Neuroimaging GABA Physiology in Fragile X Syndrome

Stanford University

Status and phase: Terminated; Phase 1

Conditions: Idiopathic Intellectual Developmental Disorder (IDD); Fragile X Syndrome (FXS)

Treatments: Drug: [18F]flumazenil

Study type: Interventional

Funder types: Other

Identifiers

NCT04308954

IRB 32149

Details and patient eligibility

About

The investigators wish to compare the brain distribution of GABA(A) receptors and GABA levels in young adult males with Fragile X Syndrome compared to idiopathic intellectual developmental disorder. The radiopharmaceutical [18F]flumazenil has been used to study GABA(A) receptor distribution in other genetic syndromes with autistic features; however, despite overwhelming evidence supporting the importance of the GABAergic system in FXS, no clinical investigation of this system in human FXS has been reported in the literature. Therefore, this study will provide the first in vivo comprehensive examination of the GABAergic system in FXS using hybrid positron emission tomography/ magnetic resonance imaging (PET/MRI).

Full description

Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder (ASD). Converging evidence suggests that GABAergic dysfunction occurs in FXS. The investigators wish to examine brain distribution of GABA (A) receptors in young adult males with FXS using hybrid PET/MRI with [18F]flumazenil. This project will study the distribution of GABA(A) receptors in 15 young male adults with FXS (18-30 years old) compared to 15 age-matched male subjects with idiopathic intellectual developmental disorder (IDD) as controls. Simultaneous PET/MRI acquisition is an optimal technique to study in vivo GABAergic dysfunction and GABAa receptor distribution.

Enrollment: 17 patients

Sex: Male

Ages: 18 to 30 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria for participants with FXS:

1. Have an established diagnosis of FXS (full mutation with aberrant FMR1 methylation) by genetic testing
2. Diagnosis of intellectual disability
3. Males who are physically healthy
4. Age 18 to 30 years inclusive
5. IQ between 40 and 80 points
6. Ability to remain seated for more than 10 minutes
7. Ability to travel to Stanford

Exclusion criteria for participants with FXS:

1. Diagnosis of a known genetic disorder (other than FXS).
2. Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders.
3. Significant sensory impairments such as blindness or deafness.
4. DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia.
5. Pre-term birth (<34 weeks' gestation) or low birth weight (<2000g).
6. Current use of benzodiazepines.
7. Contraindication for PET or MRI.

Inclusion criteria for participants with IDD:

1. Age 18 to 30 years inclusive
2. Adults who are physically healthy
3. No significant recent changes in psychosocial stressors per history
4. Diagnosis of intellectual disability
5. IQ between 40 and 80 points
6. Ability to remain seated for more than 10 minutes
7. Ability to travel to Stanford

Exclusion Criteria for participants with IDD:

1. Genetic diagnosis of FXS.
2. Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders.
3. Significant sensory impairments such as blindness or deafness.
4. DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia.
5. Pre-term birth (<34 weeks' gestation) or low birth weight (<2000g).
6. Current use of benzodiazepines.
7. Contraindication for PET or MRI.

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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17 participants in 2 patient groups

Fragile X Syndrome

Experimental group

Description:

Adult males aged 18-30 years diagnosed with FXS will undergo a non-invasive F18 FMZ PET/MRI scan to determine GABA(A) receptor density; developmental dynamics of GABA(A) receptor distribution, and structural neuroanatomy and connectional anatomy.

Treatment:

Drug: [18F]flumazenil

Idiopathic Intellectual Developmental Disorder

Experimental group

Description:

Adult males aged 18-30 years diagnosed with idiopathic intellectual developmental disorder will undergo a non-invasive F18 FMZ PET/MRI scan to determine GABA(A) receptor density; developmental dynamics of GABA(A) receptor distribution, and structural neuroanatomy and connectional anatomy.

Treatment:

Drug: [18F]flumazenil