Unmethylated Mosaic Full Mutation Males without Fragile X Syndrome.

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (ID) and single gene cause of autism. Although most patients with FXS and the full mutation (FM) have complete methylation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, some have mosaicism in methylation and/or CGG repeat size, and few have completely unmethylated FM alleles. Those with a complete lack of methylation are rare, with little literature about the cognitive and behavioral phenotypes of these individuals. A review of past literature was conducted regarding individuals with unmethylated and mosaic FMR1 FM. We report three patients with an unmethylated FM FMR1 alleles without any behavioral or cognitive deficits. This is an unusual presentation for men with FM as most patients with an unmethylated FM and no behavioral phenotypes do not receive fragile X DNA testing or a diagnosis of FXS. Our cases showed that mosaic males with unmethylated FMR1 FM alleles may lack behavioral phenotypes due to the presence of smaller alleles producing the FMR1 protein (FMRP). However, these individuals could be at a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) due to the increased expression of mRNA, similar to those who only have a premutation.

Open-Label Sulforaphane Trial in FMR1 Premutation Carriers with Fragile-X-Associated Tremor and Ataxia Syndrome (FXTAS).

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.

Fragile X Syndrome and Fetal Alcohol Syndrome: Occurrence of Dual Diagnosis in a Set of Triplets.

BACKGROUND: Fragile X syndrome (FXS) and fetal alcohol syndrome disorders are both common causes of intellectual disability in children. When both conditions are present in the same individual, the resultant phenotype may make identification of clinical issues and management challenging. CASE PRESENTATION: In this case report, we present a case of triplets who had significant in utero alcohol exposure; 2 of whom also have FXS and the other not having the fragile X mutation. The siblings with FXS have subtle differences in the physical phenotype compared with the other one, who has prominent features of partial fetal alcohol syndrome instead. However, all 3 siblings have intellectual impairment (although this is more severe in the 2 with FXS), meet diagnostic criteria for autism spectrum disorder, and present with severe behavioral challenges. The clinical presentation of the 2 siblings with FXS is much more severe as compared to a child with FXS alone, and this is likely due to the additive effect of in utero alcohol exposure and environmental factors. We discuss the combination of these 2 pathologies and how this can affect the overall clinical presentation. CONCLUSION: In the management of children with FXS, evaluation for other risk factors that can have neurobehavioral sequelae is important, and these can affect clinical presentation and prognosis.

Clinical implications of somatic allele expansion in female FMR1 premutation carriers.

Carriers of a premutation allele (PM) in the FMR1 gene are at risk of developing a number of Fragile X premutation asssociated disorders (FXPAC), including Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-associated neuropsychiatric disorders (FXAND). We have recently reported somatic CGG allele expansion in female PM; however, its clinical significance remains unclear. The aim of this study was to examine the potential clinical association between somatic FMR1 allele instability and PM associated disorders. Participants comprised of 424 female PM carriers age 0.3- 90 years. FMR1 molecular measures and clinical information on the presence of medical conditions, were determined for all subjects for primary analysis. Two sub-groups of participants (age ≥ 25, N = 377 and age ≥ 50, N = 134) were used in the analysis related to presence of FXPOI and FXTAS, respectively. Among all participants (N = 424), the degree of instability (expansion) was significantly higher (median 2.5 vs 2.0, P = 0.026) in participants with a diagnosis of attention deficit hyperactivity disorder (ADHD) compared to those without. FMR1 mRNA expression was significantly higher in subjects with any psychiatric disorder diagnosis (P = 0.0017); specifically, in those with ADHD (P = 0.009), and with depression (P = 0.025). Somatic FMR1 expansion was associated with the presence of ADHD in female PM and FMR1 mRNA levels were associated with the presence of mental health disorders. The findings of our research are innovative as they suggest a potential role of the CGG expansion in the clinical phenotype of PM and may potentially guide clinical prognosis and management.

Tophaceous gout of the nose in a male FMR1 premutation carrier.

Premutation alleles with 55-200 CGG repeats in FMR1 can lead to fragile X-associated tremor/ataxia syndrome (FXTAS). In this case study, we report uncontrolled gout in a 68-year-old male with FXTAS with multiple sites of involvement including a rare gouty tophus in the nasal region.

Increased Pain Symptomatology Among Females vs. Males With Fragile X-Associated Tremor/Ataxia Syndrome.

Individuals with the fragile X premutation report symptoms of chronic pain from multiple systems, have increased incidence of comorbid conditions where pain is a prominent feature, and pathophysiology that supports disrupted pain regulation, inflammation, and energy imbalance. Less is known about how pain manifests for the subpopulation of carriers that develop the motor and cognitive changes of fragile X-associated tremor and ataxia syndrome (FXTAS), and how pain may differ between men and women. We gathered data collected from 104 males and females with FXTAS related to chronic pain, comorbid conditions related to pain, and medications used for pain control to further explore the types of pain experienced and to better characterize how individuals with the fragile X premutation experience pain sensation across genders. We found that women experience significantly more pain symptoms than men, particularly allodynia (20 vs. 2.0%, p = 0.008), peripheral neuropathy pain (43.9 vs. 25.4%, p = 0.0488), migraine (43.9 vs. 14.5%, p = 0.0008), fibromyalgia (26.8 vs. 0%, p = 0.0071) and back pain (48.5 vs. 23.4%, p = 0.008). We found onset of peripheral neuropathy predicts the onset of ataxia (ß = 0.63 ± 0.25, p = 0.019) and tremor (ß = 0.56 ± 0.17, p = 0.004) across gender. Women also report significantly more anxiety (82.9 vs. 39.7%, p < 0.001), which has implications for ideal pain treatment. These pain symptoms need to be recognized in the medical history and treated appropriately, with consideration for overlapping comorbidities.

Developmental aspects of FXAND in a man with the FMR1 premutation.

BACKGROUND: Fragile X mental retardation 1 (FMR1) premutation can cause developmental problems including autism spectrum disorder (ASD), social anxiety, depression, and attention deficit hyperactivity disorder (ADHD). These problems fall under an umbrella term of Fragile X-associated Neuropsychiatric Disorders (FXAND) and is separate from Fragile X-associated Tremor/Ataxia syndrome (FXTAS), a neurodegenerative disorder. METHODS/CLINICAL CASE: A 26-year-old Caucasian male with the Fragile X premutation who presented with multiple behavior and emotional problems including depression and anxiety at 10 years of age. He was evaluated at 13, 18, and 26 years old with age-appropriate cognitive assessments, psychiatric evaluations, and an MRI of the brain. RESULTS: The Autism Diagnostic Observation Scale (ADOS) was done at 13 years old and showed the patient has autism spectrum disorder (ASD). An evaluation at 18 years old showed a full-scale IQ of 64. A Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) performed at 26 years old confirmed the previous impression of social anxiety disorder, agoraphobia disorder, and selective mutism. His MRI acquired at 26 years old showed enlarged ventricles, increased frontal subarachnoid spaces, and hypergyrification. CONCLUSION: This is an exemplary case of an FMR1 premutation carrier with significant psychiatric and cognitive issues that demonstrates Fragile X-associated Neuropsychiatric Disorders (FXAND) as separate from the other well-known premutation disorders.