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

Pyruvate Carboxylase Deficiency

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

Updated: Nov 6, 2009

Introduction

Background

Pyruvate carboxylase deficiency (PCD) is a rare disorder that can cause developmental delay and failure to thrive starting in the neonatal or early infantile period. Pyruvate carboxylase deficiency results in malfunction of the citric acid cycle and gluconeogenesis, thereby depriving the body of energy; the former biochemical process derives energy from carbohydrates, whereas the latter produces carbohydrate fuel for the body when carbohydrate intake is low.

This is a diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency. The dotted line represents absent pathways. Pyruvate cannot produce oxaloacetate and is shunted to alternative pathways that produce lactic acid and alanine. The lack of oxaloacetate prevents gluconeogenesis and urea cycle function.

Metabolic acidosis caused by an abnormal lactate production is associated with nonspecific symptoms such as severe lethargy, poor feeding, vomiting, and seizures, especially during periods of illness and metabolic stress. In the most severe form, pyruvate carboxylase deficiency results in progressive neurologic symptoms, starting in the neonatal or early infantile period, include developmental delay, poor muscle tone, abnormal eye movements, or seizures. Therapies can ameliorate the biochemical abnormalities but cannot undo the progressive neurologic damage.

Pathophysiology

Pyruvate carboxylase (PC) is a biotin-dependent mitochondrial enzyme that plays an important role in energy production and anaplerotic pathways.¹ PC catalyzes the conversion of pyruvate to oxaloacetate. Oxaloacetate is 1 of 2 essential substrates needed to produce citrate, the first substrate in gluconeogenesis (Media file 1).

This is a diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency. The dotted line represents absent pathways. Pyruvate cannot produce oxaloacetate and is shunted to alternative pathways that produce lactic acid and alanine. The lack of oxaloacetate prevents gluconeogenesis and urea cycle function.

Pyruvate carboxylase deficiency affects metabolism in several major ways, including the following:

• The production of citrate, the first substrate in the citric acid cycle, is limited, thus preventing the citric acid cycle from proceeding.
• The precursor of oxaloacetate, pyruvate, is shunted towards alternate metabolic pathways, leading to an increase in lactic acid, alanine, and acetylcoenzyme A (acetyl-CoA). Acetyl-CoA cannot produce citrate without oxaloacetate and is shunted to produce ketone bodies.
• Gluconeogenesis cannot proceed without oxaloacetate, resulting in hypoglycemia during times of prolonged fasting. Tissues that are solely dependent on glucose for fuel, such as the brain, are severely compromised during fasting states. Because cells cannot use the citric acid cycle to produce energy, energy is extracted from glucose exclusively through glycolysis. The highly inefficient process of glycolysis causes glucose to be degraded at a very high rate, resulting in a glucose deficit, thereby compounding the problem.
• Aspartic acid, which is derived from oxaloacetate, is required for the urea cycle. A decrease in aspartic acid production reduces ammonia disposal and leads to increased serum ammonia levels.
• PC produces intermediates of the citric acid cycle that are important for nervous system function. Alpha-ketoglutarate is a precursor for the major CNS excitatory neurotransmitter, glutamate. It also has a role in producing myelin, the key substance involved in transmission of neuronal signals
• PC also has a role in lipogenesis in adipose tissue.

The following 3 types of pyruvate carboxylase deficiency have been defined:

• Type A: The North American phenotype is characterized by infantile onset, moderate lactate level elevation, normal lactate-to-pyruvate ratio, global developmental delay with mental retardation, and survival until adulthood.
• Type B: The French phenotype is characterized by neonatal onset, high lactate and ammonia levels, abnormal lactate-to-pyruvate ratio, and death within the first few months of life.
• Type C: The benign phenotype is characterized by recurrent episodes of mild-to-moderate lactate elevation without any neurological or cognitive symptoms.

Frequency

United States

Pyruvate carboxylase deficiency is a rare disorder, with an approximate incidence of 1 in 250,000 births. Infantile-onset pyruvate carboxylase deficiency (A type) is more common in the United States. An increased incidence has been documented among certain populations, most notably native North American Indians who speak the Algonquian dialect. A founder effect has been postulated.

International

Neonatal onset pyruvate carboxylase deficiency (B type) has a higher incidence in France.

