AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

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, while the latter produces carbohydrate fuel for the body when carbohydrate intake is low.

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. PC catalyzes the converstion of pyruvate to oxaloacetate. Oxaloacetate is one of two essential substrates needed to produce citrate, the first substrate in gluconeogenesis. PC deficiency affects metabolism in several major ways.

• 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 central nervous system excitatory neurotransmitter, glutamate. It also has a role in producing myelin, the key substance involved in transmission of neuronal signals

• Type A: The North American phenotype is characterized by infantile onset, moderate lactate 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 elevation, abnormal lactate to pyruvate ratio and death within the first few months of life. 
• Type C: The benign phenotype is characterized by recruit 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 type A pyruvate carboxylase deficiency is more common in the United States. An increased incidence has been documented among certain populations, most notably native North Americans who speak the Algonquin dialect. A founder effect has been postulated.

International

The neonatal onset type B pyruvate carboxylase deficiency has a greater incidence in France, although it has been described in Canada, Egypt, and Saudi Arabia.

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.²  The severe energy deficit in the central nervous system causes neurologic symptoms and congenital brain malformation due to a lack of energy during neurogenesis. In neonates with apparently normal brains, progressive neurologic deterioration is variable. 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 and MRI scanning.
• Most patients with the type A pyruvate carboxylase deficiency live into adulthood but have global neurological and cognitive dysfunction.

Race

See Frequency.

Age

• Age of presentation for the most serious forms varies from the prenatal period to early infancy.
• Severe disease has prenatal onset with congenital brain abnormalities.
• Type A cases manifest in early infancy.
• The benign form manifests as periods of lactic acidosis anytime during life.

CLINICAL

Section 3 of 10  

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

History

• Birth: Low Apgar scores and being small for dates are nonspecific signs of a metabolic disturbance during gestation.
• General: Development of poor feeding, vomiting, and lethargy are nonspecific but common symptoms of metabolic illnesses. Symptoms can be initiated by a mild viral illness and are out of proportion to the severity of the illness.
• Developmental: Mental, psychomotor, and/or growth retardation are nonspecific signs 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.
• Dermatologic: Skin may be mottled.

Physical

• Neurologic: Hypotonia, ataxia, tremors, and choreoathetosis are consistent with pyruvate carboxylase deficiency. Progressive motor pathway degeneration results in positive Babinski sign and spastic diplegia or quadriplegia. Ophthalmologic examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary response, and/or blindness. Prenatal 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.
• Abdominal: Hepatosplenomegaly may be appreciated.

Causes

The gene that encodes PC has been localized to chromosome band 11q13.4-q13.5. An autosomal recessive inheritance pattern is characteristic of this disorder. Neonatal pyruvate carboxylase deficiency is associated with complete absence of mRNA and the PC enzyme protein. Infantile-onset pyruvate carboxylase deficiency is associated with residual enzyme activity less than 2% of normal.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

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

WORKUP

Section 5 of 10  

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

Lab Studies

• 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 may occur during fasting because of reduced gluconeogenesis. The period of fasting required to produce symptoms is much shorter in pyruvate carboxylase deficiency than in other disorders.
• Measurement of serum amino acids reveals hyperalaninemia, hypercitrullinuria, hyperlysinemia, and low aspartic acid levels.
• • Hyperalaninemia is due to pyruvate shunting.
  • Low aspartic acid is due to the deficiency of the oxaloacetate precursor.
  • Hypercitrullinuria and hyperlysinemia results from a metabolic block in the urea cycle due to low aspartic acid.
  • 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.
• Hyperammonemia results from the poor ammonia disposal and decreased urea cycle function.
• Abnormal enzyme function can be detected by a functional assay performed on leukocytes, fibroblasts, or properly preserved tissue samples.
• The severe form of pyruvate carboxylase deficiency can be diagnosed by demonstrating the absence of PC mRNA or specific cross-reacting material.
• Cerebrospinal fluid shows an elevation of lactate and pyruvate. Cerebrospinal fluid glutamine is markedly reduced, while glutamic acid and proline levels are elevated.

Imaging Studies

• MRI
• • Type B is associated with ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts.
  • Type A 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.

