Propionic Acidemia

Other Names

Ketotic glycinemia

Ketotic hyperglycinemia

Propionyl-CoA carboxylase deficiency

Diagnosis Coding

E71.121, propionic acidemia

Disorder Category

An organic acidemia

Screening

Finding

Elevated C3 (propionyl carnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity: NA; specificity: NA

Overview

Propionic acidemia is caused by a defect in the mitochondrial enzyme propionyl-CoA carboxylase, which is responsible for converting propionyl-CoA to methylmalonyl-CoA and subsequently to succinyl-CoA that enters the Krebs cycle. Propionyl-CoA carboxylase is involved in the catabolism of isoleucine, valine, methionine, and threonine, odd-chain fatty acids, cholesterol and nucleotides. The defect results in the accumulation of propionic acid and its metabolites, and a deficiency of Krebs cycle with impaired energy production. Propionic acidemia is caused by a defect in either of two genes (PCCA and PCCB) that code for the alpha and beta subunits of the enzyme. Affected patients can present at a few days of life with progressive lethargy progressing to coma with severe metabolic acidosis and hyperammonemia. Some patients with milder mutations can present later in life with failure to thrive, vomiting, neurological symptoms (abnormal movements, seizures), and delays in development.

Prevalence

The incidence is about 1:238,346. [Therrell: 2014]

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing by amniocentesis

Other Testing

If the familial mutation is known, DNA testing is possible.

Clinical Characteristics

With treatment, normal development and IQ are possible for patients with milder variants and symptomatic improvement may be seen in individuals already affected. Without treatment, metabolic crises (severe metabolic acidosis with hyperammonemia) may lead to progressive neurologic injury and death. Symptoms generally begin within the first few days after birth, though in variant forms they may not begin until after 6 weeks of age. Symptoms may be triggered by fasting and illness and children may appear healthy between metabolic crisis episodes. Children with milder variants can present with neurological symptoms or cardiomyopathy, without acute metabolic acidosis. The typical facies of infants with propionic acidemia includes: frontal bossing, widened depressed nasal bridge, epicanthal folds, long philtrum, upturned curvature of the lips.

Initial signs/symptoms may include:
  • Poor feeding
  • Vomiting
  • Seizures
  • Lethargy progressing to coma
  • Lab findings:
    • Metabolic acidosis
    • Hyperammonemia
    • Ketonuria
    • Neutropenia and thrombocytopenia
    • Elevated glycine (usually after the newborn period) in blood and presence of methylcitric acid in urine organic acids
If not treated promptly, recurrent metabolic crises may lead to:
  • Mental retardation
  • Movement disorders
  • Dystonia
  • Spasticity
  • Stroke
  • Brain damage
  • Death
Treatment consists of a low-protein diet, medical foods restricted of isoleucine, methionine, threonine and valine, odd-chain fatty acids and cholesterol, and carnitine supplements. Prompt treatment of illnesses and avoidance of fasting is necessary. Even with appropriate management, many patients have severe hypotonia and are developmentally delayed. Patients have an increased risk of infection, bone marrow suppression, cardiomyopathy, and a recurrent pancreatitis. Older individuals can develop renal failure. Many children will need placement of a G-tube to facilitate feeding.
Liver transplantation can prevent metabolic crises, but its effect on chronic complications is still unclear. Novel therapies include the use of N-carbamylglutamate in hyperammonemic crises and chronic anaplerotic supplements (supplements that refill the Krebs cycle).

Follow-up Testing after Positive Screen

Quantitative plasma acylcarnitine profile, plasma amino acids, urine organic acids, plasma total homocysteine, and serum vitamin B12 may reveal propionic acidemia or variants. The most common cause of elevated C3 (mild elevations) is maternal vitamin B12 deficiency.

Primary Care Management

Upon Notification of the + Screen

  • Contact the family and evaluate the infant for poor feeding, lethargy, vomiting, and tachypnea.
  • Provide emergency treatment/referral for symptoms of respiratory distress, metabolic acidosis, hypoglycemia, or seizures.
  • Discontinue breast or cow milk formula feeding.
  • To confirm the diagnosis, work with the following service(s): see all Newborn Screening Programs services providers (3) in our database.
  • For evaluation and ongoing collaborative management, consult the following service(s): see all Pediatric Genetics services providers (8) in our database.

