Clinical trial NCT04681781: SLC13A5 Deficiency Natural History Study - Remote Only
Official title: SLC13A5 Deficiency: a Prospective Natural History Study - Remote Only (International)
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Citrate Transporter Deficiency
Epilepsy
Rare Diseases
Movement Disorders
Genetic Disorder
SLC13A5 Deficiency
EIEE25
Kohlschutter-Tonz Syndrome (non-ROGDI)
17p13.1 Deletions Confined to SLC13A5 Gene
Citrate Transporter Disorder
Keywords: Epilepsy
Rare Disease
Movement Disorders
Genetic Disorder
Citrate Transporter Disorder
SLC13A5 Deficiency
EIEE25
Neonatal seizures
autosomal recessive
Lead sponsor: TESS Research Foundation
Sponsor class: OTHER
Collaborators: name: Stanford University
First posted: 2020-12-23
Enrollment: 20
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Study population will consist of children or adolescents with genetically confirmed diagnosis of SLC13A5 Deficiency and consistent clinical characteristics.

Brief summary: SLC13A5 deficiency (Citrate Transporter Disorder, EIEE 25) is a rare genetic disorder with neurodevelopmental delays and seizure onset in the first few days of life. This natural history study is designed to address the lack of understanding of disease progression and genotype-phenotype correlation. Additionally it will help in identifying clinical endpoints for use in future clinical trials.

Detailed description: This is a longitudinal observational study for the natural history of SLC13A5 deficiency for up to 2 years. This study does not involve any therapeutic intervention. The study includes remote visits which will be done via telephone or remote video conferencing. Translators will be available during these remote visits for non-english speaking caregivers. The initial visit will consist of collecting a detailed medical history and medical records. Prior brain imaging and available EEGs will be collected and reviewed by the study neurologist. Neuropsychological assessments will be made using Vineland Adaptive Behavior Scale version 3. Brief standardized videos recorded by the caregiver will be reviewed and scored by study personnel for movement assessment. Caregiver of ages 2 and up will be asked to complete the QOL Family Impact Module and the QOL epilepsy module. In addition to the initial visit, assessments in 1st year (every 3 months) and 2nd year (every 4 months) of enrollment will be made through remote interviews. Caregiver will be asked to maintain a seizure diary for the duration of the study to assess seizure burden. Personnel having expertise to comprehensively evaluate biological pathways that are perturbed by SLC13A5 deficiency will analyze the collected data. Improved understanding of disease pathogenesis will guide therapeutics and reveal clinical endpoints for use in future clinical trials. Identifying genotype-phenotype correlations can guide prognostication, clinical management, and genetic counseling.

Eligibility criteria: Inclusion Criteria:

1. Parent(s)/legal representative and/or patient must be willing and able to give informed consent/assent for participation in the study.
2. Males and females of any age are eligible for this study
3. Suspected or confirmed diagnosis of SLC13A5 deficiency with genetic variants in both SLC13A5 alleles and consistent clinical characteristics. Variants of uncertain significance in one or both alleles are acceptable if deemed good candidates by participant's primary geneticist or neurologist and study personnel.
4. Participant and caregiver must be willing to provide clinical data and participate in standardized assessments.

Exclusion Criteria:

1. The presence of a second, confirmed disorder, genetic or otherwise, affecting neurodevelopment or with other overlapping symptoms of SLC13A5 deficiency.

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Primary outcomes:
measure: SLC13A5 deficiency motor scale assessments.
timeFrame: Upto 24 months
measure: Developmental assessment at baseline and longitudinally using Vineland 3
timeFrame: Upto 24 months
measure: Seizure burden and semiology
timeFrame: Upto 24 months
Secondary outcomes:
measure: Caregiver Quality of Life (QOL)
timeFrame: Upto 24 months
measure: Sleep disturbances scale for children (SDSC)
timeFrame: Upto 24 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucille Packard Children's Hospital, Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Brenda E Porter, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Klotz J, Porter BE, Colas C, Schlessinger A, Pajor AM. Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Mol Med. 2016 May 26;22:310-21. doi: 10.2119/molmed.2016.00077.
citation: Selch S, Chafai A, Sticht H, Birkenfeld AL, Fromm MF, Konig J. Analysis of naturally occurring mutations in the human uptake transporter NaCT important for bone and brain development and energy metabolism. Sci Rep. 2018 Jul 27;8(1):11330. doi: 10.1038/s41598-018-29547-8.
citation: 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. doi: 10.1016/j.ymgme.2017.06.009. Epub 2017 Jun 24.
citation: Weeke LC, Brilstra E, Braun KP, Zonneveld-Huijssoon E, Salomons GS, Koeleman BP, van Gassen KL, van Straaten HL, Craiu D, de Vries LS. Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations. Eur J Paediatr Neurol. 2017 Mar;21(2):396-403. doi: 10.1016/j.ejpn.2016.11.002. Epub 2016 Nov 19.
citation: Irizarry AR, Yan G, Zeng Q, Lucchesi J, Hamang MJ, Ma YL, Rong JX. Defective enamel and bone development in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient mice. PLoS One. 2017 Apr 13;12(4):e0175465. doi: 10.1371/journal.pone.0175465. eCollection 2017.
citation: Schossig A, Bloch-Zupan A, Lussi A, Wolf NI, Raskin S, Cohen M, Giuliano F, Jurgens J, Krabichler B, Koolen DA, de Macena Sobreira NL, Maurer E, Muller-Bolla M, Penzien J, Zschocke J, Kapferer-Seebacher I. SLC13A5 is the second gene associated with Kohlschutter-Tonz syndrome. J Med Genet. 2017 Jan;54(1):54-62. doi: 10.1136/jmedgenet-2016-103988. Epub 2016 Sep 6.
citation: Yang QZ, Spelbrink EM, Nye KL, Hsu ER, Porter BE. Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder. Child Neurol Open. 2020 Jun 8;7:2329048X20931361. doi: 10.1177/2329048X20931361. eCollection 2020 Jan-Dec.