DEPDC5 mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches
Authors: Diallo M. K.C. , Mukesh S. , Kapil L. , Singla R. , Tar D. , Tammineedi S. N. , Singer E. , Chhayani H. , Arumaithurai K. , Patel U. K. , Arora R. 
Published: January 2025

Background. DEPDC5 (disheveled, Egl-10 and pleckstrin domain-containing protein 5) familial epilepsy syndrome is a group of epilepsy disorders caused by mutations in DEPDC5 gene, which is a part of the gap activity towards rag 1 (GATOR1) complex involved in regulating the mechanism target of rapamycin (mTOR) pathway. These mutations lead to hyperactivation of the mTOR pathway, disrupting the shaping of neurons and resulting in increased excitatory transmission and the development of epilepsy. The incidence and prevalence of DEPDC5 familial epilepsy syndrome are not well established, but studies suggest it may account for up to 10% of familial focal epilepsy cases. Genetic testing, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) are important in diagnosing the disorder, although normal MRI results are common.

Objective: to explain the rare sporadic mutation in DEPDC5 gene with p.R389H, a variant of unknown significance.

Case report. A 6-year-old South-Asian girl was born at 34-weeks from non-consanguineous marriage without any prenatal events. She had hyperbilirubinemia by week-1, which was successfully treated with phototherapy. Her initial seizure occurred when she was three months old, just 2 days after the fever from the vaccination had subsided. It was considered a simple-febrile seizure and no treatment was given. At 3.5-months, she started having recurrent seizures. Workup including MRI/ infectious/metabolic panel was non-conclusive. EEG during the initial presentation showed epileptiform activity from the left temporal region. Despite being on multiple anti-epileptic drugs, the child was diagnosed with refractory epilepsy. Subsequently, EEG at 2.5-years showed inter-ictal bi-hemispheric epileptiform activity. EEG at 5-years showed inter-ictal spikes and wave discharges from bilateral fronto-temporal region with secondary generalization. By 3-years, MRI showed mildly deformed corpus callosum with inadequate thickening of splenium. DNA analysis confirmed heterozygous missense mutation in exon 16 of DEPDC5 gene, without chromosomal abnormalities. Mother was heterozygous for the same mutation but no mutations in the father was found. The child has grossly delayed milestones. Corrected age is approximately 1-year for fine motor and language, 1.5-years for gross motor, 2.5-years for cognition, social skills. She had developed autistic features as well with significant impaired auditory/visual processing. She had hypotonia (Right>Left), wide-based gait, and extrapyramidal movements.

Conclusion. DEPDC5 gene mutation results in amino acid substitution of Histidine for Arginine at codon 389. This mutation has shown to be inherited in familial pattern. This R389H variant is not present in the 1000 genomes database and is predicted to be benign. However, It rather appears to be a sporadic mutation, which is a very rarely observed phenomena. Such patients may respond well to mTOR inhibitors such as rapamycin, making prompt diagnosis and treatment crucial.