Propionic Acidemia

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

1. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.

2. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy.

3. Isolated cardiomyopathy 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, and chronic renal failure.

Diagnosis/testing: 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, propionylglycine, and lactic acid. Testing of plasma amino acids reveals elevated glycine. Confirmation of the diagnosis relies on detection of biallelic pathogenic variants in PCCA or PCCB or of deficient PCC enzymatic activity. In individuals with equivocal molecular genetic test results, a combination of enzymatic and molecular diagnostics may be necessary.

Management: Treatment of manifestations: The treatment of individuals with acutely decompensated PA is a medical emergency: treat precipitating factors such as infection, dehydration, vomiting; reverse catabolism by providing intravenous glucose and lipids; manage protein intake to reduce propiogenic precursors; remove toxic compounds using nitrogen scavenger medications, extracorporeal detoxification, and/or intravenous carnitine; transfer to 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 should be directed by an experienced physician and metabolic dietician to control the intake of propiogenic substrates and to guide increased caloric intake during illness to prevent catabolism. G-tube placement is an effective strategy to facilitate the administration of medications and nutrition during acute decompensations and to improve adherence in chronic management of PA.

Medications may include L-carnitine supplementation to enhance excretion of propionic acid and oral metronidazole to reduce propionate production by gut bacteria. Orthotopic liver transplantation (OLT) may be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and/or poor growth.

Prevention of secondary complications: Consistent evaluation of the protein intake, depending on age, sex, severity of disorder, and presence of other factors such as intercurrent illness, surgery, level of physical activity, and growth spurts to avoid insufficient or excessive protein restriction. Excessive protein restriction 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) vision and hearing (3) cardiac function for signs of cardiomyopathy; (4) metabolic status by monitoring urine organic acids and plasma amino acids; (5) complete blood count; (6) renal function.

Agents/circumstances to avoid: Prolonged fasting, catabolic stressors, and excessive protein intake. Lactated Ringer’s solution is not recommended in patients with organic acidemias. In patients with QT abnormalities, avoid medications that can prolong the QT interval. Neuroleptic antiemetics (e.g., promethazine) can mask symptoms of progressive encephalopathy and are best avoided.

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 testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.