SLC13A5 Deficiency Natural History Study - United States Only

NCT06144957 | Enrolling By Invitation

• 1 other identifier: SLC13A5USNHS
• Study Type: observational
• Target: 17
• Locations: 1 country
• Sites: 3

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. Additionally it will identify clinical and biomarker endpoints for use in future clinical trials.

Conditions

Citrate Transporter Deficiency; Epilepsy; Rare Diseases; Movement Disorders; Genetic Disorder; SLC13A5 Deficiency; EIEE25; Kohlschutter-Tonz Syndrome (Non-ROGDI); Citrate Transporter Disorder; DEE25

Keywords

Epilepsy; Rare Disease; Movement Disorders; Genetic Disorder; Citrate Transporter Disorder; SLC13A5 Deficiency; EIEE25; Neonatal seizures; autosomal recessive; DEE25

Outcome Measures

Primary Outcomes (11)

• Detailed phenotyping of the clinical course of SLC13A5 deficiency over time: general evaluations

  Conducted in patients with SLC13A5 deficiency: general appearance, HEENT, neck, chest and lungs, cardiovascular, abdomen, genitourinary, rectal, musculoskeletal, lymph nodes, extremities/skin, mental status (alertness, interaction, language (EXP) (REC)), emotional affect (calm, smiling, laughing, anxious, frowning, crying, irritable, screaming). As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.

  Up to 24 months

• Detailed phenotyping of the clinical course of SLC13A5 deficiency over time: vitals and biometrics evaluations

  Conducted in patients with SLC13A5 deficiency: height (cm), weight (kg), blood pressure (systolic and diastolic), temperature (c), heart rate (beats/minute), respiratory rate (breaths/minute), and head circumference (cm). As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.

  Up to 24 months

• Detailed phenotyping of the clinical course of SLC13A5 deficiency over time: neurologic evaluation

  Conducted in patients with SLC13A5 deficiency: motor, motor stability, muscle bulk, paresis, sensation, reflexes, coordination, gait, and autonomic. As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.

  Up to 24 months

• Detailed phenotyping of the clinical course of SLC13A5 deficiency over time: dental evaluations

  Conducted in patients with SLC13A5 deficiency: baseline pain assessment from a scale of 0-10 (0 being no pain and 10 being highest pain), temperature pain assessment for cold from a scale of 0-10 (0 being no pain and 10 being highest pain), temperate pain assessment for hot from a scale of 0-10 (0 being no pain and 10 being highest pain), toothpaste use (type and frequency), and Fluoride treatments. As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.

  Up to 24 months

• Detailed phenotyping of the clinical course of SLC13A5 deficiency over time: clinical and research laboratory studies

  Conducted in patients with SLC13A5 deficiency: Clinical: ammonia, amylase, CKMB, GGT, lactate, lipase, PT/PTT, vitamin d 25-oh, CBC with differential, comprehensive MET panel, lipid panel with calculated LDL, and urine studies (calcium/creatinine ratio, spot ph, spot citrate concentration, citrate/creatinine ratio). Research: Citrate and metabolomics. As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.

  Up to 24 months

• Detailed phenotyping of the clinical course of SLC13A5 deficiency over time: electroencephalogram (EEG)

  Conducted in patients with SLC13A5 deficiency: looking at the duration of EEG, if they are captured awake or asleep, and if it is abnormal. As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.

  Up to 24 months

• Detailed phenotyping of the clinical course of SLC13A5 deficiency over time: scoring of movement disorder and SLC13A5 deficiency symptom scales

  Conducted in patients with SLC13A5 deficiency: using scale titled "Movement Exam for SLC13A5 Natural History Study". Assessing typical gait, standing in natural position, sitting on chair, head control, attempt to vocalize, speech quality, speech content, ability to grab items, and ability to draw. Symptom scales consist of chorea, dystonia, ataxia, myoclonus, tremor, hypokinetic-rigid syndrome, and tic. As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.

  Up to 24 months

• Neurodevelopmental profile of SLC13A5 deficiency as measured using Mullen Scales of Early Learning

  Consists of a gross-motor scale and four cognitive scales: visual reception, fine motor, receptive language, and expressive language. T-Scores (mean of 50 and a standard deviation of 10) are given for individual scales, and an optional Early Learning Composite standard score (mean of 100 and a standard deviation of 15) serves as an overall estimate of cognitive functioning. This is based on child's age and there are no higher or lower scores that indicate a better or worse outcome. Developmental assessment at baseline and longitudinally, if age and ability-appropriate.

