The packet lists PCCA (chromosome 13) and PCCB (chromosome 3) as associated genes, each with ClinGen gene-disease validity rated definitive. This condition can result from variants in several different genes, and the PCCA-related and PCCB-related forms are listed as subtypes. GeneReviews describes the underlying defect as deficient propionyl-CoA carboxylase activity.

Inheritance is autosomal recessive. GeneReviews states that parents of an affected individual are presumed to be heterozygous for a PCCA or PCCB pathogenic variant, and that carriers are asymptomatic. When both parents are known carriers, each sibling of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither familial variant. When a variant is found in only one parent, GeneReviews describes a de novo or parental mosaic variant, or uniparental isodisomy, as possibilities. Family history is described as consistent with autosomal recessive inheritance when there are affected siblings or when parents share ancestry, which raises the chance that both carry the same variant.

GeneReviews notes that PA is more frequent in certain ancestral groups because of founder effects of specific variants.

Per GeneReviews, newborn screening for PA is primarily based on propionylcarnitine (C3) and the C3/C2 ratio from the acylcarnitine profile on dried blood spots. GeneReviews states that PA is included in routine newborn screening in the United States, while many countries rely on clinical presentation. Values above a laboratory cutoff are described as requiring follow-up biochemical testing, and confirmatory testing is then required.

Symptomatic individuals are described as having nonspecific findings such as developmental delay, intellectual disability, failure to thrive, protein intolerance, hypotonia, seizures, movement disorders, or cardiomyopathy. Biochemical findings consistent with PA include elevated propionylcarnitine, elevated 3-hydroxypropionate and 2-methylcitrate, tiglylglycine or propionylglycine in urine organic acids, and elevated glycine or low glutamine in plasma amino acids; normal methylmalonic acid and total homocysteine are pertinent negatives. Acute decompensation is accompanied by metabolic acidosis, hyperammonemia, and cytopenias.

GeneReviews states that because individual metabolite elevations are not entirely specific, follow-up molecular or enzymatic testing is required to establish or rule out the diagnosis.

GeneReviews notes that several acute and chronic management guidelines have been published and revised, and describes metabolic treatment as beginning immediately when PA is suspected from an abnormal newborn screen or suggestive symptoms. Care is described as involving a metabolic physician, biochemical geneticist, and specialist metabolic dietitian, with transfer to a specialist center for inherited metabolic diseases stressed, along with cardiology, neurology, nephrology, ophthalmology, and other specialty input.

Acute treatment. For symptomatic neonates, GeneReviews describes hospital admission, laboratory assessment, intravenous glucose, nutritional evaluation with possible dietary protein restriction, and carnitine supplementation.

Routine treatment. GeneReviews describes the mainstay nutritional intervention as dietary modification to limit propiogenic amino acids (isoleucine, valine, methionine, threonine) using specialized medical foods while supporting growth. It also describes oral metronidazole to reduce propionic acid production by gut flora, noting possible side effects; lifelong carnitine supplementation for secondary carnitine deficiency; gastrostomy or jejunostomy for feeding issues; and a biotin trial, noting there is no consensus and no evidence that a biotin-responsive form exists. Carglumic acid is described as a possibility in persons with recurrent acute hyperammonemia. In the packet's orphan drug records, Carbaglu (carglumic acid; Recordati Rare Diseases) is listed with approved status for treatment of organic acidemias. Liver transplant has been proposed in heart failure, with recurrence of cardiomyopathy also reported.

Surveillance. Long-term management includes regular surveillance for potential complications. GeneReviews lists growth and developmental progress at each visit, metabolic laboratory studies as clinically indicated, kidney function at least annually, and echocardiogram and EKG annually or as clinically indicated.

Circumstances associated with risk. GeneReviews lists prolonged fasting, catabolic stressors, excessive protein intake, and certain medications affecting QT interval or kidney function as circumstances of concern.

Orphan designations for mRNA-based, AAV9 gene therapy, and small-molecule agents are listed as designated, not approved. One small-molecule activator of pantothenate kinases is listed as withdrawn.

GeneReviews describes PA as having life-threatening metabolic decompensations, especially in the first years of life, with infectious complications often contributing to mortality. Long-term cognitive outcome is described as negatively correlated with the number of decompensations and with residual enzyme activity. A specific life expectancy figure is not certified in this packet.

The packet lists active ClinicalTrials.gov records relevant to PA: NCT02890342, a natural history, physiology, microbiome and biochemistry study (NHGRI; recruiting; 2016-11-29 to 2036-08-31); NCT04159103, a phase 1 open-label study of mRNA-3927 (ModernaTX; recruiting; 2021-04-15 to 2027-08-31); NCT05130437, a long-term safety extension of mRNA-3927 (ModernaTX; recruiting; 2021-11-09 to 2031-12-04); NCT05769621, a retrospective characterization study (ModernaTX; recruiting; 2023-06-16 to 2026-09-30); NCT07643844, a phase 1 study of AAVrh10-PCCA gene therapy (Mayo Clinic; recruiting; beginning 2026-07-20); and observational Carbaglu studies NCT05040178 and NCT04176523 (Recordati; recruiting). Further studies are searchable on ClinicalTrials.gov.