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Pyruvate Carboxylase Deficiency

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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

ICD-10 Coding

E74.4, Disorders of pyruvate metabolism and gluconeogenesis

Disorder Category

Energy Metabolism

Screening

Abnormal Finding

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

Tested By

Tandem mass spectrometry (MS/MS)

Description

Pyruvate carboxylase catalyzes the conversion of pyruvate into oxaloacetate, an important reaction in energy metabolism, neurotransmitter biosynthesis, and myelin sheath formation. Pyruvate carboxylase deficiency is an inherited disorder with varying degrees of severity that typically presents clinically with failure to thrive, developmental delays, and seizures, and biochemically with lactic acidosis and depending on severity, hypercitrullinemiea, hyperlysinemia, hyperalaninemia, hypoglycemia, ketonemia, and hyperammonemia.

There are 3 types of pyruvate carboxylase deficiency:

  • Type A, the infantile form, presents with symptom onset during infancy or early childhood. Children with this condition exhibit developmental delay, failure to thrive, hypotonia, ataxia, seizures, and episodic metabolic acidosis.
  • Type B, the severe neonatal form, involves symptoms that appear shortly after birth, and often leads to significantly reduced survival despite therapeutic interventions.
  • Type C, the intermittent/benign form, is milder and causes few, if any, symptoms, although blood lactic acid levels are higher than normal.

Clinical Characteristics

The therapeutic approach to pyruvate carboxylase deficiency aims to provide alternative energy sources like triheptanoin, citrate, and aspartic acid supplementation. A diet generally low in fat and high in carbohydrates and protein may also be used. In the acute setting, correcting metabolic acidosis may involve glucose infusions and other methods to reverse catabolism.
Without treatment, the prognosis is very poor for both Type A and Type B pyruvate carboxylase deficiency. Symptoms will typically progress, and episodes of metabolic decompensation may lead to irreversible neurological damage and death. Type C pyruvate carboxylase deficient patients are less likely to have severe neurological impairment but still are at risk if triggered by a metabolic stressor like fasting or illness.

Incidence

Pyruvate carboxylase deficiency is rare, 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. All 3 types 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.
  • Advise the family to avoid having the newborn fast longer than 3 hours.

Confirming the Diagnosis

  • To confirm the diagnosis of pyruvate carboxylase deficiency, work with Newborn Screening Services (see NV providers [2]).
  • Further testing is needed to differentiate among citrullinemias I and II, argininosuccinic aciduria, and pyruvate carboxylase deficiency by molecular genetic analysis. Plasma ammonia and lactate may be obtained prior to genetic testing.

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Medical Genetics (see NV providers [5]).
  • Educate the family regarding signs, symptoms such as fever or infection, and the need for urgent care when the infant becomes ill depending on disease type.
    • Encourage prevention of primary symptoms with a high carbohydrate/high protein diet with frequent feedings and prevention of dehydration.
    • Monitor lactate levels.
  • 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)
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

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

NV 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.

Confirmatory Algorithm for Elevated Citrulline (ACMG)
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.

Services for Patients & Families in Nevada (NV)

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 2020; last update/revision: July 2022
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Reviewer: Nancy C. Rose, MD
Authoring history
2020: first version: Brian J. Shayota, MD, MPHA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Callus R, De Vivo D.
Pyruvate Carboxylase Deficiency.
National Organization for Rare Disorders; (2020) https://rarediseases.org/rare-diseases/pyruvate-carboxylase-deficiency.... Accessed on 4/4/2023.

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