Genetics of Pyruvate Carboxylase Deficiency Clinical Presentation

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

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.
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Physical

Neurologic findings include the following:

  • 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.

Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.

Hepatomegaly is also noted.

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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.

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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

  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. 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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