Maria Jimena Salcedo-Arellano

The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.

Brain changes at the end-stage of fragile X-associated tremor/ataxia syndrome (FXTAS) are largely unknown due to mobility impairment. We conducted a postmortem MRI study of FXTAS to quantify cerebrovascular disease, brain atrophy and iron content, and examined their relationships using principal component analysis (PCA). Intracranial hemorrhage (ICH) was observed in 4/17 FXTAS cases, among which one was confirmed by histologic staining. Compared with seven control brains, FXTAS cases showed higher ratings of T2-hyperintensities (indicating cerebral small vessel disease) in the cerebellum, globus pallidus and frontoparietal white matter, and significant atrophy in the cerebellar white matter, red nucleus and dentate nucleus. PCA of FXTAS cases revealed negative associations of T2-hyperintensity ratings with anatomic volumes and iron content in the white matter, hippocampus and amygdala, that were independent from a highly correlated number of regions with ICH and iron content in subcortical nuclei. Post-hoc analysis confirmed PCA findings and further revealed increased iron content in the white matter, hippocampus and amygdala in FXTAS cases compared to controls, after adjusting for T2-hyperintensity ratings. These findings indicate that both ischemic and hemorrhagic brain damage may occur in FXTAS, with the former being marked by demyelination/iron depletion and atrophy, and the latter by ICH and iron accumulation in basal ganglia.

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.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disease developed by carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene. The core clinical symptoms usually manifest in the early 60s, typically beginning with intention tremor followed by cerebellar ataxia. Ataxia can be the only symptom in approximately 20% of the patients. FXTAS has a slow progression, and patients usually experience advanced deterioration 15 to 25 years after the initial diagnosis. Common findings in brain imaging include substantial brain atrophy and white matter disease (WMD). We report three cases with an atypical clinical presentation, all presenting with gait problems as their initial manifestation and with ataxia as the dominant symptom without significant tremor, as well as a faster than usual clinical progression. Magnetic resonance imaging (MRI) was remarkable for severe brain atrophy, ventriculomegaly, thinning of the corpus callosum, and periventricular WMD. Two cases were diagnosed with definite FXTAS on the basis of clinical and radiological findings, with one individual also developing moderate dementia. Factors such as environmental exposure and general anesthesia could have contributed to their clinical deterioration. FXTAS should be considered in the differential diagnosis of patients presenting with ataxia, even in the absence of tremor, and FMR1 DNA testing should be sought in those with a family history of fragile X syndrome or premutation disorders.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. In most cases, it is due to an expansion of the CGG triplet to more than 200 repeats within the promoter region of the FMR1 gene. In the premutation (PM) the trinucleotide is expanded to 55-200 repeats. PM carriers can present with disorders associated with the PM including fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated ovarian insufficiency (FXPOI). Recently fragile X-associated neuropsychiatric disorders (FXAND) was proposed as an umbrella term to include the neuropsychiatric disorders that are more prevalent in PM carriers compared to the general population such as anxiety, depression, chronic fatigue, alcohol abuse, and psychosis, among others. The patient in our study was evaluated by a team of clinicians from the University del Valle in Cali who traveled to Ricaurte, a Colombian town known for being a genetic geographic cluster of FXS. A detailed medical history was collected and complete physical, neurological and psychiatric evaluations were performed in addition to molecular and neuroradiological studies. We report the case of a 78-year-old man, PM carrier, without FXTAS whose main clinical presentation consists of behavioral changes and psychosis. Brain imaging revealed white matter lesions in the periventricular region and mild cerebral atrophy. Although anxiety and depression are the most common neuropsychiatric manifestations in PM carriers, it is important to perform a complete psychiatric evaluation since some patients may present with behavioral changes and psychosis.

Many targeted treatment studies have been carried out in individuals with Fragile X Syndrome (FXS) guided by animal studies from the Fragile X Mental Retardation 1 (FMR1) knock out (KO) mice and the fragile X Drosophila studies. Here we review the many medications that have been studied in patients with FXS and some of these medications are available for clinical use by wise clinicians. Other medications are not currently available by prescription because they are not approved by the FDA. No medication has received specific approval for treatment of FXS, although some have shown benefit from clinical studies. There is much to be done in the treatment of those with FXS and this report describes those pharmacological treatments that target the neurobiological mechanisms that are dysregulated by the lack of the Fragile X Protein (FMRP) in those with FXS.

Background: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late‐onset neurodegenerative disorder associated with premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is characterized by the presence of ubiquitin‐positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson's disease (PD).Objective: To describe the frequency of concomitant PD in FXTAS.Methods: We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD.Results: Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs.Conclusion: This report expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS and the concept that the parkinsonism found in FXTAS is sometimes indistinguishable from PD. We propose that FMR1 should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.