Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome

Abstract

Background Carriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention. Methods This was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm “converters,” 15 Pm “nonconverters,” 15 Nc) that were one-one matched on age, education, and socioeconomic status. Results Compared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters. Conclusions Accelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder.

Executive Function and Working Memory Deficits in Females with Fragile X Premutation

“…The present findings are consistent with previous studies on male premutation carriers [ 10 , 29 , 62 ]. For example, an accelerated decline in executive functions, including visual working memory and inhibitory control, was found in a group of male premutation carriers compared to the control group [ 10 ].…”

“…The Fragile X Syndrome (FXS) is the most common cause of intellectual disability and autism as well as additional difficulties. It is caused by the absence of the FMR1 protein [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. The syndrome is caused by more than 200 repeats of a sequence of three nucleotides, Cytosine–Guanine–Guanine (CGG), located in the promoter region on the long arm of the X chromosome [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

“…It is caused by the absence of the FMR1 protein [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. The syndrome is caused by more than 200 repeats of a sequence of three nucleotides, Cytosine–Guanine–Guanine (CGG), located in the promoter region on the long arm of the X chromosome [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. The expansion of the CGG trinucleotide repeats leads to methylation and the subsequent silencing of the gene, which leads to loss of expression of the FMR1 protein.…”

“…In the past, the phenotype of carrier status was considered asymptomatic, and its main significance was the risk of a further increase to a full mutation in the offspring of the carriers [ 22 , 25 ]. In recent studies, however, unique disorders related to the premutation in the FMR1 gene have been reported, including the Fragile X-associated primary ovarian insufficiency (FXPOI) and Fragile X-associated tremor/ataxia syndrome (FXTAS), with abnormal gait, memory, and executive dysfunction [ 6 , 10 , 11 , 12 , 18 , 25 , 26 ]. FXTAS has been reported in 40% of the males and 8%–16% of the females carrying the premutation and who are above 50 years of age [ 6 , 18 , 26 , 27 ].…”

Cerebellum neuropathology and motor skill deficits in fragile X syndrome

“…Despite the fact that children with premutations mostly have conventional developmental profiles and trajectories, minor but significant delays in fine motor abilities have been reported at 18 months of age (Wheeler et al, 2021). A longitudinal study of 64 male premutation carriers of Fmr1 without FXTAS reported decreased executive function and subtle motor changes (Famula et al, 2022). Additionally, pre-FXS mutations are associated with various clinical characteristics, including early ovarian failure and a high prevalence of hypertension, thyroid illness, fibromyalgia, peripheral neuropathy, and seizures (Rodriguez-Revenga et al, 2009).…”