  Up to 24 months

• Neurodevelopmental profile of SLC13A5 deficiency as measured using the Peabody Developmental Motor Scales-2

  Six subtests that measure motor ability in children: reflexes, stationary, locomotion, object manipulation, grasping, and visual motor integration. The Peabody has quotients that measure a child's motor ability: gross motor quotient, fine motor quotient, total motor quotient. This is based on child's age and there are no higher or lower scores that indicate a better or worse outcome. Developmental assessment at baseline and longitudinally, if age and ability-appropriate.

  Up to 24 months

• Neurodevelopmental profile of SLC13A5 deficiency as measured using the Vineland-III Adaptive Behavior Scale

  Vineland is a semi-structured interview that assesses adaptive behavior in several domains, summarized by the Adaptive Behavior Composite (ABC) standard score. ABC standard scores may range from 20 to 160, with a population mean of 100 and a standard deviation of 15. There are no higher or lower scores that indicate a better or worse outcome. Developmental assessment at baseline and longitudinally, if age and ability-appropriate. Additionally, Vineland-III Adaptive Behavior Scale questionnaire will be included in the remote assessment interview.

  Up to 24 months

• Seizure burden and semiology as measured using the Seizure Global Impression of Change

  Assessing the status of the patient's overall condition using a scale ranging from very much improved, much improved, slightly improved, no change, slightly worse, much worse, very much worse. Assessing the average number of participants' seizures on a scale of decreased, stayed the same, increased. Assessing the average duration of the participants' seizures on a scale of decreased, stayed the same, increased. Caregiver will be asked to maintain a seizure diary throughout the study and seizure burden will be assessed at in-person and remote assessments.

  Up to 24 months

Secondary Outcomes (3)

• Participant quality of life as measured through the Pediatric Quality of Life Inventory (PedsQL) Family Impact

  Up to 24 months

• Participant quality of life as measured through the Pediatric Quality of Life Inventory (PedsQL) Caregiver Epilepsy Module

  Up to 24 months

• Participant sleep disturbances as measured through the Sleep Disturbances Scale for Children (SDSC)

  Up to 24 months

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Study population will consist of children, adolescents, and adults with suspected or confirmed diagnosis of SLC13A5 Deficiency and consistent clinical characteristics.

You may qualify if:

• Parent(s)/legal representative and/or patient must be willing and able to give informed consent/assent for participation in the study.
• Males and females of any age are eligible for this study
• Suspected or confirmed diagnosis of SLC135 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.
• Participant and caregiver must be willing to provide clinical data, participate in standardized assessments, and provide biological samples.
• Willingness to travel to one of the three sites annually is favored, but not required.

You may not qualify if:

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

Sponsors & Collaborators

• TESS Research Foundation: lead
• Stanford University: collaborator
• Brown University: collaborator
• University of Texas Southwestern Medical Center: collaborator

Study Sites (3)

Lucille Packard Children's Hospital, Stanford University

Palo Alto, California, 94304, United States

Location

Brown University

Providence, Rhode Island, 02903, United States

Location

University of Texas Southwestern Dallas

Dallas, Texas, 75390, United States

Location

Related Publications (8)

• 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.

  PMID: 24995870 BACKGROUND

• 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.

  PMID: 26384929 BACKGROUND

• 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.

  PMID: 27261973 BACKGROUND

• 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.

  PMID: 30054523 BACKGROUND

• 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.

  PMID: 28673551 BACKGROUND

• 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.

  PMID: 27913086 BACKGROUND

• 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.

  PMID: 28406943 BACKGROUND

• 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.

  PMID: 27600704 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood and Urine of the Patients and/or their parents will be collected for lab analysis

MeSH Terms

Conditions

Epilepsy; Rare Diseases; Movement Disorders; Genetic Diseases, Inborn; Kohlschutter Tonz syndrome

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Brenda E Porter, MD, PhD

  Stanford University

  PRINCIPAL INVESTIGATOR

• Kimberly Goodspeed, MD, PhD

  University of Texas Southwestern Dallas

  PRINCIPAL INVESTIGATOR

• Judy Liu, MD, PhD

  Brown University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 7, 2022
• First Posted: November 22, 2023
• Study Start: December 1, 2021
• Primary Completion: September 30, 2025
• Study Completion: September 30, 2025
• Last Updated: August 5, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share

Locations

US (3)