Propionic Acidemia

Carrillo-Carrasco N, Venditti C.


Clinical characteristics.

The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease.

  • Neonatal-onset PA, the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, coma, and death. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.
  • Late-onset PA includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction (resulting in dystonia and choreoathetosis) and cardiomyopathy. Affected children can have an acute decompensation that resembles the neonatal presentation and is precipitated by a catabolic stress such as infection, injury, or surgery.
  • Isolated cardiomyopathy and arrhythmia can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits.

Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency (POI), and chronic renal failure.


PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Newborns with PA tested by expanded newborn screening have elevated C3 (propionylcarnitine). Testing of urine organic acids in persons who are symptomatic or those detected by newborn screening reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, and propionylglycine, which are normally not observed in the urine. Testing of plasma amino acids reveals elevated glycine. Confirmation of the diagnosis relies on detection of either deficient PCC enzymatic activity or biallelic pathogenic variants in PCCA or PCCB.


Treatment of manifestations: The treatment of persons with acutely decompensated PA is a medical emergency: treat precipitating factors such as infection; arrest catabolism by providing high calorie and fluid intake; minimize protein intake to reduce propiogenic precursors; give intravenous carnitine; correct hypoglycemia and metabolic acidosis; and care for the patient in a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.

Prevention of primary manifestations: Individualized dietary management to restrict propiogenic substrates; nasogastric or gastrostomy feeding as needed; increased caloric intake during illness to prevent catabolism; and continued multidisciplinary care with metabolic specialists. Medications may include: L-carnitine supplementation; oral metronidazole to reduce propionate production by gut bacteria; and/or N-carbamoylglutamate. Orthotopic liver transplantation (OLT) may be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and/or restricted growth.

Prevention of secondary complications: Consistent evaluation of the protein intake, depending on age, gender, severity of disease and presence of other factors such as growth spurts, can avoid insufficient or excessive protein restriction. The latter can result in deficiency of essential amino acids and impaired growth, as well as catabolism-induced metabolic decompensation.

Surveillance: Monitor closely patients with a catabolic stressor (fasting, fever, illness, injury, and surgery) to prevent and/or detect and manage metabolic decompensations early. Regularly assess: (1) growth, nutritional status, feeding ability, psychomotor development; (2) metabolic status by monitoring urine organic acids and plasma amino acids; (3) renal function; (4) complete blood count. At intervals not yet determined, screen for: cardiomyopathy and arrhythmias; optic atrophy; and premature ovarian insufficiency in females.

Agents/circumstances to avoid: Prolonged fasting; catabolic stressors.

Evaluation of relatives at risk: Testing of at-risk sibs of a patient is warranted to allow for early diagnosis and treatment.

Genetic counseling.

Propionic acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.


Clinical Diagnosis

Neonatal-onset propionic acidemia (PA), the most frequently recognized form of PA, manifests in the neonatal period as EITHER:

  • An abnormal newborn screening (NBS): elevated propionylcarnitine (C3)
    Note: Symptoms may be evident before NBS results are available.
  • Acute clinical deterioration of unexplained origin, in which an infant who appeared healthy at birth develops nonspecific symptoms including vomiting, refusal to feed, and hypotonia in the first few days of life. If untreated, encephalopathy, coma, seizures, and cardiorespiratory failure can ensue.

Late-onset PA includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and movement disorders (i.e. dystonia, choreoathetosis) [Delgado et al 2007]. These children can have an acute decompensation that resembles the neonatal presentation and is precipitated by a catabolic stress such as infection, injury, or surgery.

Isolated cardiomyopathy is a recently recognized presentation [Lee et al 2009].


PA is caused by deficiency of propionyl-CoA carboxylase (PCC) (EC, the mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC enzymatic activity deficiency results in accumulation of propionic acid and other metabolites in plasma and urine (see Molecular Genetic Pathogenesis and Figure 1).

Figure 1. . Metabolic pathway.

Figure 1.

Metabolic pathway. Propionyl-CoA carboxylase (PCC) catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which enters the Krebs cycle via succinyl-CoA. Sources of propionate include: valine, isoleucine, threonine, methionine, odd-chain fatty (more...)

