Impaired Mitochondrial Glutamate Transport in Autosomal Recessive Neonatal Myoclonic Epilepsy

Abstract

Severe neonatal epilepsies with suppression-burst pattern are epileptic syndromes with either neonatal onset or onset during the first months of life. These disorders are characterized by a typical electroencephalogram pattern--namely, suppression burst, in which higher-voltage bursts of slow waves mixed with multifocal spikes alternate with isoelectric suppression phases. Here, we report the genetic mapping of an autosomal recessive form of this condition to chromosome 11p15.5 and the identification of a missense mutation (p.Pro206Leu) in the gene encoding one of the two mitochondrial glutamate/H(+) symporters (SLC25A22, also known as "GC1"). The mutation cosegregated with the disease and altered a highly conserved amino acid. Functional analyses showed that glutamate oxidation in cultured skin fibroblasts from patients was strongly defective. Further studies in reconstituted proteoliposomes showed defective [(14)C]glutamate uniport and [(14)C]glutamate/glutamate exchange by mutant protein. Moreover, expression studies showed that, during human development, SLC25A22 is specifically expressed in the brain, within territories proposed to contribute to the genesis and control of myoclonic seizures. These findings provide the first direct molecular link between glutamate mitochondrial metabolism and myoclonic epilepsy and suggest potential insights into the pathophysiological bases of severe neonatal epilepsies with suppression-burst pattern.

AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate

“…Recognized genes function as ion channels (SCN1A, SCN2A, SCN8A, KCNQ2, KCNT2), transcription factors (ARX, ARHGEF9, CDKL5, PLCB1), synaptic proteins (PNKP, PCDH19, SPTAN1, STXBP1), a mitochondrial glutamate symporter that transports glutamate and a hydrogen ion across the inner mitochondrial membrane (SLC25A22), and now another gene associated with inner mitochondrial membrane glutamate transport (SLC25A12). While SLC25A22 mutation patients manifest both early myoclonic epilepsy and ohtahara-type early epileptic encephalopathy (Molinari et al 2005(Molinari et al , 2009Poduri et al 2013), the SLC25A12 mutation patients' epilepsy resembles instead the non-myoclonic variant. Overall, this report establishes SLC25A12 as a likely early-onset epileptic encephalopathy gene and emergence of altered glutamate handling as a functional subclass.…”

Mitochondrial Disease in Childhood: Nuclear Encoded

“…Nuclear mitochondrial genes that have been associated with epilepsy include POLG and other mtDNA depletion syndromes, complex I deficiency, complex II deficiency (SDHA), complex III deficiency (BCS1L), complex IV deficiency, FOXRED1, SCO2, TMEM70, MTATP6, CoQ10 deficiency, RARS2, TFSM, and SLC25A22. SLC25A22 is the solute transporter for glutamate and mutations in this gene have been associated with neonatal/early infantile epileptic encephalopathy with burst suppression electroencephalography (Otohara syndrome) [111]. From the first few days of life, infants have myoclonic and focal seizures, followed by microcephaly, hypotonia, and global developmental delay.…”

Novel Animal Models of Pediatric Epilepsy

“…However, TSC2 GFAP CKO mice have an earlier onset (3 weeks in TSC2 GFAP CKO vs 4 weeks in TSC1 GFAP CKO) and higher frequency of seizures (30)(31)(32)(33)(34)(35) Sz/48 h at 7 weeks in TSC2 GFAP CKO vs less than 10Sz/ 48 h at 7 weeks in TSC1 GFAP CKO), and significantly more severe histological abnormalities. The differences between these 2 transgenic mice seem to be correlated with higher levels of mTOR activation in TSC2 GFAP CKO mice.…”

“…Metabolic etiologies predominate in EME, whereas malformative etiologies predominate in EIEE. A family with an autosomal recessive form of EME enabled the identification of a missense mutation in the gene encoding the mitochondrial glutamate/proton "symporter" GC1 [32]. The identification of mutant GC1 as an etiology of EME also emphasizes the importance of the mitochondrial component of glutamate metabolism in normal brain function.…”