AUTHOR INFORMATION

Section 1 of 11

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

Coauthored by Paul J Benke, MD, PhD, Director of Clinical Genetics, Associate Professor, Department of Pediatrics, University of Miami

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

Edited by Ian Krantz, MD, Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Richard E Frye, MD, PhD
Editor's Email:	Ian Krantz, MD

eMedicine Journal, March 1 2006, VOLUME 7, Number 3

INTRODUCTION

Section 2 of 11

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 often are 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-CoA, which is one of the two essential substrates needed to produce citrate (see Image 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 central nervous system. 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 the 10th week of gestation. Maldevelopment of the corpus callosum commonly is observed in those with prenatal-onset types of PDCD.

Progressive neurological deterioration is variable 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, while a gliosis of the brainstem and basal ganglia with capillary proliferation occurs in those with Leigh syndrome. Underlying neuropathology usually is not observed in those 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:

• Internationally: 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 usually, but not always, is associated with survival into adulthood.

• All children are born with some residual enzyme activity since 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 usually is 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 more commonly are 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 11

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


• • Mental delays
  
  
  
  • Psychomotor delays
  
  
  
  • Growth retardation
  
  
  
• Progressive neurologic symptoms of 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 is associated with a deficiency of the E2 subunit, while 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
  
  
  

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 pyruvate dehydrogenase complex 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.



• 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 11

Pyruvate Carboxylase Deficiency

Other Problems to be Considered:

D-Lactic acidosis
Gluconeogenesis abnormalities
Mitochondrial electron transport chain disorders

WORKUP

Section 5 of 11

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 PDCD, these levels may be elevated only slightly under normal conditions; elevated levels also may be found during periods of crisis.
  
  
  
  • The normal lactate-to-pyruvate ratio of approximately 10-15:1 is preserved.
  
  
  
• 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 PCD.
  
  
  
  • 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 will grow if obtained within 2 days of death.
  
  
  

Imaging Studies:

• Magnetic resonance imaging


• • Magnetic resonance imaging (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 show 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 PCDC.
  
  
  
  • N-acetylaspartate and choline levels are consistent with hypomyelination.
  
  
  

TREATMENT

Section 6 of 11

Medical Care:

• Direct treatment that stimulates the pyruvate dehydrogenase complex, provides alternative fuels, and prevents acute worsening of the syndrome. Correction of acidosis does not reverse all the symptoms. Central nervous system 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. 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; however, 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 often is 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 titrated individually.



• Ketogenic diets


• • 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, central nervous system metabolic abnormalities persist, as evidenced by high lactic acid levels in the cerebrospinal fluid and progressive neurological degeneration.

  • The vulnerability of the central nervous system is a result of its dependence on glucose as a fuel.
  
  
  

MEDICATION

Section 7 of 11

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. Used clinically for the prevention and treatment of specific deficiency states.

Drug Name	Biotin -- Essential cofactor for several important enzymes, including an alternative pathway for pyruvate. Vitamin H is a synonym.
Pediatric Dose	1-5 mg/kg/d PO/IV divided bid
Contraindications	Documented hypersensitivity
Interactions	Anticonvulsants (eg, phenytoin, primidone, carbamazepine, phenobarbital) may decrease absorption, thus reducing blood levels of biotin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	None reported

Drug Name	Thiamine (Thiamilate) -- Important cofactor for the pyruvate dehydrogenase complex E1 enzyme. Some disorders are responsive to simple supplementation.
Pediatric Dose	50-100 mg/kg/d PO/IV divided qid
Contraindications	Documented hypersensitivity
Interactions	Incompatible with alkaline or neutral solutions
Pregnancy	A - Safe in pregnancy
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 oral product from light

Drug Category: Enzyme activator -- Dichloroacetate sodium (DCA) is the only drug found to activate the enzyme complex.

Drug Name	Dichloroacetate sodium -- A compound believed to activate the pyruvate dehydrogenase complex by inhibiting the inactivating kinase. This decreases lactate production and promotes pyruvate oxidation.
Adult Dose	30-100 mg/kg/d IV divided bid
Pediatric Dose	30-100 mg/kg/d IV divided bid
Contraindications	Documented hypersensitivity
Interactions	Limited data exist; inhibits glucose synthesis, caution with coadministration of hypoglycemic agents
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

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.

