Genetics of Propionic Acidemia (Propionyl CoA Carboxylase Deficiency) 

Updated: Feb 18, 2019
Author: Karl S Roth, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 



In 1961, Childs et al published the earliest clinical report of a patient who was ultimately found to be affected by a deficiency of propionyl coenzyme A (CoA) carboxylase (ie, propionic acidemia).[1] These authors noted a series of severe ketoacidotic episodes in the child that were precipitated by protein ingestion (specifically, methionine and threonine administration) but manifested by marked elevations in plasma and urinary glycine levels. Because of these observations, the disease was given the name ketotic hyperglycinemia, a phenomenological term that inadvertently drew investigators' efforts toward a defect in glycine metabolism and delayed elucidation of the biochemical basis. The clinical hallmark of the disease is severe ketoacidosis of an episodic nature.

In 1969, Hsia et al described the underlying defect in propionate carboxylation that occurs in patients with ketotic hyperglycinemia.[2] Simultaneously, Morrow et al described the concurrence of methylmalonic acidemia and ketotic hyperglycinemia; thus, although the condition had been previously considered a single disorder, it was subsequently recognized on clinical grounds to be composed of least 2 different diseases.[3]

In 1971, subsequent studies by Hsia et al of the original patient's sister demonstrated a specific defect in propionyl CoA carboxylase.[4] The study also delineated propionic acidemia from methylmalonic acidemia as a distinct biochemical disorder. Subsequent work led to further delineation of another disorder, initially called multiple carboxylase deficiency, which includes deficiency of propionyl CoA carboxylase activity in addition to defects in other carboxylases.

The defect may be present at either of 2 different gene loci. One locus, on chromosome 13, controls synthesis of the α subunit of the tetrameric enzyme apoprotein; the second locus, on chromosome 3, controls synthesis of the β subunit. The 2 types of mutations are categorized as PCCA and PCCB (also PCCC) complementation groups,[5] distinguishable from each other by complementation studies of cultured fibroblasts in vitro.[6, 7]


The formation of propionyl CoA in human metabolism is derived from many sources, chiefly catabolism of a number of essential amino acids (isoleucine, valine, threonine, methionine). Other sources of propionyl CoA include odd chain-length fatty acids and the side chain of cholesterol, although these probably contribute very little in relation to the amino acid sources. Accumulation of the 3-carbon fatty acyl-CoA within the mitochondrion leads to decreased free CoA for other reactions, which is alleviated by conversion of propionyl CoA to propionyl-carnitine.

Propionyl-carnitine is transported out of the cell and excreted in urine; the mitochondrial CoA, thus freed, can participate in other reactions or once again become involved in formation of propionyl CoA. The relative reaction rates of these simultaneous processes stand between a tenuously balanced state of equilibrium and severe ketoacidosis. Carnitine deficiency can precipitate a clinical episode by disruption of the balance. Obviously, enhanced dietary protein intake has the same net effect by flooding the mitochondrion with propionyl CoA.

A common clinical finding is mild-to-moderate blood ammonia elevation, which may contribute by direct neurotoxicity to changes in a patient's mentation. Studies suggest that the underlying cause of the hyperammonemia is the inhibition of N -acetylglutamate synthase (NAGS) activity by free propionic acid. Since N -acetylglutamate (NAG) is the allosteric activator of carbamoylphosphate synthase, the entry step into the urea cycle, decreased ureagenesis occurs with accumulation of free ammonia.[8] See the image below.

Urea cycle. Compounds that comprise the urea cycle Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (4); the reaction is mediated by argininosuccinate (ASA) synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.

Additional evidence suggests that plasma glutamine-to-glutamate ratios decrease with increasing plasma ammonia concentration; simultaneously, urinary methylcitrate excretion increases while urinary citrate diminishes. Taken together, these data might suggest mitochondrial impairment, with inability to produce adequate alpha-ketoglutarate as substrate for formation of glutamate. This hypothesis, although attractive, has not been validated. The free organic acid has also been demonstrated to inhibit bone marrow production of leukocytes, red cells, and platelets. Pancytopenia is common and usually occurs 2-3 days after the acute presentation.

The reason for elevation of serum glycine levels is unclear, although studies show inhibition of glycine cleavage to 1-carbon fragments. Unlike ketoacidosis and hyperammonemia, elevation of glycine in the circulation is not known to be harmful. Thus, propionic acidemia manifests as clinical signs and symptoms of acidosis and hyperammonemia, including tachypnea, vomiting, lethargy, irritability, shock, coma, and death.