Mortality/Morbidity

Most patients with type B pyruvate carboxylase deficiency die within the first 6 months of life. Some therapies may reduce the biochemical dysfunction. However, progressive neurologic deterioration results in significant morbidity. Severe energy deficit in the CNS causes neurologic symptoms and congenital brain malformations due to a lack of energy during neurogenesis. In neonates with apparently normal brains, progressive neurologic deterioration varies. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum with gray matter degeneration or necrotizing encephalopathy occur in some infants. Others develop Leigh syndrome, which is a gliosis of the brainstem and basal ganglia with capillary proliferation and characteristic changes on CT scanning and MRI. Most patients with the type A pyruvate carboxylase deficiency live into adulthood but have global neurological and cognitive dysfunction.

Age

The age of presentation for the most serious forms varies from the prenatal period to early infancy. Severe disease has prenatal onset and is associated with congenital brain abnormalities. Type A pyruvate carboxylase deficiency manifests in early infancy. The benign form manifests as periods of lactic acidosis anytime during life.

Clinical

History

The following are important aspects in the history of patients with pyruvate carboxylase deficiency (PCD): 

• Birth: Low Apgar scores and small size for gestational age are nonspecific symptoms of metabolic disturbance during gestation.
• General: The development of poor feeding, vomiting, and lethargy are nonspecific but common symptoms of metabolic illnesses. If these symptoms are instigated by a mild viral illness and are more severe than would be expected, a metabolic disturbance should be considered, especially after a bacterial infection has been ruled out.
• Development: Mental, psychomotor, and/or growth retardation are nonspecific symptoms of metabolic disease.
• Neurologic: Poor acquisition or loss of motor milestones, new-onset seizures, episodic incoordination, abnormal eye movements, and poor response to visual stimuli are signs of poor neurologic development or degenerative disease.
• Respiratory: A history of apnea, dyspnea, or respiratory depression is consistent with neurologic disease or severe lactic acidosis.

Physical

• Neurologic
  • Hypotonia, ataxia, tremors, and choreoathetosis are consistent with pyruvate carboxylase deficiency.
  • Progressive motor pathway degeneration results in a present Babinski sign and spastic diplegia or quadriplegia.
  • Ophthalmologic examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary response, and blindness.
  • Prenatal microcephaly or postnatal microcephaly also may be evident on physical examination.
• Respiratory: Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.
• Hepatomegaly

Causes

• The gene that encodes pyruvate carboxylase (PC) has been localized to bands 11q13.4-q13.5.
• An autosomal recessive inheritance pattern is characteristic.
• Neonatal pyruvate carboxylase deficiency is associated with complete absence of messenger ribonucleic acid (mRNA) and the PC enzyme protein.
• Infantile-onset pyruvate carboxylase deficiency is associated with a residual enzyme activity less than 2% of normal levels.

Differential Diagnoses

Biotinidase Deficiency
Holocarboxylase Synthetase Deficiency
MELAS Syndrome
Pyruvate Dehydrogenase Complex Deficiency

Other Problems to Be Considered

Gluconeogenesis abnormalities
Fatty acid beta-oxidation deficiencies
Leigh encephalopathy
Pyruvate dehydrogenase complex deficiency
Phosphoenolpyruvate carboxykinase deficiency
2-Ketoglutarate dehydrogenase deficiency
Dihydrolipoamide dehydrogenase deficiency
Fumarase deficiency

Workup

Laboratory Studies

The following should be assessed in patients with pyruvate carboxylase deficiency (PCD):

• Lactate and pyruvate levels
  • High blood lactate and pyruvate levels with or without a lactic aciduria suggests an inborn error of energy metabolism.
  • An increased lactate-to-pyruvate ratio is characteristic of citric acid cycle disorders.
  • This ratio may be particularly elevated during periods of crisis, such as illness or metabolic stress.
• Hypoglycemia
  • Hypoglycemia during fasting results from greatly reduced gluconeogenesis.
  • Period of fasting required to produce symptoms is much shorter in pyruvate carboxylase deficiency than other disorders.
• Amino acid levels
  • Measurement of serum amino acids reveals hyperalaninemia, hypercitrullinemia, hyperlysinemia, and low aspartic acid levels.
  • Hyperalaninemia is due to the pyruvate shunting.
  • Hypercitrullinuria and hyperlysinemia result from a metabolic block in the urea cycle due to a low aspartic acid.
  • Low aspartic acid is due to the deficiency in the oxaloacetate precursor.
  • Amino acid levels vary with the general metabolic state of the patient. If the patient is in a catabolic state, proteins are degraded, resulting in the elevation of many amino acids and a nonspecific amino acid profile.
• Other studies
  • Hyperammonemia results from poor ammonia disposal and decreased urea cycle function.
  • Abnormal enzyme function can be detected by functional assays performed on leukocytes, fibroblasts, or properly preserved tissue samples.
  • The severe form of pyruvate carboxylase deficiency can be diagnosed by demonstrating the absence of pyruvate carboxylase (PC) mRNA or specific cross-reacting material.
  • Cerebrospinal fluid (CSF) shows an elevation of lactate and pyruvate.
  • CSF glutamine is markedly reduced, whereas glutamic acid and proline levels are elevated.

