Lethal NARS2-Related Disorder Associated With Rapidly Progressive Intractable Epilepsy and Global Brain Atrophy
| Autor: | Nicholas J. Andersen, Surender Rajasekaran, Jeremy W. Prokop, Nick Lannen, Brad Betz, Renee Jordan, Steven T. DeRoos, Laurie H. Seaver |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mitochondrial encephalomyopathy Pediatrics medicine.medical_specialty Palliative care medicine.diagnostic_test business.industry Fulminant medicine.disease 03 medical and health sciences Epilepsy 030104 developmental biology 0302 clinical medicine Atrophy Developmental Neuroscience Neurology Global brain atrophy Pediatrics Perinatology and Child Health medicine Neurology (clinical) business 030217 neurology & neurosurgery Exome sequencing Genetic testing |
| Zdroj: | Pediatric Neurology. 89:26-30 |
| ISSN: | 0887-8994 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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