Trajectories and Markers of Neurodegeneration in Carriers of the Fragile X Premutation

University Of California At Davis, Davis CA

Investigators

Linked publications & trials

Abstract

Project Summary/Abstract “Will I get FXTAS?”, “How much time do I have?”, and “What can I do to stop it?” These are the pressing questions, without clear answers, from carriers of Fragile X Messenger Ribonucleoprotein 1 (FMR1) premutation alleles, trinucleotide repeat expansions that occur in about 1 in 110-250 females and 1 in 400-850 males worldwide (or at least 850,000 people in the U.S.). The premutation causes a toxic increase in FMR1 mRNA, which leads to a cascade of molecular, cellular and brain degenerative changes including abnormal alternative splicing, altered miRNA biogenesis, mitochondrial dysfunction, calcium dysregulation, white matter disease, and brain atrophy. These changes contribute to the development of fragile X-associated tremor ataxia syndrome (FXTAS) which is characterized by tremor, gait ataxia, parkinsonism, executive dysfunction and dementia, and eventual premature death. However, FXTAS has incomplete penetrance in FMR1 carriers, and the size of the mutation alone has limited prognostic value, highlighting the importance of other factors contributing to risk. Over the past 16 years, we have conducted a longitudinal study of male carriers at risk for FXTAS and healthy controls to examine the prodrome of the disease and the mechanisms and key markers associated with “phenoconversion” – which is when carriers begin to show the first clinically significant neurological symptoms. We have been successful in identifying several preliminary brain imaging, neuropsychological, motor and metabolomic/proteomic markers, but they have been determined using a relatively small cohort of phenoconverters without the use of rigorous predictive modeling. The goals of this phase of the project are to a) improve the precision of neurological assessment of preclinical and early FXTAS, b) validate biomarkers able to identify carriers at highest risk of phenoconversion and track disease progression and severity, c) establish brain imaging, motor and oculomotor, and neuropsychological prognostic markers for FXTAS, and d) utilize modern machine learning techniques to discern an optimal combination of markers to enhance prognostic sensitivity for FXTAS phenoconversion. To accomplish these aims, we will continue longitudinal observations of 44 carriers without FXTAS and 27 controls already enrolled in the study, and of 45 new carriers without FXTAS and 30 new controls that we will enroll during the proposed project. The overarching goal of this project is to develop an approach to identify carriers at high risk for FXTAS who are eligible for prophylactic therapeutics, and to obtain optimal measures for tracking treatment response in future clinical trials.