SLC13A5 Deficiency Natural History Study - Remote Only

Epilepsy Clinical Trial

Official title:

SLC13A5 Deficiency: A Prospective Natural History Study - Remote Only (International)

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04681781
• Other study ID #: SLC13A5RMTNHS
• Status: Enrolling by invitation
• Start date: March 1, 2021
• Est. completion date: September 1, 2025

Study information

• Verified date: November 2023
• Source: TESS Research Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 20
• Est. completion date: September 1, 2025
• Est. primary completion date: September 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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. -

Related Conditions & MeSH terms

• 17p13.1 Deletions Confined to SLC13A5 Gene
• Citrate Transporter Deficiency
• Citrate Transporter Disorder
• EIEE25
• Epilepsy
• Genetic Diseases, Inborn
• Genetic Disorder
• Kohlschutter-Tonz Syndrome (Non-ROGDI)
• Movement Disorders
• Rare Diseases
• SLC13A5 Deficiency

Locations

Country	Name	City	State
United States	Lucille Packard Children's Hospital, Stanford University	Palo Alto	California

Sponsors (2)

Lead Sponsor	Collaborator
TESS Research Foundation	Stanford University

Country where clinical trial is conducted

United States, 

References & Publications (9)

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. — View Citation

Hardies K, de Kovel CG, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, Azmi A, May P, Brilstra E, Becker F, Barisic N, Craiu D, Braun KP, Lal D, Thiele H, Schubert J, Weber Y, van 't Slot R, Nurnberg P, Balling R, Timmerman V, Lerche H, Maudsley S, Helbig I, Suls A, Koeleman BP, De Jonghe P; autosomal recessive working group of the EuroEPINOMICS RES Consortium. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain. 2015 Nov;138(Pt 11):3238-50. doi: 10.1093/brain/awv263. Epub 2015 Sep 17. — View 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. — View 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. — View 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. — View 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. — View Citation

Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Juge C, Roubertie A, Heron 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, Riviere 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. doi: 10.1016/j.ajhg.2014.06.006. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	SLC13A5 deficiency motor scale assessments.	Caregiver will be asked to record brief standardized videos capturing the degree of disordered movements. These videos will be made and reviewed for all assessment sessions. Different movements/tasks will be assessed on different scales ranging from 0 to 8. Lesser scores represent better outcome.	Upto 24 months
Primary	Developmental assessment at baseline and longitudinally using Vineland 3	The Vineland Adaptive Behavior Scales, Third Edition (Vineland 3) provides a comprehensive assessment of adaptive function and has been widely used in populations with intellectual and developmental disabilities. It is validated from birth to 90 years, and scores abilities across three core and two optional domains: communication, daily living skills, socialization, and motor skills and maladaptive behaviors, respectively. Completion time for the comprehensive interview is estimated at 50 minutes when all five domains are included. Reliability and validity are widely established. Vineland 3 Adaptive Behavior Scale questionnaire will be included in the remote interviews during the initial visit for baseline assessment and followed at 6 months, 12 months and 24 months for longitudinal neuropsychological assessment	Upto 24 months
Primary	Seizure burden and semiology	Caregiver will be asked to log number and type of seizures for the 4 weeks prior to each remote interview in a seizure tracker form. Reportable seizure types are to include: simple partial seizures (focal onset with retained awareness) WITHOUT motor signs, simple partial seizures WITH motor signs, complex partial seizures (focal onset with impaired awareness), partial (focal) seizures with secondary generalization, absences, myoclonic seizures, clonic seizures, tonic seizures, atonic seizures, and generalized tonic-clonic seizures. In addition, to assess overall change in seizure burden in 4 months between the remote interviews, Seizure Global Impression of Change (Seizure GIC) will be filled at all the remote interviews. Caregiver global impression of change will be assessed using a seven-point Likert scale. In addition, caregiver impression of change in seizure frequency and duration will be assessed using a three-point Likert scale.	Upto 24 months
Secondary	Caregiver Quality of Life (QOL)	Caregiver of patients of ages 2 and up will be asked to fill questionnaires related to PedsQL Family Impact Module and PedsQL Caregiver Epilepsy Module in the initial visit and thereafter at 6 months, 12 months and 24 months. PedsQL Family Impact Module assess the impact of pediatric chronic health conditions on parents/caregiver and family by measuring parent/caregiver self-reported physical, emotional, social, and cognitive functioning, communication, and worry. The PedsQL Epilepsy Module is a 29-item measure with five scales: Impact, Cognitive, Sleep, Executive Function, and Mood/Behavior. The Impact Scale assesses how epilepsy disrupts daily activities, interacting with peers, independence, and increased disease burden due to treatment.	Upto 24 months
Secondary	Sleep disturbances scale for children (SDSC)	Caregiver will be asked to fill a one-page questionnaire to assess dependents disorders of sleep. The Sleep Disturbance Scale for Children (SDSC) is a 27-item inventory rated on a 5 point Likert-type scale. The instrument's purpose is to categorize sleep disorders in children. As well as giving an overall score the instrument uses five subdomains: disorders of initiating and maintaining sleep, sleep breathing disorders, disorders of arousal, sleep-wake transition disorders, disorders of excessive somnolence, and sleep hyperhidrosis.	Upto 24 months