Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature

Abstract

BackgroundSLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver. Pathogenic variants of the gene cause an autosomal recessive syndrome known as “developmental and epileptic encephalopathy 25 with amelogenesis imperfecta.”ResultsHere, we have investigated six patients from three different consanguineous Saudi families. The affected individuals presented with neonatal seizures, developmental delay, and significant defects in tooth development. Some patients showed other clinical features such as muscle weakness, motor difficulties, intellectual disability, microcephaly, and speech problems in addition to additional abnormalities revealed by electroencephalography (EEGs) and magnetic resonance imaging (MRI). One of the MRI findings was related to cortical thickening in the frontal lobe. To diagnose and study the genetic defects of the patients, whole exome sequencing (WES) coupled with confirmatory Sanger sequencing was utilized. Iterative filtering identified two variants of SLC13A5, one of which is novel, in the families. Families 1 and 2 had the same insertion (a previously reported mutation), leading to a frameshift and premature stop codon. The third family had a novel splice site variant. Confirmatory Sanger sequencing corroborated WES results and indicated full segregation of the variants in the corresponding families. The patients’ conditions were poorly controlled by multiple antiepileptics as they needed constant care.ConclusionConsidering that recessive mutations are common in the Arab population, SLC13A5 screening should be prioritized in future patients harboring similar symptoms including defects in molar development.

The growing research toolbox for SLC13A5 citrate transporter disorder: a rare disease with animal models, cell lines, an ongoing Natural History Study and an engaged patient advocacy organization

“… 1 – 5 It is characterized by frequent, intractable seizures that develop hours or days after birth, hypotonia, global developmental delay, a unique, varied, and difficult to categorize movement disorder, limited expressive verbal capabilities, tooth abnormalities, and increased citrate in both the CNS and serum. 1 – 12 Seizures are frequently medically intractable, patients are often on multiple antiseizure medications and have frequent emergency room visits and hospitalizations for status epilepticus. 3 , 7 , 10 …”