Page 68 - AN-3-3

Advanced Neurology mTOR inhibition in epilepsy

Figure 3. A summary of the mTOR upstream signaling pathway, integrating extracellular stimuli via receptor tyrosine kinases or G-protein-coupled
proteins (GPCR) and intracellular amino acids or ATP. It involves complex interplay, either stimulation (black arrow) or inhibition (red, blunt arrow),
between positive (pink) and negative regulators (green) of the mTOR signaling network, regulating mTORC activity. The grey boxes with dotted lines
showed the mTORopathies and causative genes or proteins.
Abbreviations: Akt: Ak strain transforming serine-threonine protein kinase; AMPK: Adenosine monophosphate-activated protein kinase;
APC: Adenomatous polyposis coli protein; BOSD: Bottom-of-sulcus dysplasia; CLOVES: Congenital lipomatous overgrowth, vascular malformation,
epidermal nevi, and skeletal/spinal abnormalities syndrome; DEPDC5: Disheveled, Egl-10, and Pleckstrin (DEP) homology domain containing 5;
ERK: Extracellular signal-regulated kinase; FCD II: Focal cortical dysplasia type II; GATOR2: GTPase-activating protein activity towards Rags 2; GNAQ:
Guanine nucleotide-binding protein G(q) subunit alpha; GPCR: G protein-coupled receptor; GSK3: Glycogen synthase kinase-3; LKB1: Liver kinase B1;
MCAP: Megalencephaly-capillary malformation syndrome; MEK: Mitogen-activated protein kinase kinase; MPPH: Megalencephaly-postaxial polydactyly-
polymicrogyria-hydrocephalus syndrome; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; NF-1: Neurofibromin 1; NPRL2: Nitrogen permease
regulator 2-like protein; NPRL3: Nitrogen permease regulator-like 3 protein; PI3K: Phosphatidylinositol 3-kinase; PMSE: Polyhydramnios, megalencephaly,
and symptomatic epilepsy syndrome; PTEN: Phosphatase and tensin homolog; Raf: Rapidly accelerated fibrosarcoma protein; RagA: Ras-related GTP-
binding protein A; RagC: Ras-related GTP-binding protein C; Ragulator: Rregulator of lysosomal signaling with late endosomal/lysosomal adaptor, mapk,
and mtor activator subunits, forming complexes with Rag GTPase; Ras: Rat sarcoma guanosine triphosphatase (GTPase); RHEB: Ras homolog enriched
in brain protein; RSK: Ribosomal s6 kinase; STRADA: STE20-related kinase adaptor alpha; TBC1D7: TBC1 domain family member 7; TSC1: Tuberous
sclerosis 1 or hamartin; TSC2: Tuberous sclerosis 2 or tuberin; Wnt: “wingless-related integration site” protein.

mTORopathies with multisystem involvement, other than epilepsy (PMSE), caused by germline STRADA pathogenic
tuberous sclerosis complex, are very rare. These conditions variants; 25,26 megalencephaly capillary malformation–
include Smith–Kingsmore syndrome caused by germline polymicrogyria syndrome caused by germline and somatic
and somatic MTOR variants; Pretzel syndrome, also known PIK3CA variants; congenital lipomatous overgrowth,
24
27
as polyhydramnios, megalencephaly, and symptomatic vascular malformation, epidermal nevi, scoliosis/skeletal
Volume 3 Issue 3 (2024) 4 doi: 10.36922/an.3568