SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy

Abstract

Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants to the gene SLC13A5 that results in deficiency of the sodium/citrate cotransporter. Patients typically experience seizure onset within the first week of life and have developmental delay and intellectual disability. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and non-epileptic features of SLC13A5 deficiency disorder. Gene therapy may offer hope to these patients and better clinical outcomes than current available treatments. Here, we discuss SLC13A5 genetics, natural history, available treatments, potential outcomes and assessments, and considerations for translational medical research for an AAV9-based gene replacement therapy.

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

“…The pharmacological outcome of the inhibitors reflects the metabolic changes observed in Slc13a5 -deficient mice [ 14 , 36 ] and they might be promising candidates for modulating NaCT activity. Furthermore, adeno-associated virus (AAV)-based gene replacement therapies [ 85 , 86 ] may be a promising approach for the treatment of patients with impaired NaCT activity but more clinical data are critically needed. To date, effective therapies are severely limited and treatment strategies based on a ketogenic diet or valproate have different outcomes in patients with SLC13A5 deficiency [ 27 , 87 ].…”

Epileptic phenotypes inslc13a5loss-of-function zebrafish are rescued by blocking NMDA receptor signaling

“…Other associated comorbidities include developmental delays, teeth hypoplasia, cognitive impairments, sleeping difficulties and slow motor progress (11)(12)(13). Its Drosophila homolog, Indy, initially was associated with longevity (14) but upon re-examination was found to exhibit a loss of glutamatergic neurons and an overlooked "bang-induced" seizure-like phenotype (15).…”

“…Mutations in SLC13A5 cause developmental epileptic encephalopathy 25 (DEE25) characterized by prolonged and frequent seizures as early as the first day of life (6–10). Other associated comorbidities include developmental delays, teeth hypoplasia, cognitive impairments, sleeping difficulties and slow motor progress (11–13). Its Drosophila homolog, Indy, initially was associated with longevity (14) but upon re-examination was found to exhibit a loss of glutamatergic neurons and an overlooked “bang-induced” seizure-like phenotype (15).…”

“…Individuals suffering from SLC13A5 epilepsy harbor either homozygous or compound heterozygous SLC13A5 pathogenic variants. Anti-seizure medications such as stiripentol or a combination of acetazolamide and valproic acid reduce seizure frequency in some SLC13A5 individuals; however most children are refractory and complete seizure freedom is never attained even in those that do respond to anti-seizure medications (13). In vitro functional studies on several SLC13A5 mutations have revealed disrupted transporter activity pointing towards a loss of function (6, 19), but the molecular mechanisms contributing to seizures are still poorly understood.…”

Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system

“…Since its initial description, there has been a significant increase in knowledge about the etiology and clinical manifestations of this monogenic disorder ( Hardies et al, 2015 ; Anselm et al, 2016 ; Klotz et al, 2016 ; Bainbridge et al, 2017 ; Schossig et al, 2017 ; Weeke et al, 2017 ; Arvio and Lähdetie, 2020 ; Matricardi et al, 2020 ; Yang et al, 2020 ; Brown et al, 2021 ; Duan et al, 2021 ; Goodspeed et al, 2022 ); although as mentioned previously, a comprehensive characterization phenotypically and metabolically is still lacking. Epilepsy is the most common presentation of SLC13A5 citrate transporter disorder due to its neonatal onset.…”