Optical Imaging in X-linked Disorders.

NCT06868979 | Recruiting

• 2 other identifiers: 69HCL23_04092024-A01730-47
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 1

Brief Summary

Fragile X syndrome (FXS, OMIM #300624) and Creatine Transporter Deficiency (CTD, #300352) are the two most common causes of X-linked intellectual disability. FXS and CTD affect hemizygous males and with highly variable severity heterozygous females. Both these neurodevelopmental disorders (NDDs) have a dramatic impact on the family quality of life and the health-care system. These disorders share common clinical traits, including intellectual disability, autistic-like features, behavioural and mood alterations and seizures. Brain anatomy appears largely normal, suggesting that functional deficits result from subtle changes in synaptic connectivity. Moreover, common physiological mechanisms related to brain energetics might concur to the pathophysiology of FXS and CTD. Indeed, FMR1 and SLC6A8 are directly involved in the regulation of metabolism and the loss-of-function of both genes leads to a disruption of the mitochondrial network. There is no cure for these disorders and the efficacy study of potential treatments is hindered by the scarcity of unbiased, quantitative, non-invasive biomarkers for monitoring brain function. This is a critical problem, since the often-used phenotypic observation of behavioural endpoints to score NDDs such as FXS and CTD is highly prone to subjective bias. For successful clinical trials, the availability of objective readouts is crucial to evaluate the therapeutic response to new drugs. There are multiple techniques to visualize neural circuit activity in the living brain. Interestingly, FXS and CTD are the only two NDDs that at preclinical level show an abnormally large hemodynamic response to sensory stimulation in functional imaging studies of intrinsic optical signals. The objective of this project is to exploit optical imaging techniques to devise a measurable and non-invasive biomarker of brain function in FXS and CTD. Since a disruption of brain energy metabolism is a major disease mechanism linking these disorders, we hypothesized that the assessment of the cerebral blood flow and oxygen consumption represents a sensitive readout for quantifying functional alterations of neural circuits. Functional near-infrared spectroscopy (fNIRS), allows quantifying changes of hemoglobin species and local blood flow in the cerebral cortex of humans, providing an indirect measure of neuronal activity. In the clinical framework, this blood-oxygen-level-dependent signal is similar to that detected with functional MRI (fMRI). However, fNIRS has the advantage of being completely non-invasive, low-cost, portable, noiseless, endowed with high experimental flexibility and easy to implement in both laboratory and clinical settings. Moreover, fNIRS is more tolerant to motion artifacts than fMRI, and robust methods for motion detection/correction allow to image very young children without sedation. These methodological strengths make fNIRS as an outstanding choice for investigating neural circuits in clinically relevant populations at the very-low cost. Although introduced into the clinical care almost 40 years ago, fNIRS gained much popularity in the study of brain development and NDDs only recently. To date, however, fNIRS has been used primarily to investigate the typical maturation of speech perception and language, sensory and motor functions, social communication and interaction, object and action processing in toddlers and children. In this proposal, the investigators hypothesize that by combining the above-mentioned strengths of fNIRS to the clinical study of several cognitive and motor parameters, the investigators can define unique "fNIRS signatures" for FXS and CTD as brain biomarkers for the diagnosis and the assessment of treatment outcomes. Since the measurement of visual responses has been introduced as a quantitative method to assess brain function in NDDs, the investigators will test the value of visually-evoked fNIRS signals in classifying patients and predicting symptom severity in the FXS and CTD clinical population. Preliminary data in the mouse models of CTD and FXS strongly suggest that visual hemodynamic responses (vHDR) are markedly altered in the occipital cortex of mutant animals. Morever, the investigators will use a standardized procedure with high entertaining value to measure vHDR in the occipital cortex of children.

Conditions

Fragile X Syndrome (FXS); Creatine Transporter Deficiency

Keywords

Fragile X syndrome; Optical imaging; brain function; Creatine transporter; cognitive function; reasoning tasks

Outcome Measures

Primary Outcomes (2)

• Amplitude of the visual hemodynamic response

  Cortical hemodynamic activity data recorded via fNIRS imaging in response to visual stimulation (task-evoked) using a cartoon-based stimulus. Measure of the amplitude of the peak response to viewing radial checkerboard blended with the animated cartoon for total Hb, OxyHb and DeoxyHb concentration change.

  Inclusion visit

• Latency of the visual hemodynamic response

  Cortical hemodynamic activity data recorded via fNIRS imaging in response to visual stimulation (task-evoked) using a cartoon-based stimulus. Measure of the latency of the peak response to viewing radial checkerboard blended with the animated cartoon for total Hb, OxyHb and DeoxyHb concentration change.

