Pyruvate Carboxylase Deficiency

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Ataxia with lactic acidosis, type II
Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency
Leigh syndrome due to pyruvate carboxylase deficiency
PC deficiency
Pyruvate carboxylase deficiency disease
Type II ataxia with lactic acidosis

ICD-10 Coding

E74.4, Disorders of pyruvate metabolism and gluconeogenesis

Disorder Category

Amino Acidemia

Screening

Abnormal Finding

Elevated citrulline on the newborn screen. Further testing is needed to differentiate among citrullinemias I and II, argininosuccinic aciduria, and pyruvate carboxylase deficiency.

Tested By

Tandem mass spectrometry (MS/MS)

Description

Pyruvate carboxylase generates glucose in energy production in the mitochondria and is necessary for neurotransmitter and myelin sheath production. Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other toxic compounds to accumulate in the blood. High levels then damage the various organs and tissues, particularly the nervous system.
There are 3 types of pyruvate carboxylase deficiency:
  • Type A, the infantile form, causes severe symptoms in infancy. Children with this condition exhibit global developmental delay and usually live only a few years.
  • Type B, the severe neonatal form, involves symptoms that appear shortly after birth, and affected infants usually survive only a few months.
  • Type C, intermittent/benign form, is milder and causes few symptoms, although blood lactic acid levels are higher than normal.

Clinical Characteristics

No definitive treatment is available for pyruvate carboxylase deficiency; however, symptomatic treatment is aimed at providing alternative sources of energy for the body and alternative means of metabolizing pyruvate. A diet that is low in fat and high in carbohydrates and protein may be helpful. Intravenous fluids, hydration, and correction of the metabolic acidosis can limit individual flare-ups. Thiamine, lipoic acid, dichloroacetate, aspartic acid, biotin, triheptanoin, and citrate are sometimes tried.
  • In type A, the infantile form, developmental delay and high blood lactic acid lead to vomiting, fatigue, muscle weakness, and difficulty breathing made worse by episodes of illness and/or fasting.
  • In type B, the severe neonatal form, symptoms appear shortly after birth with high blood levels of lactic acid and ammonia and liver failure. Babies have hypotonia, seizures, abnormal movements, and coma.
  • In type C, the milder form, little treatment is needed. Illnesses should be treated promptly and fasting should be avoided.

Incidence

Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1:250,000 births worldwide. Type A is found more often in North America, and type B is more common in Europe, particularly France. [Callus: 2020]

Inheritance

Pyruvate carboxylase deficiency is caused by mutations in the pyruvate carboxylase PC gene, which is found in the mitochondria and necessary for energy production. All 3 types of pyruvate carboxylase deficiency have autosomal recessive inheritance.

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and arrange an emergent consult with a metabolic specialist.
  • Provide emergency treatment/referral for lethargy, hypotonia, seizures, signs of liver damage, or as needed. Transport the newborn to the hospital in consultation with the metabolic specialist.

Confirming the Diagnosis

  • To confirm the diagnosis of pyruvate carboxylase deficiency, work with Newborn Screening Services (see UT providers [3]).
  • Further testing is needed to differentiate among citrullinemias I and II, argininosuccinic aciduria, and pyruvate carboxylase deficiency.

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Medical Genetics (see UT providers [6]).
  • Educate the family regarding signs, symptoms, and need for urgent care when the infant becomes ill depending on disease type.
  • Consider a palliative care consult for infants with severe neonatal or infantile citrullinemia that is determined to be due to pyruvate carboxylase deficiency.

Resources

Information & Support

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Pyruvate Carboxylase Deficiency (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; from Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Pyruvate Carboxylase Deficiency (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Communicating Newborn Screening Results to Families (ACHDNC) (PDF Document 289 KB)
One-page guide to help clinicians effectively communicate positive newborn screening results to parents; Advisory Committee on Heritable Disorders in Newborns and Children.

For Parents and Patients

Support

Pyruvate Carboxylase Deficiency (MedlinePlus)
Information from families, including description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

General

Pyruvate Carboxylase Deficiency (GARD)
Information for families, including symptoms, inheritance, diagnosis, finding a specialist, related diseases, and support organizations; from the Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Sciences.

Pyruvate Carboxylase Deficiency (NORD)
Information for families, including synonyms, signs & symptoms, causes, affected populations, related disorders, diagnosis, therapies (both standard and investigational), and support organizations; from the National Organization of Rare Disorders.

Tools

Confirmatory Algorithm for Elevated Citrulline (ACMG) (PDF Document 175 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

UT ACT Sheet for Elevated Citrulline (ACMG) (PDF Document 117 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Services for Patients & Families in Utah (UT)

Genetics clinic services throughout the US can be found through the .

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Studies

Studies of Pyruvate Decarboxylase Deficiency (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Helpful Articles

PubMed search for pyruvate carboxylase deficiency

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

Authors & Reviewers

Initial publication: March 2022
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH

Page Bibliography

Callus R and De Vivo D.
Pyruvate Carboxylase Deficiency.
National Organization for Rare Disorders; (2020) https://rarediseases.org/rare-diseases/pyruvate-carboxylase-deficiency.... Accessed on 3/2/21.