Propionic acidemia (PA) represents a rare but severe inherited metabolic disorder characterized by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase.

This enzymatic defect impairs the catabolism of certain amino acids and fatty acids, leading to the accumulation of toxic metabolites.

Neonates with PA typically present in the first few days to weeks of life, often facing life-threatening metabolic crises. Early recognition and management are pivotal to improving outcomes and reducing neurological sequelae.

Pathophysiology: Disruption at the Mitochondrial Level

In a healthy metabolic cycle, propionyl-CoA is converted to methylmalonyl-CoA, which then enters the Krebs cycle after conversion to succinyl-CoA. In PA, this conversion fails, leading to massive intracellular accumulation of organic acids and CoA derivatives. These by-products inhibit mitochondrial oxidative phosphorylation, disrupt ammonia detoxification by the urea cycle, and impair gluconeogenesis, resulting in a toxic triad of metabolic acidosis, hyperammonemia, and hypoglycemia.

Research by Dr. Matthias Baumgartner, a leading authority in inborn errors of metabolism, shows that chronic exposure to organic acidemia leads to progressive neuronal injury, basal ganglia infarction, and white matter atrophy, underscoring the disease's insidious long-term impact.

Clinical Presentation in Newborns

Newborns affected by PA typically exhibit nonspecific symptoms initially: poor feeding, vomiting, lethargy, and hypotonia. These signs often escalate rapidly to seizures, apnea, and coma. Metabolic acidosis with an elevated anion gap, hyperammonemia, and ketonuria are hallmark laboratory findings during acute decompensation. Delayed diagnosis increases the risk of irreversible brain injury due to neurotoxicity from ammonia and organic acids.

Diagnostic Strategies

Definitive diagnosis requires measurement of elevated propionylcarnitine (C3) in newborn screening using tandem mass spectrometry. Confirmation involves plasma amino acid analysis showing elevated glycine and urinary organic acid testing revealing increased 3-hydroxypropionate and methylcitrate. Molecular genetic testing of PCCA and PCCB genes identifies pathogenic variants confirming diagnosis and assisting in family counseling.

Management of Acute Metabolic Crisis

Acute management aims to halt the catabolic state and clear toxic metabolites rapidly. This involves:

- Immediate cessation of protein intake to reduce propionate production.

- Intravenous glucose infusion to provide calories and suppress endogenous protein catabolism.

- Administration of intravenous carnitine to enhance excretion of propionyl compounds.

- Ammonia scavengers such as sodium benzoate or sodium phenylacetate may be employed to reduce hyperammonemia.

- Hemodialysis is indicated in refractory cases with severe hyperammonemia or metabolic acidosis.

Long-Term Management and Prognosis

Chronic management focuses on dietary protein restriction tailored to individual tolerance and supplementation with medical foods devoid of problematic amino acids. Carnitine supplementation continues to support metabolic detoxification. Regular monitoring of metabolic markers is essential to detect and prevent intermittent decompensations triggered by infections, fasting, or stress.

Emerging therapeutic approaches such as gene therapy and enzyme replacement remain under investigation, with promising preliminary results but limited clinical application currently. Despite aggressive management, neurodevelopmental impairment remains a common outcome, underscoring the importance of early diagnosis and intervention.

Propionic acidemia poses a formidable challenge in neonatal medicine due to its rapid onset and potential for devastating metabolic crises. A multidisciplinary approach involving neonatologists, metabolic specialists, dietitians, and genetic counselors is essential for optimizing patient outcomes. Ongoing research offers hope for novel treatments that may transform prognosis in the future.