Progression of fragile X-associated tremor/ataxia syndrome revealed by subtype and stage inference

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by the premutation (55-200 CGG repeats) in the fragile X messenger ribonucleoprotein-1 (FMR1) gene. An open question is: In what sequential order do FXTAS symptoms typically appear, and how does that sequence vary among patients and between males and females? We applied the ordinal-outcomes version of the Subtype and Stage Inference algorithm ('Ordinal SuStaIn') to identify the sequential events of clinical and brain MRI changes in cross-sectional data collected during baseline visits from a longitudinal cohort of FXTAS patients at Stages 0-5. We included 28 neurodegenerative symptoms collected from 253 premutation carriers (101 females and 152 males) and 44 controls (7 females and 37 males), aged 40-86 years old at entry, who participated in two longitudinal studies, with entry dates between 2008 and 2023. We found substantial differences in order of events depending on sex, and possibly in combination of sex and CGG repeats. The main finding is the predominance of the psychiatric co-morbidities that occur early in females (often before the onset of tremor and ataxia) compared to males. These findings suggest that the sequence of neuropsychiatric symptoms for FXTAS is different in females compared to males, particularly for early symptoms in disease development and progression. This could lead to sex-specific modifications of the FXTAS diagnostic stages.