Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder

Abstract

We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients’ records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders.

SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy

“…To date, more than 40 known SLC13A5 variants that lead to epilepsy (including nonsense and missense variants, frame shift variants from single nucleotide polymorphisms, exon deletions, and whole gene deletions) are bi-allelic, with c.655G>A (p.G219R) and c.680C>T (p.T227M) being the most common [ 10 , 11 ]. Individuals with SDD may be homozygous for the loss of function variants of SLC13A5 or have compound heterozygous variants.…”

INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans

“…Most patients have tooth defects caused by lack of enamel. In addition, patients experience mild non-neurological effects such as gastrointestinal, cardiovascular and respiratory complaints ( Brown et al, 2021 ). Early growth is within the normal range but a few adolescent patients experience slower growth ( Brown et al, 2021 ).…”

“…Increased mIndy levels are associated with obesity and insulin insensitivity in patients with non-alcoholic fatty liver disease (NAFLD) ( von Loeffelholz et al, 2017 ). Moreover, mutations in the mIndy coding region and loss of mINDY function in humans are linked to early infantile epileptic encephalopathy and Kohlschütter−Tönz syndrome, which are autosomal recessive diseases characterized by epilepsy, psychomotor delay, intellectual disability, and moderate gastrointestinal and pulmonary defects ( Thevenon et al, 2014 ; Hardies et al, 2015 ; Klotz et al, 2016 ; Brown et al, 2021 ). Differences between beneficial and mild phenotypes associated with deletion of mIndy in mice and deleterious effects associated with the presence of two copies of mutations in the coding region of human mINDY, could be explained by species-specific differences in transporting characteristics, tissue-specific mINDY abundance and the cell-specific role of citrate in metabolism ( Kopel et al, 2021 ).…”

“…In addition, patients experience mild non-neurological effects such as gastrointestinal, cardiovascular and respiratory complaints ( Brown et al, 2021 ). Early growth is within the normal range but a few adolescent patients experience slower growth ( Brown et al, 2021 ). Analysis of plasma, cerebrospinal fluid, and urine from EIEE patients revealed elevated levels of plasma citrate and other TCA cycle intermediates ( Bainbridge et al, 2017 ).…”

“…Mutations in the coding region of human mIndy ( mSLC13A5 ), which would result in a loss of function, lead to early infantile epileptic encephalopathy (EIEE) ( Thevenon et al, 2014 ; Hardies et al, 2015 ; Klotz et al, 2016 ; Matricardi et al, 2020 ; Brown et al, 2021 ). This is a rare autosomal recessive disease that manifests as seizures in children within 24 h of birth, as well as limited speech and motor skills, and developmental delays.…”