Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABAB-mediated inhibition compared to controls and NF1 patients, and that GABAA-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

Alteration of Fatty Acid Profile in Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder.

Specific EEG resting state biomarkers in FXS and ASD.

BACKGROUND: Fragile X syndrome (FXS) and autism spectrum disorder (ASD) are neurodevelopmental conditions that often have a substantial impact on daily functioning and quality of life. FXS is the most common cause of inherited intellectual disability (ID) and the most common monogenetic cause of ASD. Previous literature has shown that electrophysiological activity measured by electroencephalogram (EEG) during resting state is perturbated in FXS and ASD. However, whether electrophysiological profiles of participants with FXS and ASD are similar remains unclear. The aim of this study was to compare EEG alterations found in these two clinical populations presenting varying degrees of cognitive and behavioral impairments. METHODS: Resting state EEG signal complexity, alpha peak frequency (APF) and power spectral density (PSD) were compared between 47 participants with FXS (aged between 5-20), 49 participants with ASD (aged between 6-17), and 52 neurotypical (NT) controls with a similar age distribution using MANCOVAs with age as covariate when appropriate. MANCOVAs controlling for age, when appropriate, and nonverbal intelligence quotient (NVIQ) score were subsequently performed to determine the impact of cognitive functioning on EEG alterations. RESULTS: Our results showed that FXS participants manifested decreased signal complexity and APF compared to ASD participants and NT controls, as well as altered power in the theta, alpha and low gamma frequency bands. ASD participants showed exaggerated beta power compared to FXS participants and NT controls, as well as enhanced low and high gamma power compared to NT controls. However, ASD participants did not manifest altered signal complexity or APF. Furthermore, when controlling for NVIQ, results of decreased complexity in higher scales and lower APF in FXS participants compared to NT controls and ASD participants were not replicated. CONCLUSIONS: These findings suggest that signal complexity and APF might reflect cognitive functioning, while altered power in the low gamma frequency band might be associated with neurodevelopmental conditions, particularly FXS and ASD.

Corrigendum: EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome.

[This corrects the article DOI: 10.3389/fpsyt.2021.716707.].

The safety and efficacy of metformin in fragile X syndrome: An open-label study.

Fragile X syndrome (FXS) is a rare genetic disorder characterized by a deficit of the fragile X mental retardation protein (FMRP), encoded by the fragile X mental retardation gene (FMR1) on the X chromosome. It has been hypothesized that the absence of FRMP leads to higher levels of Insulin-like Growth Factor 1 (IGF-1) in the brain, possibly contributing to the intellectual impairment characteristic of the disorder. Preclinical studies have shown that metformin downregulates the insulin/IGF-1 signaling pathway, corrects dendritic defects, and improves repetitive behavior in Fmr1 knockout mice. Here, we conducted an open-label study to evaluate: (1) the safety of metformin in normoglycemic individuals with FXS; and (2) the efficacy of metformin to improve aberrant behavior, attention, and to modulate cortical functioning. Fifteen patients with FXS, aged from 17 to 44, received 500 mg of metformin twice/daily over a 9-week treatment period. The primary outcome measures were: (1) the incidence of adverse events (AE); (2) the decrease in IGF-1 levels; and (3) the global score of the Aberrant Behavior Checklist-Community, Fragile X. The secondary outcomes were: (1) the Test of Attentional Performance for children (KiTAP); and (2) the Transcranial Magnetic Stimulation (TMS) parameters measuring cortical excitability. The metformin treatment was well tolerated, with no significant related AE. The TMS data showed an increase in corticospinal inhibition mediated by GABAA and GABAB mechanisms. This study demonstrates the safety of metformin in normoglycemic patients with FXS, and suggests the potential of this medication in modifying GABA-mediated inhibition, a hallmark of FXS pathophysiology. Implications for future clinical trials are discussed.

Attentional and executive functions in children and adolescents with developmental coordination disorder and the influence of comorbid disorders: A systematic review of the literature.

Developmental coordination disorder (DCD) is a neurodevelopmental disorder affecting primarily motor skills, but attentional and executive impairments are common in affected individuals. Moreover, the presence of neurodevelopmental comorbidities is frequent in this population, which certainly influences the cognitive profile of the children concerned. Previous studies have reported deficits in visuospatial/nonverbal and planning tasks. This systematic review of the literature aims to determine if impairments can be found in other attentional and executive functions as well. The type of cognitive tasks, the tasks' modality (verbal/nonverbal), and the influence of comorbid disorders on attentional and executive profiles are systematically considered. Forty-one studies were identified through the PubMed/Medline and PsycINFO databases according to pre-established eligibility criteria. The results reveal weaknesses in inhibitory control, working memory, planning, nonverbal fluency, and general executive functioning in children with DCD. The presence of comorbid disorders seemingly contributes to the verbal working memory difficulties findings. This review contributes to a better understanding of the cognitive impairments in DCD and of the needs of children with this disorder, allowing to optimize practitioners' therapeutic interventions.

EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome.

Introduction: Fragile X syndrome (FXS) is a genetic disorder caused by a mutation of the fragile X mental retardation 1 gene (FMR1). FXS is associated with neurophysiological abnormalities, including cortical hyperexcitability. Alterations in electroencephalogram (EEG) resting-state power spectral density (PSD) are well-defined in FXS and were found to be linked to neurodevelopmental delays. Whether non-linear dynamics of the brain signal are also altered remains to be studied. Methods: In this study, resting-state EEG power, including alpha peak frequency (APF) and theta/beta ratio (TBR), as well as signal complexity using multi-scale entropy (MSE) were compared between 26 FXS participants (ages 5-28 years), and 7 neurotypical (NT) controls with a similar age distribution. Subsequently a replication study was carried out, comparing our cohort to 19 FXS participants independently recorded at a different site. Results: PSD results confirmed the increased gamma, decreased alpha power and APF in FXS participants compared to NT controls. No alterations in TBR were found. Importantly, results revealed reduced signal complexity in FXS participants, specifically in higher scales, suggesting that altered signal complexity is sensitive to brain alterations in this population. The replication study mostly confirmed these results and suggested critical points of stagnation in the neurodevelopmental curve of FXS. Conclusion: Signal complexity is a powerful feature that can be added to the electrophysiological biomarkers of brain maturation in FXS.