Central nervous system neuropathology may include poor myelination, paucity of cerebral cortex neurons, gliosis, and proliferation of astrocytes.

TREATMENT

Section 6 of 10  

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

Medical Care

Treatments 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 pyruvate dehydrogenase complex can provide an alternative pathway for pyruvate metabolism. Pyruvate dehydrogenase complex 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 administered to help optimize the residual enzyme activity, but it is usually of little use.
• Citrate supplementation reduces 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 has been reported to be treated successfully with continuous nocturnal gastric drip-feeding with uncooked cornstarch.
• Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case presumably by providing a source of acetyl-CoA and anaplerotic propionyl coenzyme A (propionyl-CoA). However, life expectancy was not prolonged.

Surgical Care

Orthotopic liver transplantation has reversed the biochemical abnormalities in one patient.

Consultations

• Evaluation of the patient 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 parents is important in order to determine recurrence risk for 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.³

FOLLOW-UP

Section 7 of 10  

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

Further Inpatient Care

• Acute decompensation during illness requires admission to the hospital 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 closely monitored.
• 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 progress and demise within the first 6 months of life is the rule.
• Pyruvate carboxylase deficiency is inherited in an autosomal recessive manner. Enzyme activity of cultured chorionic villus cells can be determined in time for early termination of the pregnancy.

Patient Education

The patient and the parents should be well educated on the factors that elicit a crisis and the early signs of decompensation.

MISCELLANEOUS

Section 8 of 10  

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

Medical/Legal Pitfalls

Caregivers must understand the poor prognosis of this disorder. Those with severe defects may not live beyond the neonatal period.

MULTIMEDIA

Section 9 of 10  

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

Media file 1:  This is a diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency (PCD). 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.
	View Full Size Image
Media type:  Image

REFERENCES

Section 10 of 10

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

1. Robinson BH. Lactic acidemia and mitochondrial disease. Mol Genet Metab. 2006;89(1-2):3-13.
2. García-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P, et al. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol. Jan 2006;59(1):121-7. [Medline].
3. Roe CR, Mochel F. Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis. Apr-Jun 2006;29(2-3):332-40. [Medline].
4. Al-Essa MA, Ozand PT. Manual of Metabolic Disease. First ed. Riyadh, Saudi Arabia: King Faisal Specialist Hospital and Research Centre; 1998:136.
5. Augereau C, Pham Dinh D, Moncion A, Marsac C, Saudubray JM, Robinson BH. Pyruvate carboxylase deficiencies: complementation studies between "French" and "American" phenotypes in cultured fibroblasts. J Inherit Metab Dis. 1985;8(2):59-62. [Medline].
6. Bartlett K, Ghneim HK, Stirk JH, Dale G, Alberti KG. Pyruvate carboxylase deficiency. J Inherit Metab Dis. 1984;7 Suppl 1:74-8. [Medline].
7. 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].
8. Higgins JJ, Glasgow AM, Lusk M, Kerr DS. MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol. Oct 1994;9(4):436-9. [Medline].
9. Kerr D, Wexler I, Zinn A. Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle. In: Inborn Metabolic Diseases: Diagnosis and Treatment. Heidelberg, NY: Springer-Verlag; 2000:127-38.
10. Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, et al. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. Apr 2005;84(4):305-12. [Medline].
11. Nyhan WL, Khanna A, Barshop BA, Naviaux RK, Precht AF, Lavine JE, et al. Pyruvate carboxylase deficiency--insights from liver transplantation. Mol Genet Metab. Sep-Oct 2002;77(1-2):143-9. [Medline].
12. Perry TL, Haworth JC, Robinson BH. Brain amino acid abnormalities in pyruvate carboxylase deficiency. J Inherit Metab Dis. 1985;8(2):63-6. [Medline].
13. Robinson B. Lactic Acidemia: Disorders of Pyruvate Carboxylase and Pyruvate Dehydrogenase. In: Scriver CR, Beaudet AL, Sly WS, Valle D. eds. The Metabolic and Molecular Basis of Inherited Disease. Vol 3. 8^th ed. New York, NY: McGraw-Hill; 2001:2275-2295.
14. 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].
15. Van Coster RN, Janssens S, Misson JP, Verloes A, Leroy JG. 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].

Article Last Updated: Nov 2, 2007