Propionic acidaemia

Propionic acidaemia (PA) is a severe organic acidaemia with multisystem involvement. Most affected individuals become symptomatic in the first weeks of life; a healthy-appearing newborn develops poor feeding, decreased arousal, and progressive encephalopathy manifesting as lethargy, seizures, or coma, which without prompt management can result in death.

A late-onset subset remains asymptomatic during infancy and presents later with cardiomyopathy, , , metabolic crisis, or basal-ganglia injury, often precipitated by catabolic stress such as intercurrent illness, surgery, high-protein intake, or prolonged fasting.

Long-term involvement spans neurologic (developmental delay, movement disorders, basal ganglia injury), cardiovascular (dilated or hypertrophic cardiomyopathy with reported prevalence between 7% and 39%, median onset 7 to 14.4 years), renal (chronic kidney disease in approximately half of affected individuals, occasionally progressing to kidney failure), haematologic, gastrointestinal, ophthalmologic, and dermatologic systems. Clinical expression is highly variable between and within families.

The estimated incidence is 0.32 to 2.20 per 100,000 live births in Europe.

Propionic acidaemia is caused by biallelic germline pathogenic variants in PCCA (13q32.3, ~50%) or PCCB (3q22.3, ~50%). These genes encode the alpha and beta subunits of propionyl-CoA carboxylase (PCC), a biotin-dependent mitochondrial heterododecamer (α6β6) that catalyses the conversion of propionyl-CoA to D-methylmalonyl-CoA. Loss of PCC function results in accumulation of propionic acid and propionyl-CoA-related metabolites, inhibition of oxidative phosphorylation, and reduced production of Krebs cycle intermediates. The underlying disease mechanism is loss of function.

Propionic acidaemia is inherited in an autosomal recessive manner. The parents of an affected individual are typically obligate heterozygotes, and each sibling of an affected individual has a 25% risk of being affected, a 50% risk of being a heterozygous carrier, and a 25% risk of being unaffected and not a carrier. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis is suspected on newborn-screening acylcarnitine profile showing elevated propionylcarnitine (C3) and an elevated C3/C2 ratio. Supportive biochemical findings include elevated urinary 3-hydroxypropionate, 2-methylcitrate, tiglylglycine and propionylglycine on urine organic acids, hyperglycinaemia or low glutamine on plasma amino acids, and normal methylmalonic acid and total plasma homocysteine, which distinguish PA from methylmalonic acidaemia and cobalamin disorders. Significantly reduced propionyl-CoA carboxylase activity measured in lymphocytes or cultured skin fibroblasts can confirm the diagnosis when molecular genetic testing is inconclusive.

Main differential diagnoses include:

• Isolated : elevated propionylcarnitine (C3) on newborn screening shared with PA but distinguished by elevated methylmalonic acid on urine organic acids and plasma; MMUT, MMAA, MMAB, MMADHC, MCEE
• (cobalamin C/D/F and related defects): elevated C3 on newborn screening with abnormal homocysteine metabolism; MMACHC, MMADHC, ABCD4, LMBRD1, e.g. and others
• Multiple carboxylase deficiency ( and holocarboxylase synthetase deficiencies): elevated 3-hydroxypropionate and 2-methylcitrate accompanied by elevated lactic acid, 3-hydroxyvaleric acid, and 3-methylcrotonylglycine; biotin-responsive; BTD, HLCS

• Establishing the molecular diagnosis confirms the clinical suspicion, ends the diagnostic odyssey, and provides the basis for genetic counselling of the affected individual and the family.
• Identification of the underlying pathogenic variants is a prerequisite for targeted medical care and informs specific and individualised clinical management, which remains the responsibility of the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variants are known, carrier testing of at-risk relatives and reproductive counselling become possible for the wider family.

• Galarreta Aima CI, Shchelochkov OA, Jerves Serrano T, Venditti CP. Propionic acidemia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024 [updated 2024 Sep 26]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK92946/. PMID: .
• Almási T, Guey LT, Lukacs C, Csetneki K, Vokó Z, Zelei T. Systematic literature review and meta-analysis on the epidemiology of propionic acidemia. Orphanet J Rare Dis. 2019;14(1):40. doi:10.1186/s13023-018-0987-z. PMID: . PMCID: PMC6375193.
• Forny P, Hörster F, Ballhausen D, Chakrapani A, Chapman KA, Dionisi-Vici C, et al. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. J Inherit Metab Dis. 2021;44(3):566–592. doi:10.1002/jimd.12370. PMID: . PMCID: PMC8252715.