Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2‐related mitochondrial disease
Jessie Poquérusse,
Melinda Nolan,
David R. Thorburn,
Johan L. K. Van Hove,
Marisa W. Friederich,
Donald R. Love,
Juliet Taylor,
Christopher A. Powell,
Michal Minczuk,
Russell G. Snell,
Klaus Lehnert,
Emma Glamuzina,
Jessie C. Jacobsen
Affiliations
Jessie Poquérusse
School of Biological Sciences The University of Auckland Auckland New Zealand
Melinda Nolan
Department of Neurology Starship Children's Health Auckland New Zealand
David R. Thorburn
Murdoch Children's Research Institute Melbourne Victoria Australia
Johan L. K. Van Hove
Department of Pediatrics, School of Medicine University of Colorado Anschutz Medical Campus Aurora Colorado USA
Marisa W. Friederich
Department of Pediatrics, School of Medicine University of Colorado Anschutz Medical Campus Aurora Colorado USA
Donald R. Love
Diagnostic Genetics LabPLUS, Auckland City Hospital Auckland New Zealand
Juliet Taylor
Genetic Health Service New Zealand Auckland City Hospital Auckland New Zealand
Christopher A. Powell
MRC Mitochondrial Biology Unit University of Cambridge Cambridge UK
Michal Minczuk
MRC Mitochondrial Biology Unit University of Cambridge Cambridge UK
Russell G. Snell
School of Biological Sciences The University of Auckland Auckland New Zealand
Klaus Lehnert
School of Biological Sciences The University of Auckland Auckland New Zealand
Emma Glamuzina
Adult and Paediatric National Metabolic Service Auckland City Hospital Auckland New Zealand
Jessie C. Jacobsen
School of Biological Sciences The University of Auckland Auckland New Zealand
Abstract Disorders of mitochondrial function are a collectively common group of genetic diseases in which deficits in core mitochondrial translation machinery, including aminoacyl tRNA synthetases, are key players. Biallelic variants in the CARS2 gene (NM_024537.4), which encodes the mitochondrial aminoacyl‐tRNA synthetase for cysteine (CARS2, mt‐aaRScys; MIM*612800), result in childhood onset epileptic encephalopathy and complex movement disorder with combined oxidative phosphorylation deficiency (MIM#616672). Prior to this report, eight unique pathogenic variants in the CARS2 gene had been reported in seven individuals. Here, we describe a male who presented in the third week of life with apnoea. He rapidly deteriorated with paroxysmal dystonic crises and apnoea resulting in death at 16 weeks. He had no evidence of seizure activity or multisystem disease and had normal brain imaging. Skeletal muscle biopsy revealed a combined disorder of oxidative phosphorylation. Whole‐exome sequencing identified biallelic variants in the CARS2 gene: one novel (c.1478T>C, p.Phe493Ser), and one previously reported (c.655G>A, p.Ala219Thr; rs727505361). Northern blot analysis of RNA isolated from the patient's fibroblasts confirmed a clear defect in aminoacylation of the mitochondrial tRNA for cysteine (mt‐tRNACys). To our knowledge, this is the earliest reported case of CARS2 deficiency with severe, early onset dystonia and apnoea, without epilepsy.