The need for biochemical testing in beta‐enolase deficiency in the genomic era
Ralph Wigley,
Renata S. Scalco,
Alice R. Gardiner,
Richard Godfrey,
Suzanne Booth,
Richard Kirk,
David Hilton‐Jones,
Henry Houlden,
Simon Heales,
Ros Quinlivan
Affiliations
Ralph Wigley
Enzyme Laboratory, Department of Chemical Pathology, Cameilia Botnar Laboratories Great Ormond Street Hospital for Sick Children London UK
Renata S. Scalco
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery London UK
Alice R. Gardiner
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery London UK
Richard Godfrey
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery London UK
Suzanne Booth
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery London UK
Richard Kirk
Sheffield Diagnostic Genetic Service Sheffield Children's NHS Foundation Trust Sheffield UK
David Hilton‐Jones
Department of Clinical Neurology West Wing, John Radcliffe Hospital Oxford UK
Henry Houlden
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery London UK
Simon Heales
Enzyme Laboratory, Department of Chemical Pathology, Cameilia Botnar Laboratories Great Ormond Street Hospital for Sick Children London UK
Ros Quinlivan
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery London UK
Abstract Glycogen storage disease type XIII (GSDXIII) is a very rare inherited metabolic myopathy characterized by autosomal‐recessive mutations in the ENO3 gene resulting in muscle β‐enolase deficiency, an enzymatic defect of the distal part of glycolysis. Enzyme kinetic studies of two patients presenting with exertion intolerance and recurrent rhabdomyolysis are reported. Next generation sequencing confirmed patient 1 was homozygous for p.E187K in ENO3, while patient 2 was homozygous for p.C357Y. ENO3 variants pathogenicity was confirmed by functional studies in skeletal muscle. p.E187K caused extremely low total enolase activity. p.C357Y was associated with a higher level of residual activity but kinetic studies showed a lower maximum work rate (Vmax). This study illustrates that GSDXIII may be caused by either null mutations leading to β‐enolase deficiency or by mutations that alter the enzyme's kinetic profile. This study highlights the importance of carrying out functional studies as part of the diagnostic process following the identification of variants with next generation sequencing.