If the Diagnosis is Confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Propionic Acidemia - Information for Parents (STAR-G)).
  • Frequent low-protein, low-leucine, low-valine, low-methionine, low-threonine, and high-carbohydrate meals may be indicated for affected children (this will usually involve medical formulas and foods).
  • Avoid fasting; see the child promptly when illness causes poor intake.
  • Oral L-carnitine, antibiotics, and biotin may be indicated for some children.
  • Bicarbonate and glucose may be indicated during metabolic crisis episodes.
  • Monitoring of amino acid levels through blood and urine tests, and ketones through urine tests, may be indicated.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Collaboration

Refer for initial consultation and ongoing collaboration of dietary management, monitoring, and for assuring implementation of up-to-date management and genetic counseling for the family.

Resources

Information & Support

For Professionals

Propionic Acidemia - Information for Professionals (STAR-G)
Structured list of information about the condition and links to more information; Screening, Technology, and Research in Genetics.

Propionic Acidemia (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

Propionic Acidemia (OMIM)
Extensive review of literature that provides technical information on genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

National Newborn Screening & Global Resource Center (NNSGRC)
Fact sheets, data reports, publications, and information for clinicians about genetic screening that includes links to state genetic contacts.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Utah Newborn Screening Program (UDOH)
Provides information about the program, related legislation, training for practices, and newborn conditions; Utah Department of Health.

For Parents and Patients

Support

Propionic Acidemia Foundation
Family support organization offering information, a care notebook for the condition, links for a registry, and research grants.

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.

General

Propionic Acidemia (Genetics Home Reference)
Excellent, detailed review of the condition for patients and families; sponsored by the U.S. National Library of Medicine.

Propionic Acidemia - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

Baby's First Test (Genetic Alliance)
A clearinghouse for newborn screening information. Provides resources about screening at the local, state, and national levels and ways for people to share their viewpoints and questions about newborn screening; supported by the U.S. Department of Health and Human Services.

Newborn Screening Information for Families (NNSGRC)
Information for families about genetic screening. Links to support groups, advocacy groups, and state genetic contacts; National Newborn Screening and Global Resource Center.

Center for Parent Information and Resources (DOE)
A large resource library related to children with disabilities. Parent Centers in every state provide training to parents of children with disabilities and provide information about local conferences, support groups, and finding schools and other local services; Department of Education, Office of Special Education.

Tools

ACT Sheet for Elevated C3 Acylcarnitine (ACMG) (PDF Document 352 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithms for Elevated C3 Acylcarnitine (ACMG) (PDF Document)
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.

Propionic Acidemia Acute Illness Protocol (NECMP)
A guideline for health care professionals treating the sick infant/child who has previously been diagnosed with propionic acidemia; developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs.

Services

Genetics-related clinical services throughout the world can be found through Genetics Clinic Directory (GeneTests).

Newborn Screening Programs

See all Newborn Screening Programs services providers (3) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (8) in our database.

For other services related to this condition, browse our Services categories or search our database.

Helpful Articles

PubMed search for propionic acidemia in infants, last 5 years

Fraser JL, Venditti CP.
Methylmalonic and propionic acidemias: clinical management update.
Curr Opin Pediatr. 2016;28(6):682-693. PubMed abstract / Full Text

Filipowicz HR, Ernst SL, Ashurst CL, Pasquali M, Longo N.
Metabolic changes associated with hyperammonemia in patients with propionic acidemia.
Mol Genet Metab. 2006;88(2):123-30. PubMed abstract
This study's results suggest that hyperammonemia in propionic acidemia might be related to inability to maintain adequate levels of glutamine precursors through a dysfunctional Krebs cycle.

Schwahn BC, Pieterse L, Bisset WM, Galloway PG, Robinson PH.
Biochemical efficacy of N-carbamylglutamate in neonatal severe hyperammonaemia due to propionic acidaemia.
Eur J Pediatr. 2010;169(1):133-4. PubMed abstract
The authors conclude that NCG should be tried early in acute neonatal hyperammonaemia because it can remove the need for extracorporal detoxification in some cases and can improve long-term outcome.

Vara R, Turner C, Mundy H, Heaton ND, Rela M, Mieli-Vergani G, Champion M, Hadzic N.
Liver transplantation for propionic acidemia in children.
Liver Transpl. 2011;17(6):661-7. PubMed abstract / Full Text
Study conclusion: LT has a role in the management of PA: it reduces the risk of metabolic decompensation and improves the quality of life. The potential for the development of metabolic sequelae is not completely eliminated.

Authors

Author: Nicola Longo, MD, PhD - 7/2011
Reviewing Author: Nicola Longo, MD, PhD - 7/2017
Content Last Updated: 7/2017

Page Bibliography

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text