Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants in PC and analysis of the genotype-phenotype correlation

Hum Mutat. 2019 Jun;40(6):816-827. doi: 10.1002/humu.23742. Epub 2019 Apr 13.


Pyruvate carboxylase deficiency (PCD) is caused by biallelic mutations of the PC gene. The reported clinical spectrum includes a neonatal form with early death (type B), an infantile fatal form (type A), and a late-onset form with isolated mild intellectual delay (type C). Apart from homozygous stop-codon mutations leading to type B PCD, a genotype-phenotype correlation has not otherwise been discernible. Indeed, patients harboring biallelic heterozygous variants leading to PC activity near zero can present either with a fatal infantile type A or with a benign late onset type C form. In this study, we analyzed six novel patients with type A (three) and type C (three) PCD, and compared them with previously reported cases. First, we observed that type C PCD is not associated to homozygous variants in PC. In silico modeling was used to map former and novel variants associated to type A and C PCD, and to predict their potential effects on the enzyme structure and function. We found that variants lead to type A or type C phenotype based on the destabilization between the two major enzyme conformers. In general, our study on novel and previously reported patients improves the overall understanding on type A and C PCD.

Keywords: PC tetramerization domain; biotin carboxyl carrier protein domain; biotin carboxylase domain; carboxyl transferase domain; neurodevelopmental delay; pyruvate carboxylase; pyruvate carboxylase deficiency.

MeSH terms

  • Child
  • Child, Preschool
  • Enzyme Stability
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Male
  • Models, Molecular
  • Mutation*
  • Protein Conformation
  • Pyruvate Carboxylase / chemistry*
  • Pyruvate Carboxylase / genetics*
  • Pyruvate Carboxylase Deficiency Disease / classification
  • Pyruvate Carboxylase Deficiency Disease / genetics*
  • Structural Homology, Protein


  • Pyruvate Carboxylase