PCCB – Propionic Acidemia

Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by biallelic loss-of-function variants in PCCB, the gene encoding the beta subunit of propionyl-CoA carboxylase (PCC). Deficiency of PCC leads to mitochondrial accumulation of propionyl-CoA and downstream toxic organic acids, resulting in recurrent metabolic decompensation, hyperammonemia, and multisystem organ dysfunction (PMID:2249848; PMID:9683601).

Inheritance is autosomal recessive, with compound heterozygous or homozygous variants causing PA. Over 150 unrelated probands across more than 30 independent cohorts have been reported, with robust segregation of pathogenic PCCB alleles in affected sibships and multiplex families (Definitive gene-disease association) (PMID:2249848, PMID:9683601).

The variant spectrum includes missense, nonsense, small insertions/deletions, and deep intronic changes. A recurrent founder insertion c.1538_1540dup (p.Ala513_Arg514insPro) is prevalent in Greenlandic Inuit, accounting for 5% carrier frequency and linked to severe neonatal PA (PMID:10820128). A common missense change c.1229G>A (p.Arg410Gln) is associated with late-onset cardiomyopathy presentations and residual PCC activity (PMID:19238581).

Functional assays demonstrate that carboxy-terminal PCCB mutations disrupt alpha-beta and beta-beta subunit assembly, whereas some amino-terminal substitutions cause folding defects recoverable at lower temperatures. For example, mutations R512C, L519P, W531X, and N536D impair heteromeric and homomeric assembly, confirming a loss-of-function mechanism (PMID:11749052).

No significant conflicting evidence has been reported. Deep intronic variants may require genome sequencing and RNA analysis to uncover pseudoexon activation, as shown by identification of c.654+462A>G following exome negative findings.

In summary, PCCB-related PA is a well-established autosomal recessive disorder with definitive clinical validity. Genetic testing of PCCB should include sequencing and dosage analysis to detect deep intronic and structural variants. Early molecular diagnosis enables dietary and supportive interventions, informs carrier screening and prenatal diagnosis, and guides genotype-based management strategies.

References

• Genomics • 1990 • Two distinct mutations at the same site in the PCCB gene in propionic acidemia PMID:2249848
• American journal of human genetics • 1998 • Human propionyl-CoA carboxylase beta subunit gene: exon-intron definition and mutation spectrum in Spanish and Latin American propionic acidemia patients PMID:9683601
• American journal of human genetics • 2000 • High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase PMID:10820128
• Journal of inherited metabolic disease • 2009 • Unusual presentation of propionic acidaemia as isolated cardiomyopathy PMID:19238581
• Molecular genetics and metabolism • 2001 • Effect of PCCB gene mutations on the heteromeric and homomeric assembly of propionyl-CoA carboxylase PMID:11749052

Evidence Based Scoring (AI generated)