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

Abstract

Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation.Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed.Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes.Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders.

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

“…TESS grantees and research partners have conducted extensive studies on citrate transporter activity as well as measuring citrate of patients’ serum and cerebrospinal fluid (CSF) demonstrating increased citrate levels in all subjects studied to date. 2 , 4 , 5 , 9 , 26 , 29 , 30 Thus, elevated citrate in serum and CSF appears to be an orthogonal, functional molecular marker of the disease and helpful to further confirm the disease etiology in those suspected of SLC13A5 but with VUS on genetic testing. Of note, a recent study using genetic and metabolomics data was able to show that plasma citrate level is a plausible biomarker for SLC13A5 function.…”

“…SLC13A5 citrate transporter disorder is an ultra-rare, autosomal recessive, neurodevelopmental disorder that severely impacts cognition and motor control. 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.…”

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

“…Brain MRI and EEG recordings from SLC13A5 epilepsy patients show punctate white matter lesions and abnormal brain activity, respectively (56, 57). Here, the electrical field recordings, as well as the upregulation of the immediate early gene, fosab, and perturbed E/I balance, is consistent with an epilepsy phenotype in our slc13a5 mutants.…”

Novel Approaches to Studying SLC13A5 Disease

“…Also, some patients experience subclinical seizures, nonconvulsive status epilepticus, and absence or atypical absence seizures [1,2,28]. The primary treatment for these seizures involves anti-seizure medications, although their effectiveness in controlling seizures varies among affected children [9,29]. Despite identifying the pathogenic variants, our understanding of the molecular mechanisms that drive the development of neuronal dysfunction and epilepsy in this context is minimal.…”

“…Pathogenic bi-allelic variants in the gene result in the loss of protein activity, affecting children within a few hours of life with frequent seizures [2]. Children with the same genetic variant present different behaviors and clinical responses, even in closely related genetic backgrounds [9]. Although the precise pathophysiology underlying how loss-of-function variants lead to the clinical phenotype remains unknown, the current hypothesis suggests that the depletion of intracellular citrate may disrupt cellular metabolism in neurons [10].…”