Citrate Transporter Deficiency, SLC13A5 Gene Mutation
Conditions
Keywords
citrate transporter deficiency, SLC13A5 gene, citric acid cycle, energy metabolism
Brief summary
The purpose of this study is to determine whether triheptanoin (UX007) is effective in the treatment of neurological symptoms related to citrate transporter deficiency (SLC13A5 gene mutation).
Detailed description
This compassionate use research study has been developed to study an investigational drug, triheptanoin (UX007), for the treatment of neurological symptoms related to citrate transporter deficiency, a disease with no existing treatment. The hypothesis is that triheptanoin will restore deficient energy metabolism in these patients, leading to improved seizure control, mental clarity, and physical strength. Based on the literature, the SLC13A5 gene product is a citrate transporter. However, there is the possibility that other compounds are transported as well. The gene may be expressed in human neurons and function at the level of the plasma membrane. The hypothesis is that the transport of citrate across the plasma membrane from the extracellular space into the cytoplasm plays a role in maintaining the pool size of citrate in both the cytoplasm and mitochondrial matrix. Triheptanoin therapy may increase the metabolism of odd-chain fatty acids in neuronal mitochondria and thereby increase the levels of succinyl-CoA, leading to an increase in citrate concentrations. The increased level of citrate in the mitochondrial matrix may lead to an increased efflux of citrate from the matrix to the cytoplasm, thus increasing the cytoplasmic pool of citrate and allowing the malfunctioning citrate transporter to be bypassed. If successful, triheptanoin treatment will improve neuronal function and lead to an improvement in CNS function for patients. While investigators will follow the course of subjects with considerable interest and may use some of the collected data for clinical research, this study is done for humanitarian reasons.
Interventions
DRUGtriheptanoin
Triheptanoin (UX007) is a medium chain triglyceride of three seven-carbon fatty acids (C7), on a glycerol backbone, with a molecular formula of C24H44O6. It is being evaluated as a substrate replacement therapy for the treatment of long-chain fatty acid oxidation disorders (LC-FAOD) and for the treatment of seizures associated with Glut 1 DS. Triheptanoin is metabolized to provide substrate replacement for both fatty acid metabolism and anaplerosis (replacement of TCA cycle intermediates) required to restore the efficient generation of energy and the net production of glucose in patients. The mechanism of action of triheptanoin in restoring energy metabolism is dependent on its medium-chain length as well as its odd-carbon properties. Triheptanoin is a highly purified form intended for oral administration.
Sponsors
Irina A Anselm
Eligibility
Sex/Gender
ALL
Age
4 Years to 9 Years
Inclusion criteria
* Diagnosis of citrate transporter deficiency due to mutations in the SLC13A5 gene. * Presentation with severe global developmental delay and seizures.
Exclusion criteria
* Valproate is an AED that partially inhibits the TCA cycle via alpha-ketoglutarate dehydrogenase and should not be administered to subjects taking UX007.
Countries
United States
Outcome results
None listed