Clinical, biochemical, and molecular profiles of three Sri Lankan neonates with pyruvate carboxylase deficiency

Abstract

Objectives: Pyruvate carboxylase, a mitochondrial enzyme, catalyses the conversion of glycolytic end-product pyruvate to tricarboxylic acid cycle intermediate, oxaloacetate. Rare pyruvate carboxylase deficiency manifests in three clinical and biochemical phenotypes: neonatal onset type A, infantile onset type B and a benign C type. The objective of this case series is to expand the knowledge of overlapping clinical and biochemical phenotypes of pyruvate carboxylase deficiency.

Case presentation: We report three Sri Lankan neonates including two siblings, of two unrelated families with pyruvate carboxylase deficiency. All three developed respiratory distress within the first few hours of birth. Two siblings displayed typical biochemical findings reported in type B. The other proband with normal citrulline, lysine, moderate lactate, paraventricular cystic lesions, bony deformities, and a novel missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC gene, biochemically favoured type A.

Conclusions: Our findings indicate the necessity of prompt laboratory investigations in a tachypneic neonate with coexisting metabolic acidosis, as early recognition is essential for patient management and family counselling. Further case studies are required to identify overlapping symptoms and biochemical findings in different types of pyruvate carboxylase deficiency phenotypes.

Keywords: citrulline; genotype; neonate; phenotype; pyruvate carboxylase deficiency.

Figure 1:

Pedigree charts of Family A and Family B. The families include unaffected siblings as well as diseased siblings whose exact genotypes are unknown (A? and ?? respectively). The diseased siblings are likely to be homozygous (aa) for the pathogenic variants. A: dominant allele, a: recessive allele, ?: unknown allele.

Figure 2:

Biochemical changes associated with pyruvate carboxylase deficiency; the intermediates of the tricarboxylic acid (TCA) cycle are decreased. Gluconeogenesis is impaired due to reduced oxalate availability. The urea cycle is impaired due to aspartate deficiency resulting in hypercitrullinemia. Lysine degradation may be impaired due to alpha-ketoglutarate deficiency. Increased acetyl-CoA is directed towards ketogenesis, fatty acid synthesis, and cholesterol synthesis. Cytoplasmic NAD⁺/NADH ratio is decreased while mitochondrial NAD⁺/NADH ratio is increased. α-KG, alpha-ketoglutarate; B7, biotin; BHB, beta-hydroxybutyrate; Cit, Citrulline; HMG-CoA, β-hydroxy β-methylglutaryl-CoA; NAD⁺, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; OAA, oxaloacetate; PC, pyruvate carboxylase.