GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

Abstract

The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non‐lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.

Laser interstitial thermal therapy for NPRL3-related epilepsy with multiple seizure foci: A case report

“…Given that the brain MRI and PET were normal, the MCD may be related only to altered cortical lamination in this patient, although the tissue was not biopsied so could not be confirmed by histopathology. The clinical manifestations in this case were consistent with those of NPRL3 variants reported in the literature [1] , [2] . Intellectual function, neurological examination, and neuroimaging were normal.…”

“…NPRL3 (nitrogen permease regulator-like 3) variants have been linked to familial focal cortical dysplasia type II, which is pathologically characterized by dysmorphic neurons and balloon cells [1] , [2] . Mutations in the NPRL3 gene cause an autosomal dominant familial focal epilepsy with variable foci (FFEVF) characterized by focal seizures originating from different cortical regions, including temporal, frontal, parietal, and occipital lobes [3] .…”

Current Approaches and Future Directions for the Treatment of mTORopathies

“…Recent sequencing studies revealed that somatic brain mutations in mTOR regulators including mTOR itself, PIK3CA , RHEB , AKT3 , TSC1 , and TSC2 [79-82] can result in FCD (Table 1) [81, 83]. In addition, mutations in DEPDC5 , NPRL2 , and NPRL3 , which are components of the mTORC1 inhibitor GATOR complex 1 [84], have been linked to FCD, infantile spasms, focal epilepsy, and sudden unexpected death in epilepsy [85-87].…”

Variants inCHRNB2andCHRNA4Identified in Patients with Insular Epilepsy

“…[31][32][33][34] More specifically, it has been described in various lesional and nonlesional epileptic disorders such as familial focal epilepsy with variable foci or ADNFLE. [31][32][33][34][35][36] The "two-hit" mutational hypothesis may explain the presence of the c.77C>T (p. Thr26Met) variant in CHRNB2 in the asymptomatic father of one of our patients. While both this patient and her father are carrying the c.77C>T (p. Thr26Met) germline variant in CHRNB2, only she would by carrying the second, somatic, CHRNB2 variant in her brain cells resulting in the epileptogenesis.…”