Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990–2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. In P301S transgenic mice, chronic Fyn inhibition prevented deficits in spatial memory and passive avoidance learning. The behavioral improvement was coupled with reduced accumulation of phospho-Tau in the hippocampus, with reductions in glial activation and with recovery of presynaptic markers. We extended this analysis to a trauma model in which very mild repetitive closed head injury was paired with chronic variable stress over 2 weeks to produce persistent memory deficits and Tau accumulation. In this model, Fyn inhibition beginning 24 h after the trauma ended rescued memory performance and reduced phospho-Tau accumulation. Thus, inhibition of Fyn kinase may have therapeutic benefit in clinical Tauopathies.

Background: The fragile X premutation carrier state (PM) (55–200 CGG repeats in the fragile X messenger ribonucleoprotein 1, FMR1 gene) is associated with several conditions, including fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor ataxia (FXTAS), with current literature largely primarily investigating older PM individuals. The aim of this study was to identify the prevalence of fragile X-associated neurodevelopmental disorders (FXAND) in a sample of young PM individuals. Methods: This was a retrospective study conducted through a medical record review of PM individuals who were seen either for clinical concerns (probands, 45.9%) or identified through the cascade testing (non-probands, 54.1%) of an affected sibling with fragile X syndrome. Information on the presence of autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, long-term psychiatric medication intake, and cognitive function, based on standardized assessments, was obtained. Molecular data, including CGG repeat number and FMR1 mRNA levels, were also available for a subset of participants. Analysis included descriptive statistics and a test of comparison to describe the clinical profile of PM individuals pertinent to FXAND. Results: Participants included 61 individuals (52 males and 9 females) aged 7.8 to 20.0 years (mean 12.6 ± 3.4) with a mean full-scale IQ of 90.9 ± 22.7. The majority (N = 52; 85.2%) had at least one mental health disorder, with anxiety being the most common (82.0% of subjects), followed by ADHD (66.5%), and ASD (32.8%). Twenty-seven (87.1%) of non-probands also had at least one mental health condition, with probands having lower cognitive and adaptive skills than non-probands. ASD was present in 20 participants (17/52 males and 3/9 females; 15 probands) with significantly lower FSIQ in those with ASD (mean 73.5 vs. 98.0, p < 0.001). Participants with ASD had a higher number of long-term medications compared to those without (2.32 vs. 1.3, p = 0.002). Conclusions: Our findings indicate a high rate of FXAND diagnoses within a cohort of young PM individuals, including those identified via cascade testing, although this was not a population sample. An awareness of the entity of FXAND and the early recognition of the symptoms of associated conditions may facilitate timely and appropriate care for PM individuals.

Introduction: Poor quality sleep has often been cited as a cause of lowered quality of life in patients with affective disorders such as major depressive disorder (MDD) and generalized anxiety disorder (GAD). As sleep and affective disorders are affected by multi‐network interactions, we hypothesize that the modulation of the central executive network (CEN), salience, and default mode networks (DMNs) through individualized repetitive transcranial magnetic stimulation (rTMS) may improve sleep and quality of life.Methods: A retrospective analysis from 2020 to 2023 was conducted in patients with affective disorders at Cingulum Health. Multiple targets were selected based on anomalies detected from individual, functional connectivity networks from a machine‐learning connectivity software. rTMS was conducted with accelerated continuous or intermittent theta burst stimulation (TBS) based on the anomaly detected. Pittsburgh Sleep Quality Index (PSQI), EuroQol (EQ5D), Beck's Depression Inventory (BDI), and the General Anxiety Disorder‐7 (GAD‐7) questionnaires were administered prior to, after, and at follow‐up of rTMS.Results: Twenty‐seven patients were identified, and the most common diagnoses were MDD (41%) or MDD with GAD (41%). All patients had at least one rTMS target in the CEN. The most common target (19 patients) was L8Av in the dorsolateral prefrontal cortex (dlPFC). Patients experienced significant improvements in sleep, quality of life, depressive, and anxiety symptoms after rTMS and during follow‐up. Improvements in sleep correlated with quality of life at follow‐up.Conclusion: This study suggests that personalized, parcel‐guided rTMS is safe and may provide sustained improvements in sleep, quality of life, and affective symptoms for patients with affective disorders.

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60–88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

Background: Not all patients with major depressive disorder (MDD) benefit from the US Food and Drug Administration‐approved use of repetitive transcranial magnetic stimulation (rTMS) at the dorsolateral prefrontal cortex. We may be undertreating depression with this one‐size‐fits‐all rTMS strategy.Methods: We present a retrospective review of targeted and connectome‐guided rTMS in 26 patients from Cingulum Health from 2020 to 2023 with MDD or MDD with associated symptoms. rTMS was conducted by identifying multiple cortical targets based on anomalies in individual functional connectivity networks as determined by machine learning connectomic software. Quality of life assessed by the EuroQol (EQ‐5D) score and depression symptoms assessed by the Beck Depression Inventory (BDI) were administered prior to treatment, directly after, and at a follow‐up consultation.Results: Of the 26 patients treated with rTMS, 16 (62%) attained remission after treatment. Of the 19 patients who completed follow‐up assessments after an average interval of 2.6 months, 11 (58%) responded to treatment and 13 (68%) showed significant remission. Between patients classified with or without treatment‐resistant depression, there was no difference in BDI improvement. Additionally, there was significant improvement in quality of life after treatment and during follow‐up compared to baseline.Limitations: This review is retrospective in nature, so there is no control group to assess the placebo effect on patient outcomes.Conclusion: The personalized, connectome‐guided approach of rTMS is safe and may be effective for depression. This personalized rTMS treatment allows for co‐treatment of multiple disorders, such as the comorbidity of depression and anxiety.