Fragile X-Associated Tremor/Ataxia Syndrome Mimicking Normal-Pressure Hydrocephalus: Clinical, Neuroimaging, and Genetic Clues to the Diagnosis

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of an FMR1 premutation. Its manifestations, including gait disturbance, cognitive impairment, urinary dysfunction, parkinsonism, and ventriculomegaly, may overlap with normal-pressure hydrocephalus (NPH), potentially leading to inappropriate invasive treatment. Case presentation: A 75-year-old Arab man with long-standing diabetes initially developed bilateral upper-limb tremor, followed by progressive gait ataxia, urinary incontinence, and cognitive decline. Computed tomography demonstrated ventriculomegaly, prompting referral for consideration of ventriculoperitoneal shunting for presumed NPH. Neurological examination, however, demonstrated orthostatic hypotension, executive and cognitive dysfunction, symmetric rigidity and bradykinesia, postural instability, bilateral upper-limb ataxia, and intention tremor. Brain magnetic resonance imaging showed cerebral and cerebellar atrophy with ventriculomegaly and T2/FLAIR hyperintensities involving the periventricular white matter, corpus callosum, bilateral middle cerebellar peduncles, and cerebellar white matter adjacent to the dentate nuclei. The characteristic middle cerebellar peduncle sign and splenium sign together with the clinical phenotype, raised suspicion for FXTAS. Molecular testing demonstrated an FMR1 premutation with 90 CGG repeats. Subsequent family evaluation revealed a grandson with autism spectrum disorder who carried a full FMR1 mutation (>200 CGG repeats). These findings established the diagnosis of FXTAS and prompted genetic counseling of the family. Conclusion: FXTAS should be considered in older adults presenting with an NPH-like phenotype, particularly when intention tremor, cerebellar ataxia, parkinsonism, autonomic dysfunction, or characteristic white-matter abnormalities accompany ventriculomegaly. Recognition of these clinical and radiological clues can prompt appropriate FMR1 testing and may prevent unnecessary CSF diversion procedures.