There is a spectrum of involvement in those with the FMR1 premutation that ranges from developmental problems in childhood and psychopathology in adulthood to neurodegeneration in aging;the latter includes the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) that we have identified with our Australian collaborators. However, some individuals with the premutation have no overt clinical involvement, whereas others experience mild or severe deficits in childhood, adulthood or aging. Typically, the developmental problems are thought to be related to FMRP deficits, whereas the aging problems to RNA toxicity secondary to elevated FMR1-mRNA. We will assess the influence of specific domains of molecular/cellular dysfunction, including mitochondrial dysfunction, inter-tissue (lymphocyte-fibroblast) mosaicism, occult methylation, and increases of disease-associated antisense FMR1 (ASFM1) isoforms on the nature and degree of the clinical phenotypes in both children and adults who are carriers of premutation alleles. Specific clinical outcome measures will be used that can document mild to severe involvement in the neurocognitive, motor and psychiatric realms. We will assess 189 patients (10 to 30 years) including 63 carriers who are affected, 63 who have normal development (asymptomatic) and 63 normal controls matched on age and sex to define the relationship between the severity of premutation developmental problems, including cognitive, motor and social deficits, and the presence of specific molecular abnormalities (Specific Aim 1). We will extend these studies to characterize the nature and severity of molecular dysfunction in adults with the premutation who have psychiatric and/or neurological dysfunction but do not meet clinical criteria for FXTAS (Specific Aim 2);we will recruit 201 patients (30 to 65y), divided between carriers who are affected with neurological or psychiatric problems, asymptomatic carriers, and controls matched for age and sex. We will determine whether the spectrum of clinical involvement in premutation adults is paralleled by severity of molecular dysregulation or whether the molecular features of FXTAS are distinct, and whether early biomarkers can be identified to use in future treatment endeavors. Lastly we will utilize sensitive neuroimaging techniques (diffusion tensor imaging;DTI) to assess involvement in adults with the premutation to determine the degree of concordance between the loss of integrity of fiber tracts in white matter and the severity of the mitochondrial dysfunction in adul carriers with psychiatric and/or neurological problems compared to unaffected carriers and controls (Specific Aim 3). This work will continue to include the Australia team, who will carry ou the occult methylation studies on blood and fibroblasts for all patients seen at both sites, in addition to limited recruitment for Aims 1 and 2. Our studies will provide biomarkers of early involvement and lay the basis for treatments such as mitochondrial based interventions, targeted treatment for low FMRP, or medications that block RNA toxicity early on.
The premutation is common in the general population (approximately 1 in 130-810) and it can cause developmental problems including intellectual deficits and autism spectrum disorders, adult psychiatric disorders and neurological problems in aging including the fragile X-associated tremor ataxia syndrome (FXTAS). However, most individuals with the premutation are unaffected and we do not know why some individuals with the premutation suffer from these problems and others do not. This grant will assess detailed molecular mechanisms including mitochondrial abnormalities, mosaicism between the lymphocytes and fibroblasts, the antisense FMR1 (ASFMR1) splice isoforms and occult methylation to determine the molecular markers of premutation clinical involvement.
|Rogers, Hailee; Ariza, Jeanelle; Monterrubio, Angela et al. (2016) Cerebellar Mild Iron Accumulation in a Subset of FMR1 Premutation Carriers with FXTAS. Cerebellum 15:641-4|
|Schneider, A; Johnston, C; Tassone, F et al. (2016) Broad autism spectrum and obsessive-compulsive symptoms in adults with the fragile X premutation. Clin Neuropsychol 30:929-43|
|Salcedo-Arellano, MarÃa J; Lozano, Reymundo; Tassone, Flora et al. (2016) Alcohol use dependence in fragile X syndrome. Intractable Rare Dis Res 5:207-13|
|Annesley, Sarah J; Lay, Sui T; De Piazza, Shawn W et al. (2016) Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity. Dis Model Mech 9:1295-1305|
|Song, Gyu; Napoli, Eleonora; Wong, Sarah et al. (2016) Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor/ataxia syndrome: use of antioxidants in precision medicine. Mol Med 22:|
|Wheeler, Anne C; Sideris, John; Hagerman, Randi et al. (2016) Developmental profiles of infants with an FMR1 premutation. J Neurodev Disord 8:40|
|Giulivi, Cecilia; Napoli, Eleonora; Tassone, Flora et al. (2016) Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers. Front Mol Neurosci 9:71|
|Ligsay, Andrew; Hagerman, Randi J (2016) Review of targeted treatments in fragile X syndrome. Intractable Rare Dis Res 5:158-67|
|Saldarriaga, Wilmar; Lein, Pamela; GonzÃ¡lez Teshima, Laura Yuriko et al. (2016) Phenobarbital use and neurological problems in FMR1 premutation carriers. Neurotoxicology 53:141-7|
|Lozano, Reymundo; Azarang, Atoosa; Wilaisakditipakorn, Tanaporn et al. (2016) Fragile X syndrome: A review of clinical management. Intractable Rare Dis Res 5:145-57|
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