Drug-Resistant Focal Epilepsy in Infancy with the Development of a West Syndrome in DEPDC5 Mutation: Can Genetic Results Open up Therapeutic Pathways?

Background: The gene DEPDC5 is involved in the pathogenesis of focal idiopathic as well as lesional epilepsies. A pharmacological therapeutic approach can be postulated in the knowledge of the gene function and the relationship to tuberous brain sclerosis (TSC).

Case Report: The 3-month-old daughter of healthy, nonrelated parents developed tonic-psychomotor seizures. Ictal EEG showed left temporocentral seizure patterns and interictal left temporal epileptiform discharges; the MRT was without pathological findings. The epilepsy was therapy resistant for valproic acid, levetiracetam, and oxcarbazepine. Under anticonvulsive therapy, the girl developed a West syndrome. She became seizure free with a combination of prednisolone and vigabatrin.

Results: Currently, the girl is still seizure free and develops well under vigabatrin monotherapy. The EEG shows left temporal sharp waves. A heterozygous DEPDC5 mutation (c.3241A>C; p.Thr1081Pro) was found. DEPDC5 is together with the proteins NPRL2 and NPRL3, a member of the GATOR1 complex. The GATOR1 and GATOR2 complex interacts with the mTOR complex and regulate the activity of the mTOR signaling pathway. In a truncating DEPDC5 mutation, the physiological feedback mechanism of the mTOR pathway is disturbed. Also in TSC, the gene products lead to a lack of inhibition of the mTOR pathway.

Conclusion: Looking at the seizure disorder and the molecular genetic findings, TSC and DEPDC5-positive focal epilepsies share common semiologic and pathophysiological findings. Further studies are needed to review a pharmacological use of Everolimus. Vigabatrin is the therapy of choice in children with TSC and West syndrome; our patient is also seizure free with a low-dose vigabatrin monotherapy. The use of vigabatrin should therefore be considered in difficult-to-treat focal epilepsies with detection of a DEPDC5 mutation.