  • Abnormalities frequently (but not universally) seen during acute decompensation common to other organic acidemias:
    • Mild to severe high-anion gap metabolic acidosis
    • Elevated ketones in blood or urine (normally absent in healthy newborns)
    • Low to normal blood glucose concentration
    • Hyperammonemia (frequent)
    • Neutropenia and occasionally thrombocytopenia
  • Specialized biochemical evaluations for the diagnosis of propionic acidemia:
    • Urine organic acids:
      • Elevated 3-hydroxypropionate (normal value: 3-10 mmol/mol Cr)
      • Methylcitrate (normally absent)
      • Tiglylglycine (normally absent)
      • Propionylglycine (normally absent)
      • Occasionally lactate
    • Plasma amino acids: Elevated glycine
    • Acylcarnitine profile: Elevated C3 (propionylcarnitine)

Note: The elevation of 3-hydroxypropionate is also seen in holocarboxylase synthetase deficiency and biotinidase deficiency; however, these disorders also have elevated 3-hydroxyisovalerate and 3-methylcrotonylglycine because of defective activity of pyruvate carboxylase, propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase.

Newborn screening. Acylcarnitine profile performed by tandem mass spectrometry (MS/MS) on dried blood spots shows an elevation of C3 in newborns with PA, usually above 5 μM (C3: normal range <0.33 μM).

Note: Some children with a benign variant of propionic acidemia are detected by NBS [Yorifuji et al 2002, Dionisi-Vici et al 2006]. (See also Differential Diagnosis of elevated C3.)

Propionyl-CoA carboxylase (PCC) enzyme activity can be determined in peripheral blood leukocytes or cultured skin fibroblasts by assaying the substrate-dependent fixation of 14C from NaH14CO3 or 1-14C-propionate.

Molecular Genetic Testing

Genes. PCCA and PCCB are the two genes in which biallelic pathogenic variants are known to cause PA.

The enzyme propionyl-CoA carboxylase (PCC) comprises alpha and beta subunits encoded by PCCA and PCCB, respectively [Huang et al 2010]. Biallelic mutation of either PCCA or PCCB results in PA.

Table 1.

Table 1.

Summary of Molecular Genetic Testing Used in Propionic Acidemia

Testing Strategy

To confirm/establish the diagnosis in a proband. Clinical suspicion of PA may be based on abnormal newborn screening, clinical presentation, and/or family history. Any individual thought to have PA should be evaluated and managed immediately by a metabolic team at an institution with expertise in caring for individuals with inborn errors of metabolism (see Management).


Routine initial laboratory studies: blood gases, electrolytes, glucose, serum ammonia concentration, and complete blood count; renal function tests; liver function tests; and urine ketones


Specialized biochemical evaluations: urine organic acids, plasma amino acids, and acylcarnitine profile


Confirmatory testing: either determination of PCC enzymatic activity or molecular genetic testing of PCCA and PCCB

See Figure 2.

Figure 2.

Figure 2.

Immediate management and testing algorithm to be pursued simultaneously after the clinical or laboratory suspicion of PA

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

See Table 2 for a summary of major clinical findings in propionic acidemia (PA).

Neonatal onset. The typical presentation involves a healthy newborn who develops poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Unless diagnosed correctly and managed promptly, neonates develop progressive encephalopathy, seizures, and coma that result in death.

Late onset. The onset of symptoms in PA varies depending on several factors including residual enzymatic activity, the intake of propiogenic precursors, and the occurrence of catabolic stressors.

Isolated cardiomyopathy in the absence of clinical metabolic decompensation or neurocognitive deficits has been reported on rare occasion [Lee et al 2009].

Table 2.

Table 2.

Clinical Phenotypes

Early detection by newborn screening (NBS) and optimized management strategies offer the potential to improve the survival and long-term outcome of individuals with PA:

  • A study of 49 patients with PA treated at European centers showed a lower mortality rate (~30%) in the first year of life than previously reported [Sass et al 2004].
  • A more recent study showed that although mortality was decreased in patients with PA diagnosed through NBS, their neurologic outcome did not improve [Grünert et al 2012]. In this study, 63% of those detected through NBS were symptomatic at the time of diagnosis.

