Clinical trial NCT04308954: Neuroimaging GABA Physiology in Fragile X Syndrome
Official title: Cross-Species Multi-Modal Neuroimaging to Investigate GABA Physiology in Fragile X Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Fragile X Syndrome (FXS)
Idiopathic Intellectual Developmental Disorder (IDD)
Keywords: FXS, Intellectual Disability
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2020-03-16
Enrollment: 17
Sex: MALE
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 15 male subjects with FXS will be compared to 15 subjects with idiopathic intellectual developmental disorder, who will be the control group. Young male adults with idiopathic intellectual developmental disorder will be (group) matched to FXS participants for mean age (and age range), handedness, socioeconomic status and ethnicity.
Primary purpose: BASIC_SCIENCE

Brief summary: 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).

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Non-displaceable binding potential of [18F]flumazenil (F18 FMZ)
timeFrame: Up to 2 hours per scan on a single study day
measure: GABA (A) receptor density in fragile X syndrome (FXS) patients relative to control group comprising individuals with idiopathic Intellectual Developmental Disorder (IDD)
timeFrame: Up to 2 hours per scan on a single study day
Secondary outcomes:
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Frederick T Chin, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lucignani G, Panzacchi A, Bosio L, Moresco RM, Ravasi L, Coppa I, Chiumello G, Frey K, Koeppe R, Fazio F. GABA A receptor abnormalities in Prader-Willi syndrome assessed with positron emission tomography and [11C]flumazenil. Neuroimage. 2004 May;22(1):22-8. doi: 10.1016/j.neuroimage.2003.10.050.
citation: Holopainen IE, Metsahonkala EL, Kokkonen H, Parkkola RK, Manner TE, Nagren K, Korpi ER. Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA(A) receptor beta3 subunit deletions. Ann Neurol. 2001 Jan;49(1):110-3. doi: 10.1002/1531-8249(200101)49:13.0.co;2-t.