Anti-PARS2 monoclonal antibody Made to order

Biallelic pathogenic variants in mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) PARS2 are associated with mitochondrial cytopathy. Here, we report the tenth case of an individual with biallelic PARS2 pathogenic variants, detected by exome sequencing (ES), and a literature review of ten cases of PARS2 mutations. Our patient displayed symptoms and clinical and laboratory findings similar to those reported previously with normal lactate levels. These symptoms included seizure disorder (which was managed with antiepileptics), developmental delay, and progressive cardiomyopathy which manifested at 19 years of age. The patient received a vitamin regimen including antioxidants as part of his treatment regimen. While further studies are required to conclusively establish the beneficial role of vitamin and cofactor administration on the mitochondria in PARS2-associated mitochondrial disease, these factors may have delayed the onset of cardiomyopathy.

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.G1n56Arg) and c.631T>A (p.Phe211lle) 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. (C) 2018 Elsevier Inc. All rights reserved.