Imaging Studies

• MRI
  • Type B pyruvate carboxylase deficiency is associated with ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts.
  • Type A pyruvate carboxylase deficiency is associated with symmetric cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum and/or generalized hypomyelination, as well as hyperintensity of the subcortical fronto-parietal white matter.
• Magnetic resonance spectroscopy (MRS): Brain MRS shows high lactate levels, as well as levels of N -acetylaspartate and choline consistent with hypomyelination.

Histologic Findings

• Histologic examination of the liver may reveal lipid droplet accumulation.
• CNS neuropathology may include poor myelination, paucity of cerebral cortex neurons, gliosis, and proliferation of astrocytes.

Treatment

Medical Care

• Treatments in patients with pyruvate carboxylase deficiency (PCD) are aimed at stimulating the pyruvate dehydrogenase complex (PDC) and providing alternative fuels. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment.
• The PDC can provide an alternative pathway for pyruvate metabolism PDC activity can be optimized by cofactor supplementation with thiamine and lipoic acid and administration of dichloroacetate. Increased pyruvate metabolism through this pathway can help reduce the pyruvate and lactate levels.
• Biotin supplementation is given to help optimize the residual enzyme activity but is usually of little use.
• Citrate supplementation reduces the acidosis and provides the needed substrate in the citric acid cycle.
• Aspartic acid supplementation allows the urea cycle to proceed and reduces the ammonia level.
• One patient reportedly was successfully treated with a continuous nocturnal gastric drip feeding of uncooked cornstarch.
• Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing a source of acetyl-CoA and anaplerotic propionyl-CoA. However, life expectancy was not prolonged.
• Orthotopic liver transplantation has reversed the biochemical abnormalities in one patient.²

Consultations

• Evaluation by an expert in metabolic and genetic disorders is necessary to confirm the diagnosis, guide the appropriate treatment, and determine the prognosis.
• Genetic counseling for the parents is important in order to determine the risk of recurrence in future pregnancies.

Diet

• Diet has a small effect on outcome.
• A high-carbohydrate, high-protein diet may help to maintain an anabolic state and prevent activation of gluconeogenesis.

Medication

Enzyme activator

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

Sodium dichloroacetate

Designated as an orphan drug in the United States. Used to treat lactic acidosis. This is a compound that is believed to activate the PDC by inhibiting the inactivating kinase, resulting in decreased lactate production and promotion of pyruvate oxidation.

Dosing

Adult

30-100 mg/kg/d IV divided bid

Pediatric

Administer as in adults

Interactions

Reduces urate clearance and may counteract the effect of uricosuric drugs

Contraindications

Documented hypersensitivity

Precautions

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

Sedation is common; stimulates myocardial contractility; may elevate serum transaminases; polyneuropathy has been reported with long-term administration of DCA; urinary oxalate crystal formation has been reported and is a dose-related phenomenon; DCA is 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.

Sodium bicarbonate

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

Dosing

Adult

Acidosis during acute attacks: 1-2 mEq/kg IV infused over 20 min; infusion can be repeated up to q30min prn in an emergency setting but careful monitoring of blood pH must be obtained
Chronic acidosis: 1-3 mEq/kg/d PO qid

Pediatric

Acidosis during acute attacks: Administer as in adults
Chronic acidosis: 2-5 mEq/kg/d PO qid

Interactions

Sodium bicarbonate inactivates catecholamines, calcium salts, and atropine when mixed together; shown to decrease therapeutic levels of methotrexate, tetracyclines, and salicylates due to urinary alkalinization

Contraindications

Alkalosis; hypernatremia; severe pulmonary edema; hypocalcemia; unknown abdominal pain

Precautions

Pregnancy

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

Precautions

May precipitate hypernatremia, circulatory overload, and hypocalcemia; may cause a metabolic alkalosis; avoid extravasation; carefully monitor arterial or venous blood pH with IV infusion; response to bicarbonate should be checked 10-20 min after infusion; guide repeat treatment with bicarbonate by clinical change in the patient's condition along with laboratory values; take particular care when using with neonates because of increased risk of intraventricular hemorrhage

Citrate solutions (Bicitra, Polycitra)

Several solutions containing 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.

