Monday, February 3, 2020

SLC13A5 Deficiency

A foundation established by Menlo Park parents of children who suffer from a rare genetic epilepsy has received a $450,000 grant from the Chan Zuckerberg Initiative (CZI) toward its efforts to find treatments and a cure.

The grant is part of CZI’s newly announced $13.5 million in funding to 30 patient-led organizations working to find treatments and cures for rare diseases, called the Rare As One Project.

The TESS Foundation, founded by Kim and Zach Nye, announced it will use the CZI grant to construct infrastructure aimed at raising funding for collaborative research and a cure for SLC13A5 Deficiency, which causes a lifetime of debilitating seizures that begin within hours of birth. The grant will also fund an international research roundtable in March that will join patients, clinicians, researchers and industry to discuss the issue.

Of the Nyes’ four children, two, 16-year-old Tessa and 6-year-old Colton, suffer from SLC13A5 Deficiency. They launched TESS Research Foundation in 2015. The foundation’s research and collaborations have enabled treatments for the disorder to move into clinical trials within the next two years with sufficient funding, according to CZI.

“As a pediatric neurologist for the past 23 years, I have taken care of many children with severe neurologic disorders, and the quest for a cure seemed like an unrealistic vision,” said Dr. Brenda Porter, professor of neurology and head of the TESS Research Foundation Scientific Advisory Board. “Today, I am excited as the path forward for curing genetic disorders including SLC13A5 may be attainable with tools under development.”

Priscilla Chan, co-founder and Co-CEO of CZI, said her organization is “committed to finding cures for rare diseases.”

“We are proud to support patient-led organizations as they pursue diagnoses, information, and treatment options in partnership with researchers and clinicians,” Chan said.

Alhakeem A, Alshibani F, Tabarki B. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy. Brain Dev. 2018 Oct;40(9):827-829.


SLC13A5-related epileptic encephalopathy is a recently described autosomal recessive disorder that is characterized by infantile epilepsy and developmental delay. Seizures are markedly drug resistant and often induced by fever; they mainly occur in clusters, sometimes evolving into status epilepticus.

We report the use of stiripentol as an adjunctive therapy in three siblings with drug-resistant SLC13A5-related epilepsy. The three patients showed remarkable improvement in the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness.

These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted.

Bainbridge MN, Cooney E, Miller M, Kennedy AD, Wulff JE, Donti T, Jhangiani SN, Gibbs RA, Elsea SH, Porter BE, Graham BH. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. Mol Genet Metab. 2017 Aug;121(4):314-319.


To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay.

Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects.

Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain.

Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease.

Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Jugé C, Roubertie A, Héron D, Mignot C, Raffo E, Isidor B, Wahlen S, Sanlaville D, Villeneuve N, Darmency-Stamboul V, Toutain A, Lefebvre M, Chouchane M, Huet F, Lafon A, de Saint Martin A, Lesca G, El Chehadeh S, Thauvin-Robinet C, Masurel-Paulet A, Odent S, Villard L, Philippe C, Faivre L, Rivière JB. Mutations in SLC13A5 cause
autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life. Am J Hum Genet. 2014 Jul 3;95(1):113-20.


Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.

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