Metabolic decompensations. Children with PA can develop episodic metabolic decompensations, especially in the first years of life. Acidosis, hyperammonemia, pancreatitis, metabolic stroke, cardiomyopathy, bone marrow suppression, seizures, and encephalopathy can accompany acutely deranged metabolism. These episodes, which typically require hospitalization and can be life threatening, are usually precipitated by illnesses, infections, surgery, or any stress augmenting catabolism.

The long-term cognitive outcome of individuals with PA is negatively correlated to the number of metabolic decompensations [Grünert et al 2012]. Therefore, metabolic decompensations should be recognized and treated promptly (see Management, Treatment of Manifestations, Neonatal/Acute Decompensation). Of note, normal cognitive development has been described in several individuals with late-onset (mild) forms of PA.

Growth impairment may become evident with age. Failure to thrive may be exacerbated by malnutrition secondary to poor feeding and excessive protein restriction.

Neurologic manifestations include hypotonia, developmental regression, neurocognitive deficits, stroke-like episodes [Scholl-Bürgi et al 2009], seizures, and movement disorders.

Seizures are frequent in early-onset PA and include tonic-clonic, myoclonic, focal, or absence seizures. EEG abnormalities may precede the onset of seizures. In a study of 17 individuals with PA, all who had clinical seizures had abnormal MRI findings and a history of more than ten metabolic decompensations [Haberlandt et al 2009].

Individuals with PA are predisposed to basal ganglia lesions, especially during episodes of acute encephalopathy or metabolic instability [Broomfield et al 2010, Davison et al 2011]. Basal ganglia infarction may be preceded by an acute “stroke-like” episode and manifest as altered mental status, dystonia, choreoathetosis, and/or hemiplegia.

Brain MRI shows delayed myelination, symmetric basal ganglia disease, and cerebral atrophy.

Cardiomyopathy has recently been recognized as a common complication of PA. Romano et al [2010] reported cardiomyopathy in six of 26 children from a retrospective study; mean age of detection was age seven years. The age of diagnosis of PA, amount of metabolic control, or amount of residual enzymatic activity do not seem to modify the risk for cardiomyopathy [Romano et al 2010]. Most individuals with cardiomyopathy have mild to moderate forms of PA that are well controlled. Cardiomyopathy may resolve or progress to cardiac failure and has been associated with sudden death in a child with PA [Dionisi-Vici et al 2006].

Cardiac rhythm abnormalities include prolonged QTc interval associated with syncope [Kakavand et al 2006, Baumgartner et al 2007] and cardiac arrest [Jameson & Walter 2008].

Pancreatitis, a well-known complication of PA and other organic acidemias, may be recurrent and should be suspected in those with anorexia, nausea, and/or abdominal pain.

Hematologic abnormalities. Neutropenia, thrombocytopenia, and rarely pancytopenia are seen during acute decompensations. Affected persons are predisposed to infections. Myelodysplasia has also been reported [Sipahi et al 2004].

Dermatologic manifestations resembling acrodermatitis enteropathica are frequently associated with deficiency of essential amino acids, particularly isoleucine, which is excessively restricted in the diet of persons with PA [Domínguez-Cruz et al 2011].

Other rare complications

Genotype-Phenotype Correlations

In general:

Other PCCB pathogenic variants such as p.Glu168Lys result in a wide variety of clinical manifestations among affected individuals [Pérez-Cerdá et al 2003].

The PCCB pathogenic variant p.Tyr435Cys has been identified in asymptomatic children through newborn screening in Japan [Yorifuji et al 2002].


The term ketotic hyperglycinemia was used in the 1960s before PCC deficiency was discovered to be the underlying defect in persons with PA.


The worldwide incidence of PA is estimated at 1:50,000 to 1:100,000.

The incidence is much higher in certain populations:

  • Among the Inuit in Greenland the frequency at birth is 1:1000 [Ravn et al 2000].
  • In Saudi Arabia an incidence of 1:2000 to 1:5000 births has been reported.

Differential Diagnosis

Elevated C3 on newborn screening (NBS) can be caused by methylmalonic acidemias (resulting from methylmalonyl-CoA mutase deficiency, intracellular cobalamin metabolism) and severe maternal B12 deficiency.

