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Propionic acidemia

Synonym(s) Ketotic hyperglycinemia
Propionic aciduria
Propionyl-CoA carboxylase deficiency
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
  • E71.1
  • C0268579
  • C0311298
  • D056693
MedDRA -


Disease definition

Propionic acidemia (PA) is an organic aciduria caused by the deficient activity of the propionyl Coenzyme A carboxylase and is characterized by life threatening episodes of metabolic decompensation, neurological dysfunction and that may be complicated by cardiomyopathy.


The prevalence rate is probably about 1 in 100,000 live births worldwide. A high prevalence rate is noted in certain countries like Saudi Arabia.

Clinical description

Propionic acidemia can present in one of the following forms: severe neonatal onset, intermittent late onset or a chronic progressive form. In the severe neonatal onset form, the affected infants present with symptoms of metabolic intoxication (poor feeding, vomiting, altered sensorium) and pancytopenia within several hours to weeks after birth. In the intermittent late onset form, the disease presents after a year or even later in life with episodes of metabolic decompensation provoked by periods of catabolic stress like fever, vomiting and trauma. Patients may also present with acute neurological crisis characterized by dystonia, rigidity, choreoathetosis and dementia (due to infarction of basal ganglia). In the chronic progressive form, the disease presents as failure to thrive, chronic vomiting, psychomotor delay, hypotonia, seizures and movement disorders. Intellectual disability, optic neuropathy, cardiomyopathy, long QT syndrome, pancreatitis, dermatitis, and immune dysfunction are known complications.


PA is caused by mutations in either the PCCA (13q32) or PCCB (3q21-q22) genes encoding the α- and β-subunits of the propionyl CoA carboxylase.

Diagnostic methods

Extended newborn screening test identifies PA by detecting an elevated level of propionyl carnitine. Symptomatic cases present during metabolic decompensation with acidosis, ketosis, increased anion gap, hyperlactatemia, hyperglycinemia, hyperammonemia, hypoglycemia and cytopenias. Urine analysis by gas chromatography-mass spectrometry reveals a characteristic pattern with 3 hydroxy propionate, methyl citrate, propionyl glycine and propionyl carnitine that persists in between crisis. Confirmation of the diagnosis relies on detection of either deficient enzymatic activity or mutations in PCCA or PCCB genes.

Differential diagnosis

Differential diagnosis includes neonatal sepsis, other branched chain organic acidurias, pyloric stenosis or other common causes of increased anion gap acidosis. In the infantile chronic form, failure to thrive, chronic vomiting and neutropenia may mimic cow milk intolerance, celiac disease (see this term) or immune deficiencies.

Antenatal diagnosis

Prenatal diagnosis can be made by measuring propionyl carnitine, methyl citrate and 3 hydroxy propionate in the amniotic fluid or by DNA assay or direct enzyme assay in families with a known mutation.

Genetic counseling

Inheritance is autosomal recessive.

Management and treatment

Confirmation of the diagnosis is not indispensable to start the treatment. Reversal of catabolism by stopping protein intake and administering non-protein calories in the form of intravenous fluids is the mainstay of treatment of a crisis. Hyperammonemia is treated by administering sodium benzoate, carbamyl glutamate or by hemodialysis. Nutrition management, in particular protein restriction, is a cornerstone to the long term treatment of patients with PA. Growth is regularly monitored. Carnitine supplementation helps in detoxification. Avoiding metabolic decompensation and promptly treating the episodes with standard treatment may improve intellectual outcome.


Early detection and treatment has led to a reduction in the mortality rate in the first year of life and improved survival rates in early and mid-childhood but morbidity in terms of impaired cognitive development remains high. The question whether a liver transplantation can be performed early in infancy to improve the prognosis is still under investigation.

Expert reviewer(s)

  • Pr Jean-Marie SAUDUBRAY

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