Swallowing and choking difficulties as potential markers of FXTAS progression in FMR1 premutation carriers
Narueporn Likhitweerawong1,2,3, Federica Alice Maria Montanaro4,5, Ellery R Santos1,6
1University of California Davis MIND Institute, UC Davis Health, Sacramento, CA, 95817, USA.
Abstract:
Fragile X-associated tremor/ataxia syndrome (FXTAS) affects motor and coordination pathways and is linked to swallowing and choking difficulties, which can lead to aspiration pneumonia, a leading cause of death in late-stage FXTAS. Despite their severity, these issues are under-investigated. This study examined their association with FXTAS stages and potential as markers of disease progression in FMR1 premutation (PM) carriers. A secondary analysis of Genotype-Phenotype cohort data (2017-2025, MIND Institute, UC Davis) examined swallowing/choking problems, FXTAS stage, neuroimaging, and psychological distress (Symptom Checklist-90-Revised; SCL-90-R). Associations between independent and dependent variables were tested using Generalized Estimating Equation (GEE) regression due to their correlated data. The study included 169 PM carriers (mean age 65 ± 10.9 years; 54% male), with approximately 35% reporting swallowing/choking difficulties. After adjusting for age and sex, individuals in the severe stage of FXTAS (stage 4-5) had a significantly higher risk of swallowing/choking problems compared to those without FXTAS (adjusted odds ratio [aOR] = 4.17; 95%CI = 1.28-13.58). PM carriers with swallowing/choking problems showed a significantly increased association with magnetic resonance imaging (MRI) findings of moderate to severe abnormalities in several brain regions, including cerebral atrophy (aOR = 2.69, p = 0.027), cerebellar atrophy (aOR = 3.34, p = 0.013), cerebellar white matter hyperintensity (aOR = 3.33, p = 0.012), and pons white matter hyperintensity (aOR = 3.93, p = 0.035). Swallowing/choking problems are common in FXTAS, particularly in later stages, and may represent an important clinical marker of disease progression. These patients should be referred to speech-language pathologists for evaluation and treatment. Such interventions could reduce morbidity-mortality associated with these problems.
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