O.08 Biallelic variants in the mitochondrial form of phosphoenolpyruvate carboxykinase (PCK2) cause a recessive form of Charcot-Marie-Tooth disease

Abstract

Mutations in over 100 genes have been associated with Charcot-Marie-Tooth disease (CMT). Despite testing availability, many patients remain genetically unresolved. In this study, a new cause of CMT was identified in <i>PKC2</i>. Phosphoenolpyruvate carboxykinase (PCK) plays a critical role in cytosolic gluconeogenesis. PCK is encoded by <i>PCK1</i>, the cytosolic gene associated with hypoglycemia during fasting, and <i>PCK2</i>, the mitochondrial gene not yet associated with human disease. Whole exome sequencing (WES) and nerve conduction studies (NCS) were performed. PCK enzymatic activity and protein production were assessed from patient fibroblasts. To validate the association, a mouse knockout model of <i>PCK2</i> deficiency was generated. Three patients from 2 families were identified with biallelic variants in <i>PCK2</i> via WES. Compound heterozygous variants (p.Ser23Ter/p.Pro170Leu) were identified in one patient and a homozygous variant (p.Arg193Ter) in two siblings. All 3 patients presented with weakness and gait abnormalities. Fibroblast cultures showed a reduction or absence of <i>PCK2</i> protein and profound reduction in <i>PCK2</i> activity with no obvious metabolic phenotype. NCS showed reduction in conduction velocities with temporal dispersion and conduction block, consistent with a demyelinating peripheral neuropathy. Corroborating the human phenotype, the mouse model had abnormal NCS and peripheral nerve pathology. In all, this study suggests a new cause of CMT, biallelic variants in <i>PCK2</i>. This supports the growing evidence for the importance of mitochondrial dysfunction in CMT which may inform future therapeutic targets.