Genetics of Pyruvate Carboxylase Deficiency Workup

  • Author: Richard E Frye, MD, PhD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 12, 2012
 

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.

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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.

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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.

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Contributor Information and Disclosures
Author

Richard E Frye, MD, PhD  Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Medical School 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 Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina School of Medicine; 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.

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 and Genetics, Director RSA, 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.

References

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  2. Marin-Valencia I, Roe CR, Pascual JM. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab. Sep 2010;101(1):9-17. [Medline].

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

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

  5. 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].

  6. Bartlett K, Ghneim HK, Stirk JH. 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. 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].

  9. 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].

  10. 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].

  11. 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].

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

  14. 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].

  15. 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].

  16. 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].

  17. 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].

  18. 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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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.
 
 
 
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