Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts

Abstract

Neonatal epileptic encephalopathies with suppression bursts (SBs) are very severe and relatively rare diseases characterized by neonatal onset of seizures, interictal electroencephalogram (EEG) with SB pattern and very poor neurological outcome or death. Their etiology remains elusive but they are occasionally caused by metabolic diseases or malformations. Studying an Arab Muslim Israeli consanguineous family, with four affected children presenting a severe neonatal epileptic encephalopathy, we have previously identified a mutation in the SLC25A22 gene encoding a mitochondrial glutamate transporter. In this report, we describe a novel SLC25A22 mutation in an unrelated patient born from first cousin Algerian parents and presenting severe epileptic encephalopathy characterized by an EEG with SB, hypotonia, microcephaly and abnormal electroretinogram. We showed that this patient carried a homozygous p.G236W SLC25A22 mutation which alters a highly conserved amino acid and completely abolishes the glutamate carrier's activity in vitro. Comparison of the clinical features of patients from both families suggests that SLC25A22 mutations are responsible for a novel clinically recognizable epileptic encephalopathy with SB.

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.…”

Genetic Testing in Epilepsy: What Should you be Doing?

“…Ohtahara syndrome has also been associated with mutations in ARX (29) and in SLC25A22 encoding a mitochondrial glutamate carrier (30).…”

The Genetics of the Epilepsies

“…It is most commonly associated with underlying structural brain malformations but is related, in other cases, to mutations in a variety of genes (e.g., STXBP1, KCNQ2, SCN2A, ARX, SLC25A22, CDKL5, PNPO, BRAT1, CASK, and PIGA) [19,22,[42][43][44][45][46][47][48]. EME is distinguished from OS by the predominance of myoclonic seizures with burst suppression pattern more prominently seen in sleep.…”