Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: A case report

Abstract

Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898‐164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3‐like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.

Everolimus precision therapy for the GATOR1‐related epilepsies: A case series

“…Sirolimus treatment produced varied outcomes in two infants with NPRL3 ‐related hemimegalencephaly. One infant had reduced seizures but stopped treatment after 3.5 months due to recurrent infections [15], while the other stopped sirolimus after 17 days due to lack of efficacy [16].…”

Refractory neonatal seizures caused by hemimegalencephaly

“…Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures. 7 Similarly, Kulkarni et al 5 reported a term infant with HME who had more than 90% reduction in seizures with good developmental outcome on follow-up after hemispherectomy. In addition, Chand and colleagues 8 reported a neonate who presented with focal seizures.…”

“…The intractable seizures in the context of this condition usually necessitate anatomical or functional hemispherectomy to provide effective seizure control. Chandrasekar and colleagues7 reported a female newborn who had refractory seizures due to HME. WES analysis revealed a likely pathogenic deletion involving the NPRL3 (nitrogen permease regulator 3-like protein) gene, which is involved in the mammalian target of rapamycin (MTOR) signalling pathway.…”

“…However, sirolimus, an MTOR inhibitor drug, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures 7…”

SEA and GATOR 10 Years Later

“…Cases with simultaneous mutations in different GATOR1 genes have not been described thus far. Several Nprl2 or Nprl3 variants found in individuals with FCD or hemimegaloencephaly (HME) have been reported recently [184,185]. Interestingly, NPRL3 single nucleotide polymorphism has been associated with ischemic stroke susceptibility and post-stroke mortality [186], which can be related with increased mTOR activity, that is known to accelerate brain recovery after stroke.…”