Propionic Acidemia

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Ketotic glycinemia
Ketotic hyperglycinemia
Propionyl-CoA carboxylase deficiency

ICD-10 Coding

E71.121, Propionic acidemia

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Elevated C3 (propionyl carnitine)

Tested By

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

Description

Propionic acidemia is caused by a deficiency of the propionyl-CoA carboxylase, the enzyme responsible for converting propionyl-CoA to methylmalonyl-CoA and subsequently to succinyl-CoA as it enters the Krebs cycle. This defect in protein and fat metabolism results in the accumulation of propionic acid and other organic acid by-products, which have a toxic effect on multiple other metabolic processes. Affected individuals typically present within the first few days of life with poor feeding, lethargy, neutropenia, thrombocytopenia, severe metabolic acidosis, hypoglycemia, hyperammonemia, and progressive encephalopathy. Late complications include cardiomyopathy, renal disease, pancreatitis, and optic atrophy. A much more rare late onset form of propionic acidemia presents with failure to thrive, intermittent vomiting, hypotonia, movement disorders, seizures, cardiomyopathy, and developmental delays or regression.

Clinical Characteristics

With treatment, normal development and IQ are possible for mild cases that have treatment initiated early. In the more classic severe presentation, developmental delays and cognitive disability are still to be expected but much less significantly than when untreated. Additional proper early treatment can significantly reduce the risk of life-threatening metabolic crises (severe metabolic acidosis with hyperammonemia) and neurologic injury.
Without treatment, metabolic crises may lead to progressive encephalopathy, seizures, and death. Life-threatening crises may be triggered at any age by prolonged fasting, infectious illness, or gut bacteria overgrowth.
Initial symptoms/signs may include:
  • Poor feeding
  • Vomiting
  • Seizures
  • Lethargy
  • Lab findings:
    • Metabolic acidosis
    • Hyperammonemia
    • Ketonuria
    • Neutropenia and thrombocytopenia
    • Elevated C3 (propionylcarnitine) and glycine in blood
    • Elevated 3-hydroxypropionate, propionylglycine, tiglylglycine, and methylcitric acid in urine
If not treated promptly, recurrent metabolic crises may lead to:
  • Intellectual disability
  • Movement disorders
  • Dystonia
  • Developmental regression
  • Death
Treatment consists of a low-protein diet and medical formulas free of propiogenic substrates (isoleucine, valine, methionine, and threonine). Prompt treatment of illnesses and avoidance of fasting is necessary to mitigate metabolic crises. For acutely ill patients, quickly resolving the metabolic acidosis and hyperammonemia is key. N-carbamylglutamate is one targeted therapy to treat the hyperammonemia.
Even with appropriate management, many patients experience developmental delay and intellectual disability. Patients have an increased risk for bone marrow suppression, cardiomyopathy, and recurrent pancreatitis. Older individuals can develop renal failure and optic atrophy. Many children will need a G-tube to facilitate feeding goals.
Liver transplantation is a viable option for many and has been shown to prevent metabolic crises and reduce the number of hospitalizations, but its effect on chronic complications is still unclear. [Pillai: 2019]

Incidence

The incidence for propionic acidemia of about 1:242,741. [Chapman: 2018]

Inheritance

Autosomal recessive

Other Testing

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

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for poor feeding, lethargy, vomiting, and tachypnea.
  • Consult with a pediatric metabolic specialist immediately.
  • Provide emergency treatment/referral for symptoms of respiratory distress, metabolic acidosis, hypoglycemia, or seizures.

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see UT providers [3]).
  • Follow-up testing may include quantitative plasma acylcarnitine profile, plasma amino acids, urine organic acids, plasma total homocysteine, and serum vitamin B12. The most common cause of elevated C3 (mild elevations) is maternal vitamin B12 deficiency.
  • Diagnosis confirmation may require molecular genetic testing.

If the Diagnosis is Confirmed

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

Propionic Acidemia (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.

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

Utah Newborn Screening Program (UDHHS)
Information about the program, related legislation, training for practices, and newborn conditions; Utah Department of Health & Human Services (Formerly UDOH).

For Parents and Patients

Propionic Acidemia (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the 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)
Clearinghouse for local, state, and national newborn screening education, programs, policies, and resources. Also, provides many ways for people to connect and share their viewpoints and questions about newborn screening, supported by the U.S. Department of Health and Human Services.

Center for Parent Information and Resources (DOE)
Parent Centers in every state provide training to parents of children with disabilities and provide information about special education, transition to adulthood, health care, support groups, local conferences, and other federal, state, and local services. See the "Find Your Parent Center Link" to find the parent center in your state.

Tools

UT ACT Sheet for Propionic Acidemia (ACMG) (PDF Document 140 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 Algorithms for Elevated C3 Acylcarnitine (ACMG) (PDF Document 194 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.

Propionic Acidemia (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 for Patients & Families in Utah (UT)

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

Propionic Acidemia in Children (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Helpful Articles

PubMed search for propionic acidemia in infants, last 3 years

Forny P, Hörster F, Ballhausen D, Chakrapani A, Chapman KA, Dionisi-Vici C, Dixon M, Grünert SC, Grunewald S, Haliloglu G, Hochuli M, Honzik T, Karall D, Martinelli D, Molema F, Sass JO, Scholl-Bürgi S, Tal G, Williams M, Huemer M, Baumgartner MR.
Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision.
J Inherit Metab Dis. 2021;44(3):566-592. PubMed abstract / Full Text

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.

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

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

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

Authors & Reviewers

Initial publication: March 2007; last update/revision: January 2024
Current Authors and Reviewers:
Author: Rachel Cowley
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2017: update: Nicola Longo, MD, Ph.D.A
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Chapman KA, Gramer G, Viall S, Summar ML.
Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data.
Mol Genet Metab Rep. 2018;15:106-109. PubMed abstract / Full Text

Forny P, Hörster F, Ballhausen D, Chakrapani A, Chapman KA, Dionisi-Vici C, Dixon M, Grünert SC, Grunewald S, Haliloglu G, Hochuli M, Honzik T, Karall D, Martinelli D, Molema F, Sass JO, Scholl-Bürgi S, Tal G, Williams M, Huemer M, Baumgartner MR.
Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision.
J Inherit Metab Dis. 2021;44(3):566-592. PubMed abstract / Full Text

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

Pillai NR, Stroup BM, Poliner A, Rossetti L, Rawls B, Shayota BJ, Soler-Alfonso C, Tunuguntala HP, Goss J, Craigen W, Scaglia F, Sutton VR, Himes RW, Burrage LC.
Liver transplantation in propionic and methylmalonic acidemia: A single center study with literature review.
Mol Genet Metab. 2019;128(4):431-443. PubMed abstract / Full Text

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.