General description

Pyruvate carboxylase deficiency results from mutations in the PC gene located at 11q13.4-q13.5, which encodes a biotin-dependent mitochondrial enzyme essential for multiple metabolic pathways. The enzyme catalyzes the conversion of pyruvate to oxaloacetate, serving as a critical anaplerotic reaction that replenishes citric acid cycle intermediates and facilitates gluconeogenesis.

Clinical manitestations and disease subtypes

Pyruvate carboxylase deficiency exhibits considerable clinical heterogeneity, with researchers identifying three distinct types based on severity and age of onset.

• Type A: Children with Type A disease generally have limited survival, typically not extending beyond infancy or early childhood.
• Type B: Type B pyruvate carboxylase deficiency constitutes the most severe form, with life-threatening manifestations appearing shortly after birth. The clinical course of Type B disease is particularly aggressive, with most infants surviving less than three months after birth.
• Type C: Type C pyruvate carboxylase deficiency represents the mildest form, characterized by episodic lactic acidosis with relatively preserved neurological function. Neurological development remains normal or shows only mild impairment, though some patients may experience dystonia, episodic ataxia, dysarthria, transitory hemiparesis, or seizures. The prognosis for Type C disease is generally favorable, with minimal impact on life expectancy.

References

1. Mhanni, Aizeddin A., et al. "Prenatal onset of the neuroradiologic phenotype of pyruvate carboxylase deficiency due to homozygous PC c. 1828G> A mutations." JIMD reports 61.1 (2021): 42-47.