Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder

Abstract

Mutations in the SLC13A5 gene, a sodium citrate cotransporter, cause a rare autosomal recessive epilepsy (EIEE25) that begins during the neonatal period and is associated with motor and cognitive impairment. Patient’s seizure burden, semiology, and electroencephalography (EEG) findings have not been well characterized. Data on 23 patients, 3 months to 29 years of age are reported. Seizures began during the neonatal period in 22 patients. Although seizures are quite severe in many patients later in life, seizure freedom was attainable in a minority of patients. Multiple patients’ chronic seizure management included a few common medications, phenobarbital and valproic acid in particular. Patients EEGs had a relatively well-preserved background for age, even in the face of frequent seizures, little slowing and multiple normal EEGs and do not support an epileptic encephalopathy. Other causes for the motor and cognitive delay beyond epilepsy warrant further study.

Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder

“…As SLC13A5 Citrate Transporter Disorder patients age, they experience increasingly severe motor and cognitive delays, along with ongoing seizures [6,7]. Patient weight and height from 2-20 years of age were compared with CDC normative data.…”

“…The SLC13A5 gene and its transcribed protein, NaCT, are highly expressed in the liver at levels thought to be several-fold higher than in the brain [4]. However, the loss of citrate transport, presumably throughout the body, has only been associated with neurologic and dental abnormalities in humans [5][6][7][8][9]. Citrate levels were elevated in the CSF and plasma of the few patients tested [10].…”

Molecular Mechanisms of the SLC13A5 Gene Transcription

“…The effects of genetic variants on gene expressions and associated disease propensity have long been recognized. Accumulating evidence reveals that several non-synonymous mutations of the SLC13A5 gene are phenotypically linked to neonatal epilepsy, developmental delay, and tooth hypoplasia [28,30,82]. Early onset epileptic encephalopathy (EOEE) is a clinically and etiologically heterogeneous subgroup of epilepsy syndromes with a developmental delay and high mortality rate [28].…”

Gene Transfer Therapy for Neurodevelopmental Disorders

“…Patients with SDD almost invariably present with convulsive seizures within the first week of life and often progress to drug-resistant epilepsy that persist throughout the lifespan [100-102, 104, 110]. Most seizures are convulsive (e.g., hemiclonic, myoclonic, and generalized tonic clonic), but some patients are reported to have subclinical seizure, nonconvulsive status epilepticus, and absence or atypical absence seizures [100, 101, 104, 111]. In vivo experiments in Slc13a5 −/− mice recapitulated this aspect of the disease, albeit to a greatly reduced extent, as compared to patients and showed a gender difference with female mice having a more severe susceptibility to seizures [112].…”

“…A characteristic pattern of punctate white matter lesions that progressed to gliosis were identified in a small cohort of SDD patients but are not of clear clinical significance [113]. A review of EEGs of patients with SDD reveals an evolution from status epilepticus with a discontinuous background in the neonatal period, when seizures are at their peak, that improve to normalization of the background with multifocal sharp waves later in life when seizures diminish [111]. Even in patients with a significant seizure burden, the background EEG was well organized and not suggestive of an epileptic encephalopathy [100].…”