X and 2 regulatory enzymes. Thiamine pyrophosphate and lipoic acid are important PDC cofactors. Dysfunction in all 3 substrate-processing enzymes, as well as protein X and thiamine dependence of the E1 alpha enzyme, has been described; however, dysfunction of the E1 alpha enzyme subunit is most common.
• The E1 alpha subunit gene is located at Xp22.2-p22.1. More than 90 mutations of the E1 alpha enzyme subunit impair either polypeptide stability or catalytic efficiency.
• The gene for the E1 beta enzyme subunit of the PDC has been mapped to 3p13-q23; an isolated deficiency in E1 beta enzyme subunit has recently been documented.
• A thiamine triphosphate synthesis inhibitor may cause PDC E1 enzyme thiamine dependence in some patients who present with Leigh syndrome.
• Recently a post-translational modification in which EGFR-PTK-mediated tyrosine-phosphorylation of the E1ss protein led to enhanced ubiquitination followed by proteasome-mediated degradation has been described.¹
• A deficiency of lipoic acid, the E2 enzyme cofactor, has been described.
• A deficiency of the E2 enzyme has been described.
• The gene for the X protein of the PDC is located at 11p13 and has an autosomal recessive inheritance. Eleven cases of PDC X protein deficiency have been documented.
• The E3 enzyme is mapped to 7q31-32 and has an autosomal recessive inheritance. The E3 enzyme is also active in the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

D-Lactic acidosis
Gluconeogenesis abnormalities
Mitochondrial electron transport chain disorders

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• Lactate and pyruvate levels
• • High blood lactate and pyruvate levels with or without lactic acidemia suggest an inborn error of metabolism at the mitochondrial level.
  • Cerebrospinal fluid also shows elevation of lactate and pyruvate (at times even in the absence of elevated blood levels).
  • In mild cases of pyruvate dehydrogenase complex deficiency (PDCD), these levels may be elevated only slightly under normal conditions; elevated levels may also be found during periods of crisis.
  • A recent study suggests that the lactate-to-pyruvate ratio is only diagnostically useful to differentiate PDCD from other forms of congenital lactic acidosis at higher lactate levels (>5.0 mmol/L).²
• Serum and urine analysis
• • Serum and urine amino acid analyses reveal hyperalaninemia.
  • Deficiency of the E3 enzyme also causes an elevation in branched-chain amino acids in the serum and alpha-ketoglutarate in the serum and urine.
  • Amino acid levels vary with the general metabolic state of the patient; a catabolic state, in which gluconeogenesis is activated and proteins are degraded, elevates many amino acids, leading to a nonspecific amino acid profile.
  • Hyperammonemia and nonspecific amino acid elevation are associated with E2 enzyme deficiency, which is more common during acute illnesses.
  • Thiamine pyrophosphate-adenosine triphosphate phosphoryl transferase inhibitor can be detected in urine or blood by a specific assay.
• Other studies
• • Definitive diagnosis is made by showing abnormal enzyme function.
  • Functional assays can be performed on leukocytes, fibroblasts, or properly preserved tissue samples. PDC activity should be measured with and without thiamine in order to detect cases of thiamine-responsive PDCD.
  • Blood and fibroblasts are the easiest to obtain, but mosaicism can cause normal enzymatic activity in leukocytes and fibroblasts, requiring a tissue biopsy if the diagnosis is strongly suspected.
  • A skin sample grows if obtained within 2 days of death.

Imaging Studies

• MRI
• • MRI shortly after birth may show ventricular dilation, cerebral atrophy, hydranencephaly, partial or complete absence of the corpus callosum, absence of the medullary pyramids, or abnormal and ectopic inferior olives.
  • MRI of infants with progressive neurological symptoms may reveal symmetric cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum, or generalized hypomyelination.
  • Individuals with a deficiency in the E2 subunit may demonstrate discrete lesions restricted to the globus pallidus.
• Magnetic resonance spectroscopy
• • Magnetic resonance spectroscopy (MRS) of the brain shows high lactate levels in individuals with PDCD.
  • N-acetylaspartate and choline levels are consistent with hypomyelination.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

• Direct treatment that stimulates the 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 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 PDCD. However, administration of all of these cofactors to all patients with PDCD is typical in order to optimize PDC function.
• Ketogenic diets (with restricted carbohydrate intake) have been used to control lactic acidosis with minimal success.
• Dichloroacetate reduces the inhibitory phosphorylation of PDC. 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.³
  • 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 PDCD is important in order to estimate the recurrence risk for future pregnancies.
• Progressive renal failure is common in PDCD. A nephrologist should be consulted if signs of renal failure are evident.
• Anesthesia can be complicated by PDCD. 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Drug Category: 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.

Drug Category: Enzyme activator

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

Drug Category: 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Further Inpatient Care

• Acute decompensation during acute illness requires admission and management of acidosis with intravenous bicarbonate.

Further Outpatient Care

• Provide close follow-up for children with pyruvate dehydrogenase complex deficiency (PDCD). Closely monitor lactate levels.
• To help evaluate dietary manipulations and to ensure compliance, have caregivers of children with PDCD complete a dietary log.
• Advise caregivers of individuals with PDCD to always carry an informational statement that describes PDCD and the appropriate medical treatment for the disorder in an emergency setting.

Prognosis

• Individuals with mild deficiencies in the E1 enzyme of the PDC have a better prognosis than those with deficiencies in the E2 and E3 PDC enzymes.
• Prediction of prognosis is unclear because of the small number of children with PDCD studied and the large number of mutations involved.
• In most cases of neonatal- and infantile-onset of PDCD, 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 PDCD.⁴
• Dichloroacetate appears to produce biochemical correction of PDCD 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 PDCD 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 PDCD 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.

Patient Education

• Educate the patient with PDCD and the caregivers regarding the factors that may elicit a crisis and the early signs of decompensation.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  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.
	View Full Size Image
Media type:  Image

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

1. 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].
2. 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].
3. 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].
4. 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].
5. Al-Essa MA, Ozand PT. Manual of Metabolic Diseases. Saudi Arabia: King Faisal Specialist Hospital and Research Centre, Riyadh; 1998.
6. Brown GK, Otero LJ, LeGris M, Brown RM. Pyruvate dehydrogenase deficiency. J Med Genet. Nov 1994;31(11):875-9. [Medline].
7. 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].
8. 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].
9. 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].
10. 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].
11. 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].
12. 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].
13. Morris AA, Leonard JV. The treatment of congenital lactic acidoses. J Inherit Metab Dis. 1996;19(4):573-80. [Medline].
14. 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].
15. 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].
16. 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].
17. 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].
18. 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].
19. 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].
20. 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].
21. 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].

Article Last Updated: Dec 11, 2007