Objective: Voltage-gated sodium channel (Na v )-encoding genes are among early-onset epileptic encephalopathies (EOEE) targets, suggesting that other genes encoding Na v -binding proteins, such as fibroblast growth factor homologous factors (FHFs), may also play roles in these disorders. Methods:To identify additional genes for EOEE, we performed whole-exome sequencing in a family quintet with 2 siblings with a lethal disease characterized by EOEE and cerebellar atrophy. The pathogenic nature and functional consequences of the identified sequence alteration were determined by electrophysiologic studies in vitro and in vivo.Results: A de novo heterozygous missense mutation was identified in the FHF1 gene (FHF1A R114H , FHF1B R52H ) in the 2 affected siblings. The mutant FHF1 proteins had a strong gain-of-function phenotype in transfected Neuro2A cells, enhancing the depolarizing shifts in Na v 1.6 voltage-dependent fast inactivation, predicting increased neuronal excitability. Surprisingly, the gain-of-function effect is predicted to result from weaker interaction of mutant FHF1 with the Na v cytoplasmic tail. Transgenic overexpression of mutant FHF1B in zebrafish larvae enhanced epileptiform discharges, demonstrating the epileptic potential of this FHF1 mutation in the affected children.Conclusions: Our data demonstrate that gain-of-function FHF mutations can cause neurologic disorder, and expand the repertoire of genetic causes (FHF1) and mechanisms (altered Na v gating) underlying EOEE and cerebellar atrophy. Neurology ® 2016;86:2162-2170 GLOSSARY EOEE 5 early-onset epileptic encephalopathies; FHF 5 fibroblast growth factor homologous factor; Na v 5 voltage-gated sodium channel; OE 5 overexpression; WT 5 wild-type.Early-onset epileptic encephalopathies (EOEE) are characterized by progressive diffuse brain dysfunction with recurrent seizures starting during the neonatal or early infantile periods. These epilepsies are among the most severe, with the child typically experiencing multiple seizure types, which are often refractory to antiepileptic drugs, in the setting of developmental delay or regression. Epileptic encephalopathies can worsen over time, and the epileptic activity itself may contribute to severe cognitive, neurologic, and behavioral impairments above and beyond what might be expected from the underlying pathology alone.1 EOEE represent a broad spectrum of phenotypes that are highly heterogeneous at the clinical and molecular levels. Whereas a number of genetically determined (monogenic) forms have been recognized, in clinical practice many cases remain of unknown etiology.2 Of the genetic mutations known to be linked to EOEE, several are missense mutations in SCN8A encoding the a pore-forming subunits of the voltage-gated sodium channel (Na v ) 1.6, 3-5 with some of these mutations acting in a gain-offunction manner to enhance sodium channel current.3,4 So far there has been no report of EOEE caused by mutation of sodium channel-binding proteins, such as fibroblast growth factor *These aut...

Summary Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.