The differential diagnosis of propionic acidemia (PA) as suspected by the elevation of 3-hydroxypropionate and methylcitrate on urine organic acids includes the following:

  • Biotin disorders, which also show elevation of 3-hydroxyvalerate and 3-methyl-crotonylglycine. Biotinidase and holocarboxylase synthetase activities differentiate between biotinidase deficiency and multiple carboxylase deficiency.
  • Methylmalonic acidemias, which have elevations of 2-methylcitric acid and 3-hydroxypropionate, and additionally show massive elevations of methylmalonic acid
  • 3-hydroxyisobutyric aciduria, which also has elevation of 3-hydroxyisobutyric acid
  • Bacterial contamination (including Propionibacterium)

Propionic acidemia should also be included in the differential diagnosis of many common pediatric conditions:

Increased anion-gap metabolic acidosis. Possible causes are numerous and may include the following:

  • Those conditions included in the commonly used mnemonic MUDPILES: methanol, uremia (chronic renal failure), diabetic ketoacidosis, propylene glycol, infection, iron, isoniazid, lactic acidosis, ethylene glycol, salicylates

Neonatal “sepsis” of unclear etiology in the newborn period should always prompt a metabolic evaluation.

Pyloric stenosis. Infants with PA or other organic acidemias presenting with vomiting and refusal to feed may be given the diagnosis of pyloric stenosis which may lead to unnecessary surgery that provokes acute metabolic decompensation. Blood gas analysis of infants with pyloric stenosis usually shows hypochloremic alkalosis.

Failure to thrive or recurrent vomiting of unclear etiology may be the only manifestation of PA and other inborn errors of metabolism.

Child abuse or intoxication. PA should always be considered in the differential diagnosis of intoxications. In at least one individual with an organic acidemia the laboratory misidentified propionic acid as ethylene glycol.

Diabetic ketoacidosis. Persons with PA usually have ketoacidosis associated with hypoglycemia; however, hyperglycemia has also been reported and confused initially with diabetic ketoacidosis [Dweikat et al 2011, Joshi & Phatarpekar 2011].

Cardiomyopathy. An evaluation for PA and other inborn errors of metabolism is warranted in the evaluation of children with cardiomyopathy of unknown origin.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


The management of patients with propionic acidemia (PA) is ideally performed at a center with expertise in inborn errors of metabolism. The metabolic team comprises a metabolic physician, nutritionist, and genetic counselor.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with PA the following evaluations are recommended (see Figure 2):

  • Serial metabolic evaluations of blood gases, electrolytes, glucose, serum ammonia concentration; plasma amino acids, carnitine and acylcarnitines; urine ketones and urine organic acids to guide acute management until the patient stabilizes
  • Complete blood count to evaluate for cytopenias
  • Molecular genetic testing of PCCA and PCCB if not previously performed to aid in genetic counseling and prediction of disease severity

Once the patient becomes stable, evaluations may include:

  • Clinical assessment of growth parameters, ability to feed, developmental status, and neurologic status
  • Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias.
  • ECG and echocardiogram
  • EEG and brain MRI in symptomatic individuals
  • Age-appropriate developmental evaluation
  • Eye examination
  • Hearing evaluation

Treatment of Manifestations

Neonatal/Acute Decompensation

Injuries, illness, infections, birth, surgery, other forms of stress and hormonal changes can produce a catabolic response that leads, among other things, to protein breakdown with massive release of amino acids which may include propiogenic precursors that cannot be metabolized in PA. The stress response may be perpetuated by release of hormones. The goal of the acute management of persons with decompensated PA is to reverse this process and to remove accumulated toxins.

The treatment of persons with acutely decompensated PA is a medical emergency and requires care in a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.

Inpatient Management

Manage ventilation and circulation as necessary.

Treat precipitating factors (fever, infection, dehydration, pain, vomiting, and other sources of stress).

Aggressively stop catabolism by giving fluids and calories approximately 1.5 times above the estimated baseline requirement in a glucose infusion rate of 10 mg/kg/min, and more than 40% of calories with a parenteral lipid suspension. The use of anabolic hormones (i.e., intravenous insulin drip) that may be needed to stop catabolism is preferably undertaken in an intensive care setting.

