Laurie H Seaver1, Steven DeRoos2, Nicholas J Andersen3, Brad Betz4, Jeremy Prokop5, Nick Lannen4, Renee Jordan4, Surender Rajasekaran2. 1. Helen DeVos Children's Hospital, Grand Rapids, Michigan; College of Human Medicine Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, Michigan. Electronic address: laurie.seaver@spectrumhealth.org. 2. Helen DeVos Children's Hospital, Grand Rapids, Michigan; College of Human Medicine Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, Michigan. 3. Office of Research Administration, Spectrum Health, Grand Rapids, Michigan. 4. Helen DeVos Children's Hospital, Grand Rapids, Michigan. 5. College of Human Medicine Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, Michigan.
Abstract
BACKGROUND: Infantile epileptic encephalopathy is a heterogeneous condition that has been associated with variants in more than 200 genes. The variability in findings and prognosis creates challenges to making the correct diagnosis and initiating the appropriate therapy. Biallelic variants in NARS2, a mitochondrial aminoacyl-tRNA synthetase gene, were recently associated with neurodegenerative disorders that include epilepsy. METHODS: We describe two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. We compared the cost of diagnostic laboratory evaluation for each child. Detailed NARS2 protein analysis was performed using a sequence-to-structure-to-function workflow, merging multiple homologous structures, to suggest biologic impact of the NARS2 variants. RESULTS: Brain magnetic resonance imaging showed rapid progression to generalized atrophy. Extensive metabolic, infectious, chromosomal and genetic testing of the first infant failed to reach a specific diagnosis. The younger brother presented similarly. Rapid whole exome sequencing was performed revealing novel biallelic variants in NARS2. The variants c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile) were confirmed in a reserved sample from the older brother. Management was then redirected toward palliative care and the child died at age nine months. CONCLUSIONS: NARS2-related disorder should be considered in infants presenting with refractory seizures and rapid brain atrophy. Metabolic screening tests may be normal or yield nonspecific findings. Rapid whole exome sequencing in children with fulminant onset intractable epilepsy may minimize extensive diagnostic evaluation and aid in prognosis and medical management.
BACKGROUND: Infantile epilepticencephalopathy is a heterogeneous condition that has been associated with variants in more than 200 genes. The variability in findings and prognosis creates challenges to making the correct diagnosis and initiating the appropriate therapy. Biallelic variants in NARS2, a mitochondrial aminoacyl-tRNA synthetase gene, were recently associated with neurodegenerative disorders that include epilepsy. METHODS: We describe two infant brothers who presented with focal status epilepticus that progressed to lethal epilepticencephalopathy. We compared the cost of diagnostic laboratory evaluation for each child. Detailed NARS2 protein analysis was performed using a sequence-to-structure-to-function workflow, merging multiple homologous structures, to suggest biologic impact of the NARS2 variants. RESULTS: Brain magnetic resonance imaging showed rapid progression to generalized atrophy. Extensive metabolic, infectious, chromosomal and genetic testing of the first infant failed to reach a specific diagnosis. The younger brother presented similarly. Rapid whole exome sequencing was performed revealing novel biallelic variants in NARS2. The variants c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile) were confirmed in a reserved sample from the older brother. Management was then redirected toward palliative care and the child died at age nine months. CONCLUSIONS:NARS2-related disorder should be considered in infants presenting with refractory seizures and rapid brain atrophy. Metabolic screening tests may be normal or yield nonspecific findings. Rapid whole exome sequencing in children with fulminant onset intractable epilepsy may minimize extensive diagnostic evaluation and aid in prognosis and medical management.
Authors: K Štěrbová; M Vlčková; H Hansíková; V Sebroňová; L Sedláčková; P Pavlíček; Petra Laššuthová Journal: Neurogenetics Date: 2021-08-20 Impact factor: 2.660
Authors: Martine Uittenbogaard; Kuntal Sen; Matthew Whitehead; Christine A Brantner; Yue Wang; Lee-Jun Wong; Andrea Gropman; Anne Chiaramello Journal: Front Cell Dev Biol Date: 2021-12-22