Abstracts

Rationale: Gene panels and advanced sequencing can potentially identify pathologic mutations that may not have been suspected based on previously reported manifestations of known disease-causing genes. We have identified over a period of 6 months (July - December, 2011) three patients with mutations of known epilepsy genes who had novel and unexpected presentations. Here we present these cases and discuss the potential implications of our observations. Methods: Retrospective chart review of the above three patients observed over a 6 month period. Investigations for the underlying etiology of refractory seizures were done as clinically indicated. Genetic testing included the Infantile Epilepsy Panel (GeneDx, Gaithersburg, MD; patient 1), the Myoclonus Epilepsy Evaluation and Female Febrile Seizures Evaluation (Athena Diagnostics, Inc., Worcester, MA; patient 2), and whole exome sequencing as part of a research protocol (Katsanis lab Duke University) with subsequent confirmation of the detected mutation in a CLIA approved laboratory (patient 3). Results: Patient 1 presented with agenesis of the corpus callosum, microcephaly, optic nerve hypoplasia, cerebellar hypoplasia and infantile spasms as of the age of 4 months. Extensive workup for possible underlying etiologies was negative except for a disease causing mutation in SLC2A1 which codes for glucose transporter 1. Patient 2 presented with generalized tonic clonic febrile seizure as of the age of 10 months and subsequently developed a clinical picture of progressive myoclonic epilepsy. Extensive work up revealed a disease causing mutations in EFHC1, associated with Juvenile Myoclonic Epilepsy, and in SCN1A. The third presented with severe developmental delay, retinal pigmentary changes, and infantile onset of drug resistant tonic seizures. Testing showed a disease causing mutation in SCN2A and increased lactate peak on MRS but mitochondrial enzyme assays from fibroblast cultures were all normal. Conclusions: (1) Use of gene testing panels and/or exome sequencing can uncover disease causing mutations that would have otherwise not been suspected and can identify novel phenotypic presentations of abnormalities in these genes. (2) Such complex novel phenotypes are likely to be caused by coexistence of other factors, such as other gene mutations, separate from a single epilepsy causing gene mutation.