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

Pyruvate Carboxylase Deficiency: Differential Diagnoses & Workup

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

Updated: Nov 6, 2009

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.

More on Pyruvate Carboxylase Deficiency

Overview: Pyruvate Carboxylase Deficiency
Differential Diagnoses & Workup: Pyruvate Carboxylase Deficiency
Treatment & Medication: Pyruvate Carboxylase Deficiency
Follow-up: Pyruvate Carboxylase Deficiency
Multimedia: Pyruvate Carboxylase Deficiency
References
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References

  1. Monnot S, Serre V, Chadefaux-Vekemans B, et al. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat. May 2009;30(5):734-40. [Medline].

  2. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline].

  3. Al-Essa MA, Ozand PT. Manual of Metabolic Disease. ed. Riyadh, Saudi Arabia: King Faisal Specialist Hospital and Research Centre; 1998.

  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].

  9. Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. Apr 2005;84(4):305-12. [Medline].

  10. Nyhan WL, Khanna A, Barshop BA. Pyruvate carboxylase deficiency--insights from liver transplantation. Mol Genet Metab. Sep-Oct 2002;77(1-2):143-9. [Medline].

  11. Perry TL, Haworth JC, Robinson BH. Brain amino acid abnormalities in pyruvate carboxylase deficiency. J Inherit Metab Dis. 1985;8(2):63-6. [Medline].

  12. Robinson BH. Lactic acidemia and mitochondrial disease. Mol Genet Metab. Sep-Oct 2006;89(1-2):3-13. [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].

  15. Stacpoole PW, Barnes CL, Hurbanis MD. Treatment of congenital lactic acidosis with dichloroacetate [see comments]. Arch Dis Child. Dec 1997;77(6):535-41. [Medline].

  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].

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Further Reading

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Keywords

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

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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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