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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.

Background

Carriers of the fragile X premutation, an allelic variant of the FMR1 gene with 55–200 cytosine-guanine-guanine (CGG) repeats, are at risk of developing a late-onset, progressive neurodegenerative disease—fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is primarily characterized by intention tremor, gait ataxia, and radiological signs of white matter changes in the middle cerebellar peduncles and other regions, as well as brain atrophy. However, the disease frequently presents with comorbid cognitive changes including memory deficits and executive dysfunction and dementia in later stages [1, 2]. A primary underlying molecular mechanism is mRNA toxicity, which leads to protein sequestration, DNA damage and repeat-associated non-AUG (RAN) translation, and ultimately to FXTAS degeneration [3]. By the eighth decade of life, roughly 47% of male premutation carriers develop FXTAS, reaching 75% in those above 80 years [4]; however, clinical presentation is highly heterogeneous in terms of disease severity, age of onset, and course [5,6,7]. As the gene is X-linked, FXTAS has generally been found to have a lower penetrance and milder clinical presentation in female carriers as compared to males [8, 9].

Though recent studies have pointed toward potential biomarkers that can distinguish which carriers are at greatest risk of developing the FXTAS [10,11,12,13], clinical measures to assess individual risk, or even detect the disease in its earliest stages, are limited. Even after disease onset, some patients experience a rapid acceleration in symptom severity, while in others the disease appears to plateau or advance slowly [14, 15]. We still lack reliable methods for predicting which of these scenarios each patient will face.

The neuropsychological profile of premutation carriers of various ages with and without FXTAS has been studied broadly since the disease was first described, with all studies to date taking a cross-sectional approach [16,17,18]. Among carriers without symptoms of FXTAS, studies indicate that subtle cognitive effects may be present before motor signs develop, and the effects are associated with the extent of white matter changes in the brain [19]. Subsequent well-powered brain volumetric studies show that morphological changes may occur in carriers decades before any formal signs of FXTAS are present [20]. Significantly, functional magnetic resonance imaging (fMRI) studies of premutation carriers have revealed irregular brain activity during working memory [21, 22], associative memory recall [18], and magnitude estimation [22] tasks—further illustrating the neurological underpinnings of these neuropsychological findings. However, the cross-sectional nature of prior work, while extensive, precludes a clear delineation of the prodrome of FXTAS and how the disease first emerges from a neuropsychological perspective. Longitudinal research plays a critical role in identifying which carriers are at the greatest risk of developing the disease, which factors may influence the age of onset and rate of progression of the disease, and which treatment domains may be the most important to target in future trials. Here, we present preliminary results from a longitudinal neuropsychological and neurological study of male fragile X premutation carriers at risk for FXTAS.

Methods

Participants

The full study sample consisted of 94 males, 64 with the FMR1 premutation (Pm), and 30 non-carrier controls (Nc). FMR1 allele size was confirmed in all participants; premutation carriers had > 54 and < 200 CGG repeats, and controls had < 45 CGG repeats (Table 1). All participants were between 40 and 80 years of age at their first visit (time 1), and the groups did not significantly differ by age, IQ, education, income level, or ethnicity/race (Table 1). Of the 94 participants, 72 had follow-up data at time 2 (50 Pm; interval length = 2.33 ± 0.88 years), and 57 participants had Time 3 data (37 Pm; interval length = 2.15 ± 0.66 years). Note that the reduced sample sizes with subsequent visits do not indicate drop-out as the study is currently ongoing, and future visits at 2-year increments (or longer, given COVID pandemic constraints) will be completed and reported elsewhere.

Table 1 Group descriptive statistics

FMR1 premutation carriers were recruited primarily through announcements shared by the National Fragile X Foundation, and by referrals from colleagues at other institutions studying children with FXS and their families for research or in clinic. Non-carrier controls were recruited from the Institute’s research registry system, social media announcements, and presentations given to local organizations. Carriers traveled to UC Davis in Sacramento, CA, from various locations in North America, while the non-carrier control population was recruited locally throughout Northern California. During screening, no participants reported having symptoms of tremor or ataxia interfering with activities of daily living (ADLs), nor did they have a history of a significant medical condition or a brain injury. Upon neurological exam, 18 of the carriers (28.1%) showed no clinical signs of FXTAS at study entry (FXTAS stage 0 or 1) but developed clear FXTAS symptoms by visit 2 or 3 (FXTAS stage ≥ 2) and were classified as “Converters.”

All participants provided a full list of their current prescription and over-the-counter medications at each visit. Medication lists were reviewed for those known to have antidepressant, anxiolytic, anticonvulsant, antipsychotic, stimulant, or other known neurologic effects. Groups did not differ significantly on psychoactive medication use (Table 1).

Measures and procedures

FXTAS assessment

Diagnosis of FXTAS and the evaluation of disease stage was carried out by a physician using established guidelines [4, 16, 23]. The examination was composed of standardized movement disorder assessments from the Unified Parkinson’s Disease Rating Scale (UPDRS; [24]), International Cooperative Ataxia Rating Scale (ICARS; [25]), Clinical Rating Scale for Tremor (CRST), and the Scale for the Assessment and Rating of Ataxia (SARA; [26]) and review of brain MRI to assess white matter disease associated with FXTAS.

