PA arises from biallelic pathogenic variants in either the PCCA gene (chromosome 13) or the PCCB gene (chromosome 3), both of which encode subunits of the heterododecameric propionyl-CoA carboxylase enzyme. ClinGen has assigned definitive validity to both genes in the context of this disease. The enzyme's role in catabolism of the amino acids isoleucine, valine, methionine, and threonine—collectively termed propiogenic substrates—means that dysfunction results in systemic accumulation of propionyl-CoA and downstream toxic metabolites. Gut flora also contribute to propionic acid production. Inheritance follows an autosomal recessive pattern, requiring pathogenic variants in both alleles of the relevant gene for disease expression.

Diagnosis of PA is established through biochemical and molecular testing. Elevated propionylcarnitine (C3) on acylcarnitine profiling, detected via newborn screening programs, often prompts further evaluation. Urine organic acid analysis reveals elevated propionic acid and characteristic metabolites. Plasma amino acid analysis and plasma ammonia levels inform the degree of metabolic disruption. Complete blood count may demonstrate cytopenias. Brain MRI and EEG are employed when neurological findings are present. Electrocardiography and echocardiography assess for arrhythmia, prolonged QTc interval, and cardiomyopathy. Confirmatory molecular genetic testing identifies pathogenic variants in PCCA or PCCB. The condition is listed in OMIM as entry 606054 and in Orphanet as Orphanet:35.

Documented treatment strategies center on reducing the propiogenic substrate load while maintaining adequate nutrition. Dietary restriction of isoleucine, valine, methionine, and threonine using specialized medical foods constitutes the primary nutritional intervention. Oral levocarnitine supplementation addresses secondary carnitine deficiency. Carglumic acid (Carbaglu, Recordati Rare Diseases), an approved orphan drug, has been used for recurrent acute hyperammonemia in organic acidemias including PA. Oral metronidazole has been employed to reduce intestinal bacterial propionic acid production. Dystonic movement disorders have been managed with benzodiazepines, baclofen, trihexyphenidyl, or botulinum toxin. Liver transplantation has been reported to reduce metabolic decompensation episodes; combined heart-liver transplantation has been documented in severe cardiac cases.

The clinical course of PA is variable and influenced by disease severity, genotype, and management. Life-threatening metabolic crises can occur throughout life, particularly during periods of physiological stress. Neurological outcomes are frequently compromised, with global developmental delay present universally and intellectual disability affecting a substantial proportion of individuals. Cardiomyopathy and arrhythmia represent serious long-term complications associated with increased morbidity and mortality. Chronic kidney disease, immune dysfunction, and growth failure contribute to the overall disease burden. Some individuals have experienced improvement in cardiac function following liver transplantation, though cardiomyopathy recurrence post-transplant has also been reported in the literature. Long-term neurodevelopmental and cardiac trajectories remain subjects of ongoing natural history research.

Active investigation into PA is substantial, with 10 active clinical trials documented as of the most recent data. Moderna Therapeutics is evaluating mRNA-3927, an mRNA-based therapeutic encoding both PCCA and PCCB subunits, in Phase 1 studies (NCT04159103, NCT05130437). Mayo Clinic is recruiting for a Phase 1 gene therapy trial using an AAVrh10-PCCA vector (NCT07643844). The NIH National Human Genome Research Institute is conducting a long-term natural history study (NCT02890342). Additional designated orphan agents include 2,2-dimethylbutanoic acid (HemoShear Therapeutics) and AAV9-based gene therapy vectors targeting both PCCA and PCCB subunits sponsored by NIH NCATS. An observational study of carglumic acid across pediatric and adult populations is also ongoing (NCT05040178)。