Dosing

Adult

Chronic acidosis: 1-3 mEq/kg/d PO divided tid/qid

Pediatric

Chronic acidosis: 2-5 mEq/kg/d PO divided tid/qid

Interactions

Urine alkalinization may decrease serum levels of lithium, chlorpropamide, methenamine, methotrexate, salicylates, or tetracyclines; urine alkalinization may increase serum levels of flecainide, quinidine, or sympathomimetics

Contraindications

Severe renal impairment; acute dehydration

Precautions

Pregnancy

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

Precautions

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

Follow-up

Further Inpatient Care

• Acute decompensation during illness in patients with pyruvate carboxylase deficiency (PCD) requires admission and management of the acidosis with hydration and intravenous bicarbonate.
• The patient must be supplied with adequate carbohydrates.

Further Outpatient Care

• Lactate levels should be monitored closely.
• A dietary log should be completed to help evaluate dietary manipulations and to ensure compliance.
• An informational statement that describes the child's disorder and the appropriate medical treatment for the disorder in an emergency setting should be carried by the parents at all times.

Prognosis

• Although diet manipulation and supplementation of substrates and cofactors can reverse some of the biochemical abnormalities, neurologic abnormalities typically progress, and demise within the first 6 months of life is the rule.
• Enzyme activity of cultured chorionic villus cells can be determined in time to allow for early prenatal diagnosis.

Patient Education

• The patient and the parents should be well educated on the factors that elicit a crisis and the early signs of decompensation.
• For excellent patient education resources, please refer to eMedicinehealth.

Miscellaneous

Medicolegal Pitfalls

• Several other metabolic encephalopathies can manifest with the same signs and symptoms as pyruvate carboxylase deficiency (PCD). Exclude other disorders of the citric acid cycle, such as pyruvate dehydrogenase complex (PDC) deficiency and other mitochondropathies. Biotinidase deficiency is also important to exclude because it is potentially treatable.
• MRI brain abnormalities can be essential to the diagnosis of an energy deficiency syndrome such as pyruvate carboxylase deficiency but may not develop early in the disease course. Thus, repeat MRI scans at regular intervals in children who display signs and symptoms consistent with an energy deficiency syndrome.
• Urine organic acids may be nonspecific or may only demonstrate abnormalities during times of stress. Thus, this test may need to be repeated several times for a meaningful result.

Multimedia

Media file 1: This is a diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency. The dotted line represents absent pathways. Pyruvate cannot produce oxaloacetate and is shunted to alternative pathways that produce lactic acid and alanine. The lack of oxaloacetate prevents gluconeogenesis and urea cycle function.

References

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4. Augereau C, Pham Dinh D, Moncion A. Pyruvate carboxylase deficiencies: complementation studies between "French" and "American" phenotypes in cultured fibroblasts. J Inherit Metab Dis. 1985;8(2):59-62. [Medline].

5. Bartlett K, Ghneim HK, Stirk JH. Pyruvate carboxylase deficiency. J Inherit Metab Dis. 1984;7 Suppl 1:74-8. [Medline].

6. 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].

7. Garcia-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol. Jan 2006;59(1):121-7. [Medline].

8. Higgins JJ, Glasgow AM, Lusk M. MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol. Oct 1994;9(4):436-9. [Medline].

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14. Schiff M, Levrat V, Acquaviva C, Vianey-Saban C, Rolland MO, Guffon N. A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation. Mol Genet Metab. Feb 2006;87(2):175-7. [Medline].

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16. Ullrich K, Schmidt H, van Teeffelen-Heithoff A. Glycogen storage disease type I and III and pyruvate carboxylase deficiency: results of long-term treatment with uncooked cornstarch. Acta Paediatr Scand. Jul 1988;77(4):531-6. [Medline].

17. Van Coster RN, Janssens S, Misson JP. Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples. Prenat Diagn. Oct 1998;18(10):1041-4. [Medline].

Keywords

pyruvate carboxylase deficiency, PCD, PC, congenital infantile lactic acidosis, intermittent ataxia with lactic acidosis type II, Leigh necrotizing encephalopathy, treatment, diagnosis

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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