Biallelic pathogenic variants in the mitochondrial form of phosphoenolpyruvate carboxykinase cause peripheral neuropathy
Neal Sondheimer,
Alberto Aleman,
Jessie Cameron,
Hernan Gonorazky,
Nesrin Sabha,
Paula Oliveira,
Kimberly Amburgey,
Azizia Wahedi,
Dahai Wang,
Michael Shy,
James J. Dowling.
Affiliations
Neal Sondheimer
Departments of Paediatrics and Molecular Genetics, The University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Divisions of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; Corresponding author
Alberto Aleman
Divisions of Neurology, The Hospital for Sick Children, Toronto, ON, Canada
Jessie Cameron
Divisions of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada
Hernan Gonorazky
Divisions of Neurology, The Hospital for Sick Children, Toronto, ON, Canada
Nesrin Sabha
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
Paula Oliveira
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
Kimberly Amburgey
Divisions of Neurology, The Hospital for Sick Children, Toronto, ON, Canada
Azizia Wahedi
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
Dahai Wang
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
Michael Shy
Department of Neurology, University of Iowa, Iowa City, IA, USA
James J. Dowling.
Departments of Paediatrics and Molecular Genetics, The University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Divisions of Neurology, The Hospital for Sick Children, Toronto, ON, Canada; Corresponding author
Summary: Phosphoenolpyruvate carboxykinase (PCK) plays a critical role in cytosolic gluconeogenesis, and defects in PCK1 cause a fasting-aggravated metabolic disease with hypoglycemia and lactic acidosis. However, there are two genes encoding PCK, and the role of the mitochondrial resident PCK (encoded by PCK2) is unclear, since gluconeogenesis is cytosolic. We identified three patients in two families with biallelic variants in PCK2. One has compound heterozygous variants (p.Ser23Ter/p.Pro170Leu), and the other two (siblings) have homozygous p.Arg193Ter variation. All three patients have weakness and abnormal gait, an absence of PCK2 protein, and profound reduction in PCK2 activity in fibroblasts, but no obvious metabolic phenotype. Nerve conduction studies showed reduced conduction velocities with temporal dispersion and conduction block compatible with a demyelinating peripheral neuropathy. To validate the association between PCK2 variants and clinical disease, we generated a mouse knockout model of PCK2 deficiency. The animals present abnormal nerve conduction studies and peripheral nerve pathology, corroborating the human phenotype. In total, we conclude that biallelic variants in PCK2 cause a neurogenetic disorder featuring abnormal gait and peripheral neuropathy.
