Abstracts

Rationale:
NORSE (New-Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome, a subset of NORSE) are rare, severe seizure presentations in previously healthy adults and children.  A significant percentage of NORSE is of uncertain etiology (i.e. cryptogenic) despite extensive infectious, autoimmune and imaging studies.  Genetic susceptibility may play a role in pathogenesis, but there has not yet been a systematic study of the genetics of this rare disorder, and no genes have been consistently linked with NORSE to date. The purpose of this abstract is to report the results of gene panel testing on patients who survived cryptogenic NORSE, and discuss implications of the findings.
Method:
Case series of all four patients followed at an adult epilepsy center who survived cryptogenic NORSE/FIRES and underwent epilepsy gene panel testing. Serum and CSF autoimmune antibody testing (Mayo), infectious disease testing, and brain imaging (MRI, PET) were unremarkable. The three patients with adult-onset NORSE underwent Invitae epilepsy gene panel testing: a next-generation sequencing (NGS) assay that includes both full-gene sequencing and deletion/duplication analysis of ~150 genes known to be associated with epilepsy and >30 “preliminary-evidence” genes that have early evidence of clinical association with epilepsy. The patient with pediatric-onset NORSE underwent gene testing through Medical Neurogenetics.
Results:
Of the four patients with cryptogenic NORSE, two were found to have pathogenic gene variants and two had multiple variants (three each) of uncertain significance (VUS). Patient A, a Caucasian woman with NORSE onset at age 13, had a pathogenic mutation in POLG1 [c.1399G >A (p.Ala467Thr), heterozygous]. Patient B, a Caucasian man with NORSE onset at age 26, had a pathogenic mutation in PIGG [c.910C >T (p.Arg304*), heterozygous]. Patient C, a Philippian woman with NORSE onset age 34, had VUS (all heterozygous) in CARS2 [s.38C >T (p.Pro13Leu)], CLN3 [c.367 >T (p.Pro123Ser)], and CLN8 [c.290G >T (p.Arg97Leu)]. Patient D, a man of Caucasian and Native American descent with NORSE onset age 33, had VUS (all heterozygous) in CACNA1A [c.1998G >A (silent)], CPA6 [c.1271C >T (p.Ala424Val)], and ST3GAL5 [c.923T >C (p.Ile308Thr)].
Conclusion:
Two of the four patients who survived cryptogenic NORSE had gene panel testing that revealed pathogenic mutations, while the other two patients had multiple VUS in epilepsy-associated genes. The two pathogenic mutations were found in energy metabolism genes (PIGG, POLG) and these variants are typically associated with autosomal recessive epilepsy syndromes. Theoretically, a febrile illness could trigger oxidative stress that could functionally reduce expression or increased metabolism of the gene product(s), possibly precipitating status epilepticus. In the two patients with multiple VUS in epilepsy-associated genes, the results are equivocal; it is possible that one of the genes confers increased risk of NORSE, that polygenic burden increases risk, and/or that these variants are particularly difficult to interpret as benign or pathogenic given these two patients’ non-Caucasian heritage (since the reference population is majority Caucasian).  More research is needed to understand the etiology of cryptogenic NORSE, and genetic susceptibility may play a role in pathogenesis.
Funding:
:none