United States

The incidence rate is estimated to be approximately 1 per 100,000 live births. The caveat here is that population screening programs for the disease are not available in most areas; thus, this figure rests on clinical diagnosis. Because mild and even asymptomatic cases in which persons are genetically affected have been reported, the incidence is likely an under-representation of the true occurrence rate of homozygosity in the US population.


Although the disease is generally quite rare, the incidence rate has been reported to be as high as 1 per 2000 to 1 per 5000 births in areas of the world with restricted gene pools, such as Saudi Arabia.


In most patients in whom presentation occurs in infancy with full-blown symptoms, the morbidity is very high. Severe ketoacidosis with pH values as low as 6.8 may cause circulatory shock, hypoxia, and irreparable brain damage. Repetitive hyperammonemia causes neurotoxicity with neuronal cell death leading to mental retardation.

The pancytopenia commonly seen after clinical presentation renders the patient vulnerable to infection, which may become overwhelming and result in death. Death can occur at any time from an acute episode.

Cardiomyopathy (both hypertrophic and dilated) has become recognized as a frequent complication of propionic acidemia.[9, 10] Prolonged QTc interval, with or without evidence of cardiomyopathy, is also seen, and may be a cause of unexplained sudden death in these individuals.[11] One study suggests that the cardiomyopathy is reversible following orthotopic liver transplantation.[12]


Propionyl CoA carboxylase deficiency is inherited as an autosomal recessive trait; therefore, no sex bias is observed.


Like many autosomal recessive traits, multiple mutations at a single gene locus can account for various clinical severities, especially given the potential for mixed heterozygosity.


Although less-severely affected patients have been reported, most individuals with propionic acidemia have a classic presentation and course and a guarded prognosis. Survival is in question, and significant brain damage is likely.

Patient Education

Parents must be taught to strictly adhere to the dietary regimen as prescribed. They also must be made aware of the importance of follow-up for adjustment of diet to meet the requirements for growth.

Patients must be seen as early as feasible during the course of any intercurrent illness. Treat patients with intravenous glucose and bicarbonate immediately if indicated.




Many infants with propionyl coenzyme A (CoA) carboxylase deficiency (ie, propionic acidemia) initially present in the first month of life, often with failure to thrive due to feeding intolerance and vomiting. Somnolence is also often a part of the history; thus, poor feeding may be erroneously attributed to CNS disorders.

Other infants have a fulminant initial presentation, with rapidly developing ketoacidosis, dehydration, shock, and a precedent history of lethargy, poor feeding, and rapid breathing that only extends over 1-2 days.

As a rare autosomal recessive disease, a family history of similarly affected infants is extremely unlikely.

Occasionally, an older infant or young child may have a lifelong history of episodic lethargy, anorexia, vomiting, and acidosis that has responded to short hospital stays with intravenous glucose and bicarbonate administration.


Affected newborns have been protected from their disease by the maternal circulation and metabolism; therefore, no relevant physical findings present upon neonatal examination.

Carefully assess infants who present with unexplained vomiting for signs of ketoacidosis; urinalysis is particularly important because neonates normally do not excrete large quantities of ketones.

CNS depression, which signifies either severe acidosis or hyperammonemia, may be apparent upon examination.

Any infant with an inborn error can also be affected by other disorders.[13] Suspicion of sepsis based on the typical nonspecific signs must not eliminate the possibility of underlying disease, such as propionic acidemia, from the differential.


Propionyl CoA carboxylase is a tetrameric enzyme, comprising 4 chains of 2 α and 2 β polypeptides.

The gene for production of the β chain has a locus of 13q32, whereas the gene for production of the β chain has a locus of 3q21-q22. Thus, a mutation at either locus affects enzyme activity, but only changes that have occurred in either the α or the β chain affect the respective enzyme activity.

In a mixed heterozygotic individual, with mutations at each gene locus, both types of monomeric constituent polypeptides are affected.


In most cases, the initial presentation is severe enough to cause significant developmental delay due to brain damage.

The propionic acidemia may cause leukopenia and permit sepsis, which is devastating in an infant who is already sick.

Dietary indiscretion, intercurrent illness, and inadequate essential amino acid supplementation may precipitate a severe recurrence of the initial episode.

Optic nerve atrophy has been observed in male long-term survivors, as well as in at least two female patients.[14, 15]





Laboratory Studies

Expanded newborn metabolic screening techniques involving tandem mass spectrometry include propionic acidemia among the several organic acidemias that pose an immediate threat to the survival of the neonate.

A basic metabolic panel is indicated in propionyl coenzyme A (CoA) carboxylase deficiency (ie, propionic acidemia). Serum electrolyte measurement is important. A child who is feeding poorly and vomits may have significant electrolyte abnormalities. Accumulation of free organic acids (anions) significantly increases the anion gap (see the Anion Gap calculator). Therefore, an anion gap larger than 16 mEq/L may indicate propionic acidemia. On rare occasions, affected babies do not present with an increased anion gap.

