Propionic Acidemia

Author: Virginia Giannone
Date: 10/02/2013



Propionic Acidemia is an inherited metabolic disorder in which the body is unable to process certain parts of proteins and lipids (fats) properly. It is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems.
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.

Propionic Acidemia,2012


Propionic Acidemia have an incidence ranging from 1:2500 to 1:5000 live births, while the incidence of Propionic Acidemia, estimated in the Italian pediatric population through a prospective study conducted between 1985 and 1997 in patients between 0 and 17 years with a diagnosis of metabolic disease is carried out at 23 Italian centers of 1:166.123 (95% CI: 1:99.823-1:280.538)

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.
-In Saudi Arabia an incidence of 1:2000 to 1:5000 births has been reported.

Propionic Acidemia,2012


In most cases, the features of Propionic Acidemia become apparent within a few days after birth. The initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including heart abnormalities, seizures, coma, and possibly death. Less commonly, the signs and symptoms of Propionic Acidemia appear during childhood and may come and go over time. Some affected children experience intellectual disability or delayed development. In children with this later-onset form of the condition, episodes of more serious health problems can be triggered by prolonged periods without food (fasting), fever, or infections.


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) . 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.


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.

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)

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).

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 mutations are known to cause PA.

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

Propionic Acidemia,2012


In healthy individuals, the enzyme propionyl CoA carboxylase converts propionyl CoA to methylmalonyl CoA. This is one step in the process of converting certain amino acids and fats into sugar for energy. Individuals with PA cannot perform this conversion because the enzyme propionyl CoA carboxylase is nonfunctional. The essential amino acids isoleucine, valine, threonine, and methionine and odd-chain fatty acids are simply converted to propionyl CoA, before the process stops, leading to a buildup of propionyl CoA. Instead of being converted to methylmalonyl CoA, propionyl CoA is then converted into propionic acid, which builds up in the bloodstream. This in turn causes a build-up of dangerous acids and toxins, which can cause damage to the organs.

In many cases, PA can damage the brain, heart, and liver, cause seizures, and delays to normal development like walking and talking. During times of illness the affected person may need to be hospitalized to prevent breakdown of proteins within the body. Each meal presents a challenge to those with PA. If not constantly monitored, the effects would be devastating. Dietary needs must be closely managed by a metabolic geneticist or metabolic dietician.

In addition there is an accumulation of ammonium: when the amino acids are metabolized, is freed ammonium, which is converted into urea (usually in the liver) and excreted by the kidneys. The remaining part not nitrogen that results from this process is further metabolized and utilized by the body to build other amino acids, glucose, ketone bodies or fatty tissue. In this condition the 'ammonium is converted to urea and its accumulation causes lethargy, temperatures below normal, weak pulse, gastrointestinal symptoms, coma and neurological damage.
Ammonia levels are normal in the infant <60 mmol / l in children <40 mmol / l. Ammonium levels greater than 150 mmol / l give rise to encephalopathies; ammonia levels in excess of 500 mmol / l are considered urgency. Although the neurotoxic effects are well recognized, the mode with which the 'ammonium damages the nervous system are not yet well understood.

Natural history of Propionic Acidemia,2011



Mutations in the PCCA and PCCB genes cause propionic acidemia.
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 disease-causing mutations in the family are known.

Genotype-Phenotype Correlations

In general:

Null alleles (PCCA: p.Arg313X, p.Ser562X; PCCB: p.Gly94X and several small deletions/insertions and splicing mutations) are associated with a more severe form of PA .
Missense mutations, in which partial enzymatic activity is retained (PCCA: p.Ala138Thr, p.Ile164Thr, p.Arg288Gly; PCCB: p.Asn536Asp), are associated with a milder phenotype.

Exceptions include, for example, the three PCCB missense mutations p.Gly112Asp, p.Arg512Cys, and p.Leu519Pro, which affect heterododecamer formation and are associated with undetectable PCC enzyme activity and the severe phenotype.
Other PCCB mutations such as p.Glu168Lys result in a wide variety of clinical manifestations among affected individuals .

The PCCB mutation p.Tyr435Cys has been identified in asymptomatic children through newborn screening in Japan .

Genetics Home Reference :Propionic Acidemia,2007


The most common complications in patients were hematological abnormalities including
anemia, neutropenia, thrombocytopenia or pancytopenia.
Cardiac complications, especially cardiomyopathy, may contribute
significantly to the mortality of PA patients with several fatal cases reported . More
recently, the association between PA and long-QT syndrome has been described .
Osteoporosis or osteopenia have only been documented in one patient. However, as bone
density assessment is usually not done on a regular basis in most patients, osteoporosis might
be underdiagnosed.
Pancreatitis seems to be a rare complication .
Optic atrophy is also rare.

Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent



Dietary Treatment

A protein-restricted diet is the cornerstone of treatment. A low-protein diet (1.5-2mg/kg/day), L-carnitine supplementation (100mg/kg/day), and biotin supplementation (10mg/day) are required.Carnitine, an enzyme involved in the metabolism of long-chain fatty acids, buffers the acyl-CoA metabolites that accumulate with protein-restricted diets. The acyl-carnitine that is produced by the buffering action is excreted in the urine.

Biotin is a cofactor for propionyl-CoA carboxylase (and for 3 other carboxylases). Therefore, propionic acidemia may be present in a patient suffering from the broader metabolic problem of multiple carboxylase deficiency. Biotin responsiveness may depend on the genetic heterogeneity of isolated propionic acidemia versus propionic acidemia existing as a subset of multiple carboxylase deficiency. In patients with biotin-unresponsive disease, restricting their intake of isoleucine, valine, threonine, and methionine is the only solution.

Prompt dietary modification and supplementation may reverse clinical symptoms and normalize laboratory findings. The success of therapy can be measured as changes in propionic acid level in the serum. In-home testing of urine for ketones, especially during suspected infections, has been advocated.

In the acute phase, identify and treat intercurrent infections that have triggered an acidotic episode. Dietary modifications must be made in a hospital setting.

Additional Treatment Considerations

Because gastrointestinal bacteria produce propionic acid, neomycin and metronidazole have been proposed as treatments. Clinical data about this treatment regimen are limited. Dialysis may be required for life-threatening acute phases of illnesses that are triggered by infections or other stresses.

Organ transplantation of the liver or of the liver and kidney has been attempted. However, perioperative and postoperative complications are apparently high, and the long-term benefits are unclear.

Propionic Acidemia,2011

AddThis Social Bookmark Button