Restrict intake of propiogenic precursors by avoidance of protein transiently (< 24-36 hours), or ideally, by the use of propiogenic-free parenteral amino acids, if available. Transition to enteral feedings as soon as they are tolerated (see Prevention of Primary Manifestations, Individualized dietary management).

Detoxify to reduce hyperammonemia.

  • Pharmacologic detoxification:
    • Scavenger medications, such as those used in urea cycle disorders to help control ammonia levels during acute decompensations, should be used with caution in the treatment of hyperammonemia associated with PA as they lower glutamine levels, which may in turn contribute to hyperammonemia [Al-Hassnan et al 2003, Filipowicz et al 2006]. Scavenger medications include intravenous sodium benzoate (250 mg/kg) and sodium phenylacetate (250 mg/kg) alone or in combination (Ammunol®).

      Note: To date, no studies have examined the efficacy of scavenger medications in the management of hyperammonemia associated with propionic acidemia.
    • Oral N-carbamoylglutamate (carglumic acid; 100-250 mg/kg) has also been reported to aid in the detoxification of ammonia during neonatal and acute decompensations [Filippi et al 2010, Schwahn et al 2010].
  • Extracorporeal detoxification (hemodialysis or extracorporeal membrane oxygenation [ECMO]) is frequently required in the acute infantile presentation of PA to control severe metabolic acidosis and/or hyperammonemia. Peritoneal dialysis is not recommended in this setting.
  • Carnitine supplementation (100 mg/kg/day IV) may increase the detoxification of propionic acid by conjugating into propionylcarnitine, which is excreted by the kidneys. Alternatively, it may relieve intracellular coenzyme A accretion and provide a benefit through this mechanism.

Home Management of Metabolic Status

The detection and management of metabolic decompensations at home are a critical part of the chronic management of PA. Strategies to achieve home management should be tailored for the conditions of each patient and family and may include the following:

  • At-home detection and monitoring of ketones
  • Use of anti-emetics such as ondansetron
  • Close monitoring of clinical status
  • Control of fluid-balance status
  • Modification of the diet under the direction of the metabolic team


Any injury, illness, hospitalization, or surgical procedure should involve consultation with the metabolic team.

The diagnosis and management of pancreatitis is the same as for pancreatitis of other causes.

Neutropenia and other cytopenias usually improve with metabolic control of PA.

The management of cardiomyopathy and arrhythmias is similar to that from other causes. Cardiomyopathy may resolve after liver transplantation [Romano et al 2010].

Dermatologic manifestations are usually secondary to nutritional deficiencies of essential amino acids; these should be corrected.

The management of chronic renal failure does not differ from that for other causes of renal failure; renal transplantation may be required.

Prevention of Primary Manifestations

The long-term management of PA includes the following:

  • Individualized dietary management in order to restrict propiogenic substrates (valine, methionine, isoleucine, threonine, and odd chain fatty acids), while ensuring normal protein synthesis and preventing protein catabolism, amino acid deficiencies, and growth restriction
  • Avoiding fasting and increasing calorie intake during illness to prevent catabolism
  • Metabolic monitoring (see Surveillance)
  • Supportive feeding (nasogastric or gastrostomy) as needed
  • Ongoing multidisciplinary care, including caregiver teaching and emergency bracelet
  • Medications including:
    • L-carnitine supplementation at a dose of 50-100 mg/kg/day
    • Intermittent oral metronidazole at a dose of 10-20 mg/kg/day to reduce propionate production by gut bacteria
    • N-carbamoylglutamate. However, its chronic use in PA needs to be further studied [Ah Mew et al 2010].
    • Antiepileptic drugs, as needed [Haberlandt et al 2009]
    • Therapy of arrhythmias, as needed
      Note: No persons with PA have been proven to be biotin responsive.
  • Management before, during, and after any surgery by a metabolic team to ensure adequate hydration and caloric intake in order to minimize the risk of decompensations
  • Orthotopic liver transplantation (OLT). May be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and restricted growth [Barshes et al 2006]. Reported benefits of OLT include decrease in the frequency of metabolic decompensations, improved quality of life [Vara et al 2011], and reversal of dilated cardiomyopathy [Yorifuji et al 2004, Romano et al 2010]. Liver transplantation has been performed successfully from unrelated donors [Romano et al 2010] and from heterozygous related donors [Vara et al 2011].

