Abstracts

Rationale: Channelopathies play a crucial role in causing or contributing to various types of epilepsies. Many individuals with channelopathy-related epilepsies have ubiquitous and non-specific presentations. Identification of channelopathies can have an impact on clinical management of epilepsies.Methods: We report on a neurodevelopmentally normal male with longstanding and intractable epilepsy associated with focal and generalized seizure events. Targeted exome DNA sequencing utilizing an epilepsy panel of 489 epilepsy-associated genes (epiSEEK® panel, Courtagen Life Sciences, Woburn, MA) found an unsuspected genetic variant of the TRPM6 gene amenable to magnesium supplementation.Results: A 20-year-old Caucasian male initially presented at three years of age with generalized tonic-clonic seizure events. The mother and maternal uncle and aunt had a history of infantile/childhood febrile seizures. The patient’s seizures have often been prolonged and required rectal diazepam and supplemental oxygen because of cyanosis, and can be preceded by auras. There were also events of status epilepticus requiring hospitalization. Recurrent breakthrough seizures have occurred at irregular intervals over the years despite antiepileptic drug regimens including topiramate, levetiracetam, and lamotrigine. Dense array electroencephalographic (dEEG) results have identified spike and slow wave discharges localizing to the right parietal region. Magnetic resonance imaging (MRI) has been negative. At the age of 19 years, targeted exome DNA sequencing found two autosomal recessive variants of the TRPM6 gene on chromosome 9. Variant one had a nucleotide change of T>C, and the second variant C>G. The first variant (p.Lys1939Glu) was uncommon in the population and poorly conserved through evolution, and the second variant (p.Gln1312His) was rare in the population, moderately conserved through evolution, and predicted deleterious by one of two computer algorithms of protein function. These variants were inherited in “trans” from the mother (variant one) and father (variant two). Based on the exome results, magnesium supplementation was instituted. Subsequently, the patient has been seizure and aura free since.Conclusions: Pathogenic TRPM6 mutations have been reported to cause hypomagnesemia with secondary hypocalcemia, and have been associated with seizures presenting in infancy and young children. This patient has not had identified interictal hypomagnesemia or hypocalcemia, and thus, the effects of the TRPM6 gene variations in this patient may not be dependent on serum electrolyte levels, or may be transient serum electrolyte fluctuations at the time of seizures. Treatment with magnesium supplementation has produced a seizure/aura free state. Patients with non-syndromic epilepsies can have non-specific phenotypes, and thus, results from targeted exome DNA sequencing panels may provide information that can change clinical management.