PCCA – Propionic Acidemia

Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism characterized by deficiency of propionyl-CoA carboxylase (PCC), impairing catabolism of branched-chain amino acids and odd-chain fatty acids and leading to life-threatening metabolic acidosis and hyperammonemia. PCCA encodes the α-subunit of PCC. Patients typically present in the neonatal period with high anion-gap metabolic acidosis, hyperammonemia, vomiting, lethargy, and risk of neurologic sequelae ([PMID:8819559]).

Genetic evidence for PCCA in PA is extensive. A Spanish cohort of 37 PA patients included 9 PCCA-deficient individuals with unique genotypes, demonstrating early-onset severe disease in homozygous or compound heterozygous carriers (27 early-onset, 101 late-onset cases) ([PMID:10780784]). Worldwide mutational surveys have reported >200 PCCA variants, including missense, nonsense, splice, small indel, and large deletion alleles, with no single predominant change in Caucasians and multiple recurrent alleles in specific populations ([PMID:12559849]). Segregation in affected sibships and carrier parents underscores autosomal recessive inheritance.

The variant spectrum in PCCA comprises complete loss-of-function alleles—nonsense (e.g., c.937C>T (p.Arg313Ter)), frameshift (e.g., c.877C>G (p.Gln293Glu)), splice-site, and large genomic deletions—and numerous missense substitutions affecting the biotin carboxylase and biotin-binding domains. Founder mutations have been described in Saudi Arabia (p.Gly142Asp) and Japan (c.923dup), while deep-intronic pseudoexon activations (c.1285-1416A>G) contribute to disease in other populations.

Functional studies confirm PCCA pathogenicity. Expression of PCCA missense and truncating alleles in deficient fibroblasts and E. coli systems yields markedly reduced PCC activity and unstable protein, consistent with haploinsufficiency ([PMID:12385775]). Antisense oligonucleotide-mediated pseudoexon skipping restores normal transcript and enzyme activity in patient cells ([PMID:22334403]), and aminoglycoside-mediated readthrough of PTC alleles increases PCC activity to 10–15% of control ([PMID:22334403]). Patient-derived hepatocyte and iPSC models recapitulate the biochemical block and metabolic flux defects, supporting concordant functional evidence.

No studies have refuted PCCA’s role in PA; the entirety of clinical, genetic, and experimental data supports a definitive gene–disease relationship. Additional evidence—including genotype-phenotype modifiers and long-term follow-up cohorts—exists beyond the ClinGen scoring cap.

Key take-home: Biallelic PCCA mutations cause autosomal recessive propionic acidemia; comprehensive genetic testing and functional assays enable accurate diagnosis, carrier screening, and potential splice-modulating or readthrough therapies.

References

• Acta Paediatr • 1996 • Parathyroid hormone resistance and B cell lymphopenia in propionic acidemia PMID:8819559
• Eur J Hum Genet • 2000 • Potential relationship between genotype and clinical outcome in propionic acidaemia patients PMID:10780784
• Mol Genet Metab • 2003 • Propionic acidemia: identification of twenty-four novel mutations in Europe and North America PMID:12559849
• Biochim Biophys Acta • 2002 • Functional characterization of PCCA mutations causing propionic acidemia PMID:12385775
• Hum Mutat • 2012 • Feasibility of nonsense mutation readthrough as a novel therapeutical approach in propionic acidemia PMID:22334403
• Hum Genet • 2019 • Regulating PCCA gene expression by modulation of pseudoexon splicing patterns to rescue enzyme activity in propionic acidemia PMID:38204914

PCCA | Propionic acidemia

Evidence Based Scoring (AI generated)