FXTAS and the Spectrum of FMR1 Premutation-Associated Phenotypes in Latin America: A Scoping Review.

BACKGROUND

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by FMR1 premutation expansions (55-200 CGG repeats). Although well described in populations of predominantly European ancestry, FXTAS remains poorly characterized in Latin America due to limited awareness, restricted access to molecular diagnostics, and scarce epidemiological data.

OBJECTIVE

To synthesize available evidence on FXTAS and other FMR1 premutation-associated phenotypes in Latin America, focusing on epidemiology, clinical and neuroimaging features, diagnostic approaches, and atypical presentations.

METHODS

A scoping review was conducted following PRISMA-ScR guidelines. PubMed, EMBASE, Scopus, and LILACS were searched without date restrictions (last search: April 2025). Eligible studies reported FXTAS cases or FMR1 premutation carriers from Latin American countries. Data were extracted on demographics, clinical manifestations, neuroimaging, molecular findings, and country of origin.

RESULTS

Twenty-five studies including 5531 participants reported 38 FXTAS cases and 386 premutation carriers without FXTAS. Diagnoses of FXTAS occurred mainly between ages 53 and 85 years. Gait ataxia and tremor predominated, while parkinsonism, peripheral neuropathy, executive dysfunction, and psychiatric symptoms were also reported. Generalized cerebral atrophy was more frequent than the middle cerebellar peduncle sign. Atypical phenotypes, including spastic paraparesis and progressive supranuclear palsy-like presentations, contributed to diagnostic delays. Premutation carriers commonly exhibited fragile X-associated primary ovarian insufficiency and neuropsychiatric manifestations.

CONCLUSIONS

FXTAS is likely underdiagnosed in Latin America despite recognizable clinical patterns and associated premutation-related conditions. Improving clinician awareness, access to genetic testing, and standardized diagnostic evaluation is essential. Prospective regional studies are needed to define prevalence, penetrance, and gene-environment interactions.