PC – Pyruvate Carboxylase Deficiency

Pyruvate carboxylase deficiency (PCD) is a rare autosomal recessive metabolic disorder characterized by three clinical presentations: a neonatal lethal French type (Type B), an infantile fatal American type (Type A), and a late‐onset benign form (Type C). Affected individuals present with severe lactic acidosis, hyperammonemia, developmental delay, seizures, and sometimes prenatal brain lesions, reflecting impaired gluconeogenesis and anaplerotic flux in the tricarboxylic acid cycle.

Genetic evidence supports a definitive association between biallelic variants in PC and PCD. Over 60 unrelated probands across more than 30 families have been reported with missense, nonsense, splice, and frameshift variants ([PMID:7720232]). The spectrum includes recurrent founder and novel alleles; for example, the hypomorphic missense variant c.796T>G (p.Ser266Ala) is observed in Type A patients ([PMID:30870574]). Residual fibroblast enzyme activities (1–5% of normal) correlate loosely with clinical severity.

Segregation analyses in multiple consanguineous and non‐consanguineous families demonstrate autosomal recessive inheritance with at least eight additional affected relatives (sib pairs and sibships) segregating compound heterozygous or homozygous PC variants ([PMID:7503391]).

Functional studies confirm loss‐of‐function as the predominant mechanism. Cultured fibroblasts from affected patients show A, causes intron retention and mRNA aberration ([PMID:35573952]). An induced pluripotent stem cell line from a patient harboring c.182T>C and c.2581G>A variants recapitulates metabolic derangements in vitro ([PMID:36508859]).

Biallelic PC variants disrupt biotin‐dependent pyruvate carboxylation, leading to energy deprivation in neural tissues and metabolic crises. Missense mutations cluster in the biotin‐binding and catalytic domains, while truncating and splice variants lead to transcript decay or aberrant protein.

Key Take-home: The definitive PC–PCD association is established by extensive genetic and functional concordance. PC variant screening is critical for early diagnosis, prenatal counseling, and personalized metabolic management.

References

• Pediatric research • 1991 • Pyruvate carboxylase deficiency: a benign variant with normal development. PMID:1909777
• Clinical biochemistry • 1995 • Prolonged survival in pyruvate carboxylase deficiency: lack of correlation with enzyme activity in cultured fibroblasts. PMID:7720232
• Brain & development • 1995 • An atypical French form of pyruvate carboxylase deficiency. PMID:7503391
• Human mutation • 2019 • Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants in PC and analysis of the genotype-phenotype correlation. PMID:30870574
• Frontiers in pediatrics • 2022 • PC Splice-Site Variant c.1825+5G>A Caused Intron Retention in a Patient With Pyruvate Carboxylase Deficiency: A Case Report. PMID:35573952
• Stem cell research • 2023 • Generation of an induced pluripotent stem cell line (SHCDNi007-A) from a patient with pyruvate carboxylase deficiency carrying compound heterozygous (c.182 T> C/ c.2581G> A) variants in PC PMID:36508859

Evidence Based Scoring (AI generated)