What is propionic acidemia?

What is Propionic Acidemia?

Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase, which converts propionyl-CoA to D-methylmalonyl-CoA, resulting in accumulation of toxic organic acid metabolites. 1, 2

Biochemical Defect and Pathophysiology

• PA results from mutations in either the PCCA or PCCB genes encoding the alpha and beta subunits of propionyl-CoA carboxylase 2
• The enzyme deficiency blocks the metabolism of branched-chain amino acids (isoleucine, valine, methionine, threonine), odd-chain fatty acids, and cholesterol side chains 1, 3
• Accumulation of propionyl-CoA and its metabolites (3-hydroxypropionic acid, methylcitric acid, propionylglycine) causes the characteristic organic acid profile detected by gas chromatography-mass spectrometry 1
• The metabolic block profoundly disrupts the tricarboxylic acid cycle and urea cycle, leading to deficient anaplerosis and impaired ammonia detoxification 4

Clinical Presentation

Classic presentation occurs within the first days of life with metabolic crisis, though variant forms may present later in childhood or even young adulthood. 1, 3, 5

Acute Metabolic Decompensation

• Typical symptoms include lethargy, vomiting, poor feeding, dehydration, and progression to coma if untreated 1
• Metabolic acidosis with elevated anion gap, ketonuria, and hyperammonemia are hallmark laboratory findings 1, 2, 5
• Additional laboratory abnormalities include anemia, thrombocytopenia, hypoproteinemia, and hypoglycemia or hyperglycemia 2, 5
• Triggers for metabolic crises include prolonged fasting, intercurrent illness (especially upper respiratory infections), fever, decreased nutritional intake, and catabolic stress 1, 5

Chronic Complications

• Neurologic sequelae occur in 38% of patients and include developmental delays, seizures, abnormal tone, and intellectual disability 1, 3, 5
• All patients with a history of metabolic decompensation events develop developmental delays 5
• Neuropathologic findings include white matter spongiosis in neonates and gray matter vacuolization in older children 3
• Cardiomyopathy develops in approximately 7% of patients 5
• Nutritional difficulties affect 46% of patients, including protein intolerance and growth restriction 1, 5
• Bone disease and protein catabolism result from chronic metabolic acidosis 1

Diagnosis

• Urine organic acid analysis by gas chromatography-mass spectrometry reveals elevated methylmalonic acid, 3-hydroxypropionic acid, methylcitric acid, and propionylglycine 1
• Interpretation must be based on the overall pattern of metabolites, not individual abnormalities 1
• Plasma amino acid analysis during metabolic crises shows reduced glutamine and alanine (indicating deficient anaplerosis), and hypocitrullinemia and hypoprolinemia during hyperammonemia 4
• Molecular genetic testing identifies mutations in PCCA or PCCB genes for definitive diagnosis and genetic counseling 2
• Many cases are now identified through newborn screening programs before clinical symptoms develop 1, 5

Incidence and Inheritance

• PA is among the most prevalent forms of organic acidemia, though individual incidence varies from 1 in 10,000 to 1 in 1,000 live births 1
• Inheritance is autosomal recessive, requiring both parents to be carriers 1
• Identification of an affected individual has critical implications for family members who may require genetic testing 1

Management Principles

Acute Crisis Management

• Immediate treatment focuses on stopping catabolism with intravenous glucose and fluid resuscitation 1
• Hyperammonemia refractory to medical management may require continuous kidney replacement therapy or hemodialysis 1
• Prolonged fasting before procedures or surgery can precipitate metabolic crises and must be carefully managed with intravenous glucose support 1

Chronic Management

• Dietary protein restriction (particularly branched-chain amino acids) reduces substrate load 1
• Frequent feeding schedules prevent catabolism 1
• Carnitine supplementation helps eliminate toxic metabolites 1
• Metronidazole reduces gut bacterial propionate production 1
• Liver transplantation may be indicated for patients experiencing frequent metabolic decompensations, uncontrollable hyperammonemia, restricted growth, or severe impairment of quality of life despite optimal medical management 1

Critical Clinical Pitfalls

• PA patients admitted for liver transplant evaluation may experience unexpectedly prolonged fasting during organ procurement, requiring specific metabolic monitoring protocols 1
• Liver transplantation does not completely correct the metabolic defect—serum methylmalonic acid levels improve but do not normalize, and patients remain at risk for neurological complications 1
• The diagnostic sensitivity of organic acid analysis varies with the patient's metabolic state; samples should ideally be collected during acute illness when diagnostic metabolites are highest 1
• Mild elevations of methylmalonic acid can result from intestinal bacterial metabolism or B12/folate deficiency and must be distinguished from true PA 1