Drug Name	Bicarbonate sodium -- Can be used to correct the acidosis in chronic and acute settings.
Adult Dose	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 Dose	Acute: Administer as in adults Chronic: 2-5 mEq/kg/d PO divided qid
Contraindications	Alkalosis, hypernatremia, severe pulmonary edema, hypocalcemia, and unknown abdominal pain
Interactions	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
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Name	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 Dose	1-3 mEq/kg/d PO tid/qid to control chronic acidosis
Pediatric Dose	2-5 mEq/kg/d PO tid/qid to control chronic acidosis
Contraindications	Severe renal impairment; acute dehydration
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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

FOLLOW-UP

Section 8 of 11

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 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.



• Dichloroacetate appears to produce biochemical correction of PDCD in many cases, but resolution of neurologic symptoms is exceptional. It is doubtful that structural CNS abnormalities can 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.

TEST QUESTIONS

Section 9 of 11

CME Question 1: A 5-year-old girl with a 2-day history of fever and upper respiratory tract symptoms is brought to the pediatric ED by a fire rescue unit for progressive ataxia followed by lethargy. The patient arrives receiving IV hydration. The physician administers thiamine and draws lactate and ammonia levels. Both labs are within reference ranges, and the patient's symptoms abate. Which of the following is the most appropriate next step?

A: Send serum for amino acids levels.
B: Send urine for organic acids levels.
C: Admit the patient for observation and continue hydration.
D: Discharge with written instructions and tell the caregivers of the patient to return if ataxia reoccurs.
E: Send blood for leukocyte function assay.

The correct answer is D: With childhood-onset pyruvate dehydrogenase complex deficiency (PDCD), children have high residual activity of the pyruvate dehydrogenase complex (PDC) and present with symptoms during periods of illness or stress. Treatment is usually supportive, with hydration and correction of the acidosis. Long-term sequelae are rare. The patient appears to have a childhood-onset PDCD that has resolved with hydration because the symptoms have disappeared and the lactate and ammonia levels are within reference ranges. Organic acid levels are not helpful in this case. The key amino acid levels probably are not elevated at this time because the biochemical abnormalities have resolved. If amino acids levels are elevated, they probably are nonspecific because of the general catabolic state that occurs with illness. The child is now stable and her health has returned to baseline. A written statement that outlines the suspected disorder of the child and appropriate treatment during acute decompensation should be given to the caregivers at discharge. Testing for leukocyte function in a patient with high residual PDC activity, especially in a female, has low yield and probably will not add significantly to the diagnosis.

CME Question 2: An afebrile 6-week-old child presents with severe lethargy after feeding. Although the child is not spitting up food, the parents also are concerned because the child eats very slowly and does not make good eye contact with the mother. After several laboratory tests, the physician makes the diagnosis of pyruvate dehydrogenase complex deficiency (PDCD). The physician administers dichloroacetate, and the child responds well. Which of the following is most appropriate to tell the parents about the prognosis?

A: The child will be asymptomatic and will develop normally.
B: The child will have mild-to-moderate developmental delay.
C: Although neurological symptoms and developmental delay have resolved in rare cases, neurological progression of this disease usually occurs despite resolution of the biochemical abnormalities.
D: Despite treatment, the child is likely to die within the next few months.
E: Due to the poor prognosis, treatment should be withdrawn.

The correct answer is C: All therapies for PDCD are suboptimal. Although dichloroacetate may restore enzyme activity, previous developmental insults to the central nervous system cannot be repaired. Although the brain can compensate for some early insults, resolution of the neurological damage in individuals with PDCD is rare, and neurological progression of this disease usually occurs despite resolution of the biochemical abnormalities.

Pearl Question 1 (T/F): Elevation in alanine is observed in pyruvate dehydrogenase complex E3 enzyme deficiency but not in the other types of pyruvate dehydrogenase complex deficiencies (PDCDs).

The correct answer is False: Elevations in leucine, isoleucine, and valine with the other supportive findings of pyruvate dehydrogenase complex deficiency (PDCD) strongly suggest an E3 enzyme abnormality.