  Inclusion visit

Secondary Outcomes (16)

• Clinical Endpoints_Presence of epilepsy

  Inclusion visit

• Clinical Endpoints_Type of epilepsy

  Inclusion visit

• Clinical Endpoints_Treatment of epilepsy

  Inclusion visit

• Clinical endpoints_Developmental trajectory

  Inclusion visit

• Clinical endpoints_Autism spectrum disorder (ASD)

  Inclusion visit

Study Arms (3)

CTD (Creatine Transporter Deficiency ) patients

OTHER

Male CTD patients having a confirmed mutation in the SLC6A8 gene, aged \> 5 to \< 35 years.

Other: Clinical assessment; Other: Parental questionnaires; Other: Cognitive assessment; Other: Reasoning assessment; Device: fNIRS assessement

FXS (Fragile X Syndrome) patients

OTHER

Male FXS patients having a confirmed full mutation in the FMR1 gene (\>200 GCC repeats), aged \> 5 to \< 35 years.

Other: Clinical assessment; Other: Reasoning assessment; Device: fNIRS assessement

Chronological age-matched controls

OTHER

Male aged \> 5 to \< 35 years.

Other: Clinical assessment; Other: Parental questionnaires; Other: Cognitive assessment; Other: Reasoning assessment; Device: fNIRS assessement

Interventions

Clinical assessment OTHER

Clinical examination including Medical history, developmental trajectory, epilepsy history, ASD symptoms, clinical examination at the inclusion visit by a neuropediatrist

CTD (Creatine Transporter Deficiency ) patients; Chronological age-matched controls; FXS (Fragile X Syndrome) patients

Parental questionnaires OTHER

Parental questionnaires including Vineland-2, ABC, CBCL, PPD-MRS, SRS-2 and BRIEF completed at the inclusion visit

CTD (Creatine Transporter Deficiency ) patients; Chronological age-matched controls

Cognitive assessment OTHER

Cognitive assessment including Leiter-3, PPVT 5, EVT 3 completed at the inclusion visit

CTD (Creatine Transporter Deficiency ) patients; Chronological age-matched controls

Reasoning assessment OTHER

Simple reasoning tasks on tablets performed at the inclusion visit.

CTD (Creatine Transporter Deficiency ) patients; Chronological age-matched controls; FXS (Fragile X Syndrome) patients

fNIRS assessement DEVICE

Imaging session using fNIRS (NIRSport 8x8, NIRx Medical Technologies LLC, Berlin, Germany) performed at the inclusion visit.

CTD (Creatine Transporter Deficiency ) patients; Chronological age-matched controls; FXS (Fragile X Syndrome) patients

Eligibility Criteria

• Age: 5 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• CTD patients :
• male
• having a confirmed mutation in the SLC6A8 gene
• ≥ 5 to ≤ 35 years old
• whose maternal language is French,
• having signed the informed consent and/or for whom parents (for children)/legal guardian (for protected adults) have signed the informed consent.
• affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system
• FXS patients :
• male
• having a confirmed full mutation in the FMR1 gene (\>200 GCC repeats)
• ≥ 5 to ≤ 35 years old
• whose maternal language is French,
• having signed the informed consent and/or for whom parents (for children)/legal guardian (for protected adults) have signed the informed consent.
• affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system
• Chronological age-matched controls :

You may not qualify if:

• CTD patients :
• Refusal of the subject and/or the subject's parents/legal guardian to sign the informed consent
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the neuropsychological assessment.
• FXS patients :
• Refusal of the subject and/or the subject's parents/legal guardian to sign the informed consent
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the neuropsychological assessment.
• Chronological age-matched controls :
• Refusal of the subject and/or the subject's parents/legal guardian to sign the informed consent
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the neuropsychological assessment.
• History of neurological or psychiatric disorder,
• Repetition of a grade,
• Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy).

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (1)

Woman, mother and child hospital, Hospices Civils de Lyon

Bron, 69500, France

RECRUITING

MeSH Terms

Conditions

Fragile X Syndrome; Creatine deficiency, X-linked

Interventions

Mental Status and Dementia Tests

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System

Intervention Hierarchy (Ancestors)

Neuropsychological Tests; Psychological Tests; Behavioral Disciplines and Activities

Central Study Contacts

Aurore CURIE, Dr

CONTACT

+336 70 62 69 76; Aurore.curie@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multicentric prospective, cross-sectional case control study to determine biomarkers to be used in future clinical trials in CTD and FXS patients.

Study Record Dates

• First Submitted: February 14, 2025
• First Posted: March 11, 2025
• Study Start: March 30, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029
• Last Updated: April 1, 2026

Record last verified: 2026-03

Locations

FR (1)