    Continuous hemofiltration, extracorporeal membrane oxygenation (ECMO) [Sato et al 2009], and left ventricular assist devices have been used while waiting for OLT [Ameloot et al 2011].

Prevention of Secondary Complications

It is suggested that protein intake be regularly monitored by a biochemical geneticist and a nutritionist to avoid insufficient or excessive protein restriction. Many factors should be taken into account to guide protein restriction: age, gender, severity of PA, nutritional status, and presence of other factors such as intercurrent illness, surgery, or growth spurts. The effects of excessive protein restriction can include impaired growth, essential amino acid deficiencies, and catabolism-induced metabolic decompensation.


Monitor closely patients with a catabolic stressor (fasting, fever, illness, injury, and surgery) to prevent and/or detect and manage metabolic decompensations early.

The following evaluations are performed at different intervals depending on factors including age, disease severity, and presence of catabolic stressors.

Clinical evaluation should include assessment of the following:

  • Growth
  • Nutritional status
  • Feeding ability
  • Developmental and neurocognitive progress, as age-appropriate

Laboratory evaluation should include:

  • Metabolic studies: urine organic acids (if available, quantitative plasma methylcitric and propionate are preferable), plasma amino acids, serum ammonia concentration, and quantitative acylcarnitine profile;
  • Nutritional studies: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), and trace minerals;
  • Complete blood count to monitor for cytopenias;
  • Renal function tests;
  • Amylase and lipase as needed to evaluate for pancreatitis.


  • Screening for cardiomyopathy and arrhythmias by echocardiogram, ECG, and Holter monitor. The ideal screening frequency has not been defined.
  • Brain MRI and/or EEG as clinically indicated
  • Ophthalmologic evaluations to assess optic nerve changes. Frequency has not been determined.
  • Screening for premature ovarian insufficiency (POI) in females. Frequency and recommended age to begin screening has not been determined.

Agents/Circumstances to Avoid

Avoid prolonged fasting and catabolic stressors.

Evaluation of Relatives at Risk

Testing of at-risk sibs is warranted to allow for early diagnosis and treatment. If prenatal testing has not been performed on at-risk sibs, measure urine organic acids, plasma amino acids, and acylcarnitine profile immediately in the newborn period in parallel with newborn screening (NBS). Note: The results of NBS may not be available before symptoms of PA appear.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Therapies under investigation include:

  • Anaplerotic therapy [Filipowicz et al 2006];
  • Gene therapy. Adeno-associated viral (AAV) gene delivery has been successful in the treatment of Pcca knock-out mice [Chandler et al 2011] and may represent a future treatment option for patients.

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Propionic acidemia (PA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with PA are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Biochemical testing. Quantitative plasma amino acids, urine organic acids, acylcarnitine profile, and fibroblast enzymatic analyses are not reliable for detection of heterozygotes.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the pathogenic variants have been identified in an affected family member, prenatal diagnosis for pregnancies at increased risk may be available from a laboratory offering testing for the gene of interest or custom prenatal testing.

Biochemical testing. Methylcitric acid measurement by stable-isotope dilution GC/MS in amniotic fluid is another reliable and quick method to diagnose PA in the prenatal period [Inoue et al 2008].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Propionic Acidemia Foundation
    1963 McCraren Rd
    Highland Park IL 60035
    Phone: 877-720-2192
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    United Kingdom
    Phone: 0800-652-3181
  • Organic Acidemia Association
    Phone: 763-559-1797
    Fax: 866-539-4060 (toll-free)
  • European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Propionic Acidemia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Propionic Acidemia (View All in OMIM)


Molecular Genetic Pathogenesis

Propionic acidemia (PA) is an organic acidemia (see Organic Acidemias) caused by deficiency of propionyl-CoA carboxylase (PCC), a biotin-dependent carboxylase located in the mitochondrial inner space.

PCC is a heterododecamer (α6β6) composed of six α-subunits encoded by PCCA and six α-subunits encoded by PCCB [Huang et al 2010]. The β-subunits form a central core and each of the α-subunits attaches to a β-subunit (see Figure 1).

