Novel Variant in ARHGEF15 is Associated with Epilepsy with Myoclonic-atonic Seizures in a Pediatric Patient
Aditi Trivedi1, Shannon Kilty2, Maria Montenegro1, Shifteh Sattar1, Jong M. Rho1
1Neurosciences, UCSD/Rady Children's Hospital San Diego Pediatric Neurology, 2Neurosciences, Rady Children's Hospital San Diego Pediatric Neurology
Objective:
Currently there is an incomplete understanding about the role of ARHGEF15 variants in epilepsy. Here we report - to our knowledge - the first-ever correlation between a specific variant in the ARHGEF15 gene, and a severe form of epilepsy, epilepsy with myoclonic-atonic seizures (EMAS). This case also offers a potentially favorable treatment in patients with such variants, by utilizing the ketogenic diet.
Background:
A previously healthy 3-year-old presented with a 2-week history of progressive episodes of drop spells and arm jerking movements. His video EEG captured spells consistent with electroclinical myoclonic-atonic seizures. The interictal background showed recurrent generalized epileptiform discharges and extremely high amplitude generalized 2-3Hz delta slowing. A brain MRI study was interpreted as normal. The presentation and diagnostics were overall consistent with EMAS. A multigene panel revealed a variant of uncertain significance, c.317G>T (p.Arg106Leu) on ARHGEF15. PolyPhen-2 analysis predicted this missense change to be likely disruptive to protein structure and function. The patient experienced initial improvement with levetiracetam and clobazam, but seizures continued. He was later started on a ketogenic diet and maintained seizure freedom with both classic (3:1, 4:1) and liberal (2:1) ratios for at least 6 months.
Conclusions:
This is the first case describing a particular variant in ARHGEF15 associated with EMAS. The ARHGEF15 gene, on chromosome 17 encodes the Rho guanine nucleotide exchange factor 15 (GEF), which regulates activity of RhoA and downstream effector molecules. In vitro knockout studies on this gene showed an overexpression of excitatory synapses which may help explain its role in epileptogenesis. The decrease in GEF activity from this disruptive variant, dysregulates RhoA activity, leading to increased excitatory activity in the brain, thought to cause epilepsy. This case also suggests the ketogenic diet may be an effective treatment for patients with such variants, potentially leading to seizure freedom as seen in this child.