Pearl Question 2 (T/F): Citrulline, lysine, and aspartic acid abnormalities are observed in pyruvate dehydrogenase deficiency (PDCD) but not in pyruvate carboxylase deficiency (PCD).

The correct answer is False: Citrulline, lysine, and aspartic acid abnormalities are observed in PCD.

Pearl Question 3 (T/F): Lactate-to-pyruvate ratio is normal in pyruvate dehydrogenase deficiency (PDCD) but not in pyruvate carboxylase deficiency (PCD) or mitochondrial electron transport chain disorders.

The correct answer is True: 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 PDCD, these levels may be elevated only slightly under normal conditions; elevated levels also may be found during periods of crisis. The normal lactate-to-pyruvate ratio of approximately 10-15:1 is preserved.

Pearl Question 4 (T/F): Leigh syndrome can be caused by pyruvate dehydrogenase deficiency (PDCD) and is characterized by gliosis of the brainstem and basal ganglia, with capillary proliferation.

The correct answer is True: The key feature of PDCD 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. Progressive neurological deterioration is variable 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, while a gliosis of the brainstem and basal ganglia with capillary proliferation occurs in those with Leigh syndrome. Underlying neuropathology usually is not observed in those whose onset of PDCD is in childhood.

PICTURES

Section 10 of 11

Caption: Picture 1. Pyruvate dehydrogenase complex deficiency. 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-CoA, it is shunted to other pathways that produce lactic acid and alanine.
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BIBLIOGRAPHY

Section 11 of 11

• Al-Essa MA, Ozand PT: Manual of Metabolic Diseases. King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 1998.
• Brown GK, Otero LJ, LeGris M, Brown RM: Pyruvate dehydrogenase deficiency. J Med Genet 1994 Nov; 31(11): 875-9[Medline].
• Byrd DJ, Krohn HP, Winkler L, et al: Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia. Eur J Pediatr 1989 Apr; 148(6): 543-7[Medline].
• De Meirleir L: Defects of pyruvate metabolism and the Krebs cycle. J Child Neurol 2002 Dec; 17 Suppl 3: 3S26-33; discussion 3S33-4[Medline].
• 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 2003 May; 53(5): 793-9[Medline].
• Head RA, Brown RM, Zolkipli Z, et al: Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Ann Neurol 2005 Aug; 58(2): 234-41[Medline].
• Head RA, de Goede CG, Newton RW, et al: Pyruvate dehydrogenase deficiency presenting as dystonia in childhood. Dev Med Child Neurol 2004 Oct; 46(10): 710-2[Medline].
• Morris AA, Leonard JV: The treatment of congenital lactic acidoses. J Inherit Metab Dis 1996; 19(4): 573-80[Medline].
• Morten KJ, Beattie P, Brown GK, Matthews PM: Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency. Neurology 1999 Aug 11; 53(3): 612-6[Medline].
• 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 2002 Oct 9; 1588(1): 79-84[Medline].
• 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 2002 Sep 15; 201(1-2): 33-7[Medline].
• Pastoris O, Savasta S, Foppa P, et al: Pyruvate dehydrogenase deficiency in a child responsive to thiamine treatment. Acta Paediatr 1996 May; 85(5): 625-8[Medline].
• Shevell MI, Matthews PM, Scriver CR, et al: Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol 1994 Oct; 11(3): 224-9[Medline].
• Stacpoole PW, Barnes CL, Hurbanis MD, et al: Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 1997 Dec; 77(6): 535-41[Medline].
• Stacpoole PW, Bunch ST, Neiberger RE, et al: The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis. J Pediatr 1999 Jan; 134(1): 99-102[Medline].
• Weber TA, Antognetti MR, Stacpoole PW: Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. J Pediatr 2001 Mar; 138(3): 390-5[Medline].
• Zand DJ, Simon EM, Pulitzer SB, et al: In vivo pyruvate detected by MR spectroscopy in neonatal pyruvate dehydrogenase deficiency. AJNR Am J Neuroradiol 2003 Aug; 24(7): 1471-4[Medline].

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