PCC catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA, which eventually enters the Krebs cycle as succinyl-CoA. Propionyl-CoA is common to the pathway for degradation of some amino acids (isoleucine, valine, threonine, and methionine), odd-chain fatty acids, and cholesterol. Gut bacteria (i.e., Propionibacterium sp.) are also an important source of propionate metabolized through PCC.

The deficiency of PCC enzymatic activity profoundly deranges metabolism at several levels. Possible explanations include:

  • The toxic effects of free organic acids and ammonia;
  • The accumulation of propionyl-CoA, which in turn can inhibit other enzyme systems including oxidative phosphorylation [de Keyzer et al 2009], resulting in decreased energy production;
  • Decreased production of Krebs cycle intermediates.


Gene structure. PCCA comprises 24 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. The benign variant c.1651G>T results in a change in amino acid residue.

Pathogenic allelic variants. Nearly 60 pathogenic variants in PCCA have been reported. The largest group (~40%) is missense mutations, followed by small insertions/deletions and splicing mutations [Desviat et al 2006].

Table 3.

Table 3.

Selected PCCA Allelic Variants

Normal gene product. The alpha subunit of PCC has ATP, bicarbonate, and biotin-binding domains, and is responsible for transferring bicarbonate to form carboxybiotin, the first step in the PCC reaction [Campeau et al 2001].

Abnormal gene product. Most pathogenic variants in PCCA cause protein instability, and two are predicted to impede ATP binding [Desviat et al 2004].


Gene structure. PCCB comprises 15 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Table 4 describes two normal variants that result in a change of amino acid residue.

Pathogenic allelic variants. More than 60 pathogenic variants in PCCB have been reported. The largest group (~40%) is missense mutations, followed by small insertions/deletions and splicing mutations [Desviat et al 2006].

  • The pathogenic variant c.1218_1231del14ins12 is reported to account for roughly 30% of PCCB variants in affected individuals of northern European origin [Desviat et al 2004].
  • The pathogenic variant c.1304T>C, associated with a milder form of propionic acidemia, accounts for 25% of PCCB variants in affected Japanese.
Table 4.

Table 4.

Selected PCCB Allelic Variants

Normal gene product. The beta subunit of PCC has a propionyl-CoA binding site and is responsible for transferring the carboxyl group to propionyl-CoA.

Abnormal gene product. Most pathogenic variants are predicted to alter the active site and reduce the enzymatic activity. A smaller percent of pathogenic variants affect subunit interactions, and, thus, the assembly of the heterododecamer of PCC [Desviat et al 2004].


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Suggested Reading

  1. Häberle J. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. Arch Biochem Biophys. 2013;536:101–8. [PubMed: 23628343]
  2. Shah GN, Rubbelke TS, Hendin J, Nguyen H, Waheed A, Shoemaker JD, Sly WS. Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both in ammonia detoxification and glucose metabolism. Proc Natl Acad Sci USA. 2013;110:7423–8. [PMC free article: PMC3645511] [PubMed: 23589845]
  3. van Karnebeek CDM, Shevell MI, Zschocke J, Moeschler J, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab. 2014;111:428–38. [PubMed: 24518794]
  4. van Karnebeek CDM, Sly WS, Ross CJ, Salvarinova R, Yaplito-Lee J, Santra S, Shyr C, Horvath GA, Eydoux P, Lehman AM, Bernard V, Newlove T, Ukpeh H, Chakrapani A, Preece MA, Ball S, Pitt J, Vallance HD, Coulter-Mackie M, Nguyen H, Zhang L-H, Bhavsar AP, Sinclair G, Waheed A, Wasserman WW, Stockler-Ipsiroglu S. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet. 2014;94:453–61. [PMC free article: PMC3951944] [PubMed: 24530203]

Chapter Notes

Author Notes

Dr. Carrillo-Carrasco and Dr. Venditti are physicians at the NIH Clinical Center and specialize in pediatrics and biochemical genetics. Dr. Carrillo-Carrasco leads the Clinical Section of the Therapeutics for Rare and Neglected Diseases (TRND) Program at the NIH and Dr. Venditti is the director of the Organic Acid Disorder Research Unit at the National Human Genome Research Institute.

Revision History

  • 17 May 2012 (me) Review posted live
  • 28 October 2011 (ncc) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview ‘Propionic Acidemia’ is in the public domain in the United States of America.