Clinical description:

Propionic acidemia (PPA) is an organic acidemia resulting in a deficiency in the enzyme propionyl-CoA carboxylase (PCC). PCC catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA during the catabolism of the amino acids valine, isoleucine, threonine, and methionine as well as odd-chain fatty acids, cholesterol side chains, thymine, and uracil. Impairment of PCC results in a metabolic block that leads to elevated concentrations of propionate precursors and their metabolic by-products.

Propionic acidemia is a fully penetrant disorder that displays broad clinical heterogeneity ranging from a severe neonatal onset encephalopathy to isolated cardiomyopathy presenting in late adolescence to early adulthood. The heterogeneity is due to the residual PCC enzymatic activity, with the least activity associated with the most severe presentation of the disease. The severe, neonatal-onset presentation is the classic and most-common form; patients present in the first days of life, after protein catabolism has taken place, and is characterized by poor feeding, vomiting, somnolence, and acute clinical deterioration. Affected individuals can become lethargic and encephalopathic, can develop seizures or cardiorespiratory failure, and may possibly experience coma or death. Biochemically, affected individuals have anion-gap metabolic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Patients who survive the first metabolic crisis often suffer from cognitive delay, seizures, basal ganglia lesions, growth impairment, pancreatitis, and cardiomyopathy.

Late-onset PPA (outside of the newborn period) can present during intercurrent illness, with symptoms that are similar to those in neonatal cases and ranging from mild to acute decompensation. Alternatively, there may be a chronic progressive course, with neurocognitive regression, failure to thrive, and other neurologic abnormalities. Individuals with neonatal and late-onset PPA are also susceptible to intermittent episodes of acute metabolic decompensation; such episodes are frequently precipitated by infection, injury, or physiologic stress.

Atypical presentations include adult-onset chorea and dementia without documented metabolic acidosis. Recently, PPA has been reported as a cause of isolated cardiomyopathy without metabolic acidosis or neurologic deficits. These cases have not experienced acute metabolic decompensation but have had biochemical abnormalities consistent with PPA.

Propionic acidemia is treatable by lifetime dietary restriction of the amino acids valine, methionine, isoleucine, and threonine, and by aggressive intervention during metabolic crises. Dietary therapy must be managed by a nutritionist to prevent malnutrition. Some affected individuals have been treated with a liver transplant.

Clinical sensitivity:

Pathogenic variants in PCCA account for approximately 35%–50% of diagnosed cases of propionic acidemia. Approximately 20% of these pathogenic variants are due to exonic deletions. Pathogenic variants in PCCB account for approximately 50%–65% of diagnosed cases of propionic acidemia. Deletions in PCCB have not been described. Approximately 100% of patients with a clinical and biochemical diagnosis of PPA are expected to have biallelic pathogenic variants in either PCCA or PCCB.