Because free propionic acid is known to suppress bone marrow, assessing the status of circulating elements, including platelets, is important.

Specific gravity, obtained through a routine urinalysis, is important in assessing the degree of dehydration. The presence of ketones in association with an anion gap (as mentioned above) is strongly suggestive of ketoacidosis. A low urine pH lends additional weight to this suspicion.

Obtaining blood ammonia levels is important in the assessment of the overall metabolic status of the patient, as well as to help in determination of causes for mental status changes. Blood ammonia levels are often secondarily elevated.

Obtaining plasma lactate levels is helpful in the determination of the causes for an observed anion gap. Lactate levels are often elevated but are not sufficiently high enough to account for the increase in anion gap, which should then prompt further investigation.

Assessing the urinary organic acid levels is the definitive clinical diagnostic study. Most frequently, it demonstrates large increases in beta-hydroxy propionic acid, lactic acid, and methylcitrate excretion levels.

Leukocyte propionyl CoA carboxylase activity is the study required for definitive biochemical diagnosis and appropriate genetic counseling.

Mutation analysis has provided additional insight into the nature of the many mutations reported; at least one study suggests the need for additional investigation beyond routine analysis in the identification of several subtle genomic abnormalities in PCCA mutational analysis.[16, 17]

Other Tests

ECG is recommended with annual 24-hour Holter monitoring in all patients because of the frequency of prolonged QTc intervals and decreased left ventricular contractility reported in patients with propionic acidemia.

Further evaluation with continuous ECG monitoring and echocardiography should be considered. Cardiomyopathy, both hypertrophic and dilated, is frequently seen in these individuals, requiring close follow-up, including an annual echocardiogram. Moreover, any sign of early heart failure (ie, poor growth, tachycardia, tachypnea [which can be confused with developing metabolic acidosis]) should trigger such an investigation.

Annual examination by an ophthalmologist is recommended, with careful examination of the anterior chamber and fundus due to a high risk of optic atrophy.[18, 14, 15]

Histologic Findings

A diagnosis of propionic acidemia that is missed in life is extremely difficult to make postmortem.



Medical Care

Most patients with propionyl coenzyme A (CoA) carboxylase deficiency (propionic acidemia) are so ill at presentation that they have already been admitted to a hospital, which should facilitate appropriate diagnosis and early treatment.

Because the usual major metabolic precursors of propionic acid are the essential amino acids (isoleucine, valine, threonine, methionine), halt all protein ingestion and emphasize alternative sources of calories on a temporary basis.

Ketoacidosis is best treated with increased carbohydrate calories, bicarbonate replacement, and increased fluids to enhance excretion. In severely ill patients, metabolic reversal can be expedited by an insulin drip, but this should only be administered in an intensive care setting.

Reinitiate protein feeding to a level of protein no greater than 1.5 g/kg/d after the patient's condition has normalized. From this point, the patient should be under the care of a biochemical geneticist who may prescribe a special diet prior to discharge.


See the list below:

  • Biochemical geneticist

  • Nutritionist

  • Cardiologist

  • Ophthalmologist


Appropriate dietary management is the mainstay of treatment.

Several commercially produced formulas are available that provide a protein supplement without any of the 4 amino acids that result in propionate production. However, because they are all essential in humans, closely monitored quantities of isoleucine, valine, threonine, and methionine must be added. For this reason, collaboration between the biochemical geneticist and the nutritionist is imperative.


No restriction is necessary.

Further Outpatient Care

Under no circumstances should patients with propionyl coenzyme A (CoA) carboxylase deficiency (ie, propionic acidemia) be monitored without the close and frequent input of a biochemical geneticist.

Frequently assess plasma amino acid concentrations for the need to alter dietary composition and consult a nutritionist in making such changes.

Recent observations suggest a propensity for optic nerve damage in long-term survivors. Thus, at least annual follow-up by an ophthalmologist is advisable.



Medication Summary

Some authorities recommend oral biotin supplements in pharmacological dosage (10 mg/d) for propionyl coenzyme A (CoA) carboxylase deficiency (ie, propionic acidemia). Although no complication of biotin administration is known, even in such large doses, no good clinical evidence suggests that such treatment is effective in any patient to date.

Some authorities also advocate carnitine supplementation to help prevent acute onset of symptoms.

Due to the secondary inhibition of N-acetylglutamate synthase, use of carglumic acid to expedite normal function of the urea cycle and prevent hyperammonemia is recommended.[19]