An Out-of-Place Etiology: Recognizing FMR1 Premutation in the Memory Clinic.
Guido Greco1, Caterina Motta1, Enrica Marchionni2
1Memory Clinic and Neurodegenerative Dementia Research Unit, Policlinico Tor Vergata, University of Rome "Tor Vergata", Rome, Italy.
Annals of Clinical and Translational Neurology
|December 16, 2025
Summary
The Fragile X gene premutation can cause cognitive decline, not just FXTAS. This study highlights FMR1 premutation in three males with unexplained progressive cognitive impairment.
Area of Science:
- Genetics
- Neurology
- Neuroscience
Background:
- The FMR1 gene premutation (55-200 CGG repeats) is linked to Fragile X-tremor/ataxia syndrome (FXTAS).
- However, it can also present as primary cognitive decline.
- This necessitates broader diagnostic considerations.
Purpose of the Study:
- To report on male patients with FMR1 premutation presenting with progressive cognitive impairment.
- To detail the diagnostic work-up and findings in these cases.
- To raise awareness among clinicians for this underrecognized presentation.
Main Methods:
- Case series of three male patients with progressive cognitive decline.
- Comprehensive evaluation including MRI, 18FDG-PET, CSF biomarkers, and neuropsychological testing.
- Genetic analysis for FMR1 gene premutation.
Main Results:
- All three patients were diagnosed with FMR1 premutation.
- Brain MRI showed white matter changes (callosal and peduncular).
- 18FDG-PET revealed anterior cingulate hypometabolism.
Conclusions:
- FMR1 premutation should be considered in unexplained cognitive decline, particularly in males.
- Distinct neuroimaging findings (white matter changes, hypometabolism) support the diagnosis.
- Early genetic testing can aid in diagnosing this FXTAS variant.
Keywords:
FMR1 premutationcognitive declineearly‐onset dementiafragile X‐associated tremor/ataxia syndrome (FXTAS)genetic diagnosisMore Related Videos
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