Neuropsychological assessment

The neuropsychological assessment battery consisted of an intelligence assessment [27, 28], subtests of the Wechsler Memory Scales, Third [29] or Fourth Edition [30], Behavioral Dyscontrol Scale-2 [BDS-2 [31];], Purdue Pegboard Test (Lafayette Instrument, Lafayette, IN), and the Cambridge Neuropsychological Test Automated Battery (CANTAB; Cambridge Cognition, UK). The subtests of the CANTAB included: Paired Associates Learning (PAL), Simple and Five-Choice Reaction Time (RTI), Rapid Visual Processing (RVP), Spatial Working Memory (SWM), Stop Signal Task (SST), and One Touch Stockings of Cambridge (OTS). Together, these tests yielded study measures of spatial memory, episodic memory, auditory working memory, visual working memory, motor dexterity and control, response inhibition, sustained attention, planning, and problem solving, executive control of movement, manual movement speed, and manual reaction time (Table 2).

Table 2 Neuropsychological functional domains and variables chosen for each domain

Molecular measures

Genomic DNA (gDNA) was extracted from 3 mL of peripheral blood leukocytes using standard methods (Qiagen). CGG repeat allele sizing and methylation status by Southern Blot and PCR analysis were measured as previously described [32, 33]. FMR1 mRNA expression levels were measured by real time qRT-PCR using FMR1 specific primer and probes as previously reported [34].

Statistical analyses

We first compared Pm and Nc groups at study entry on measures of age, education level, income, IQ, and use of psychoactive medication to identify any potentially confounding variables for subsequent analyses. Second, we applied age-based mixed models using the MIXED procedure in SAS [35] to compare neuropsychological function of all Pm and Nc and to examine differences between these groups in the rate of change over time for each test. Third, to examine potential effects of changes with FXTAS onset (presence vs absence) and to examine potential effects of molecular variables (FMR1 CGG size and mRNA) and in combination with increasing age, we again used mixed models, this time including only Pm. Finally, to examine differences between Pm “converters,” “non-converters” and controls, we selected 15 trios (n = 45), one-one matched on age, education level, and income and carried out the age-based mixed models described, with a specific focus on differences in the rate of change over time:

$${Y}_{it}={\upbeta}_{0i}+{\upbeta}_{1i}\bullet \mathrm{age}+{\mathrm{c}}_1\bullet {\upbeta}_{0i}+{\mathrm{c}}_2\bullet {\upbeta}_{0i}+{\mathrm{c}}_3\bullet \mathrm{age}\bullet {\upbeta}_{1i}+{\mathrm{c}}_4\bullet \mathrm{age}\bullet {\upbeta}_{1i}+{\mathrm{e}}_{it}$$

where Yit is the outcome variable for any given individual i at time t, = β0i is the intercept, β1i is the linear slope based on age, c1 is the contrast testing for differences in the intercept between Pm converters (+ 1) and nonconverters (− 1), c2 is the contrast testing for differences in the intercept between Pm converters (+ 1) and Nc (− 1), c3 is the contrast testing for differences in the age slope between Pm converters (+ 1) and Pm nonconverters (− 1), c4 is c3 is the contrast testing for differences in the age slope between Pm converters (+ 1) and controls (− 1), and eit is the residual variance. Correction for multiple comparisons was applied using the Benjamini-Hochberg [36] false discovery rate (FDR) method for all effects pertaining to group differences in change over time. Footnotes at the bottom of tables provide guidance for statistical interpretation.

Results

Demographic descriptive statistics

Demographic, general intelligence and psychoactive medication use in Pm and Nc at study entry (time 1) are shown in Table 1. The two groups did not differ significantly according to these variables and were generally well above average in intellectual functioning. At study entry, antidepressant medications were reported by 15 Pm and 5 Nc; anxiolytic medications were reported by 9 Pm and 0 Nc; anticonvulsant medications were reported by 5 Pm and 0 Nc; antipsychotic medications were reported by 0 Pm and 0 Nc; stimulant medications were reported by 0 Pm and 1 Nc; and medication with other neurologic effects were reported by 2 Pm and 0 Nc.

Neuropsychological group differences and comparisons of rates of change with age

Age-based mixed models revealed no significant differences between groups in the value for any variable at age 40 (the youngest age, used as intercept) but showed significantly different rates of change over time between Pm and Nc. Specifically, compared to Nc, Pm showed significantly greater declines in visual working memory, motor dexterity, inhibitory control, and manual movement speed over time (Table 3). However, only the differential rates of change effect in motor dexterity survived multiple comparison correction, while visual working memory and manual movement speed approached significance after correction. Changes in performance over time in the other domains of measurement did not differ between groups.

Table 3 Parameter estimates from age-based mixed models (full cohort)

Neuropsychological changes associated with FXTAS stage

The models examining changes associated with FXTAS stage revealed effects for two measures of interest: inhibitory control and manual movement speed. While higher FXTAS stage (≥ 2 on the scale) was associated with poorer inhibitory control scores at age 40, inhibitory control improved slightly over time, with a positive slope reaching statistical significance for those with FXTAS symptoms, potentially due to there being more data from those with symptoms. Manual movement speed was significantly slower at age 40 among those with higher FXTAS stage, but significant change over time was not detected for this measure. In these models, Pm without FXTAS showed significant worsening on several measures including visual episodic memory, auditory working memory, motor dexterity, inhibitory control, and manual movement speed (the “age” factor in Table 4).

Table 4 Parameter estimates from age-based mixed models (Pm group by FXTAS status)

Neuropsychological changes associated with FMR1 molecular measures

Models examining the effect of elevated FMR1 mRNA showed a significant effect on manual reaction time in Pm (higher mRNA, worsening reaction time with age) and a marginally significant negative effect of mRNA on planning. These effects did not survive multiple comparison correction, and CGG repeat number was not significantly associated with any measure of interest.

Neuropsychological changes in premutation converters, non-converters, and controls (matched trios)

In the domain of visual working memory, Pm converters performed significantly worse than Nc and better than Pm non-converters overall; however, Pm converters had a significantly greater rate of decline than Pm nonconverters (Table 5). Pm converters performed worse than Nc on motor dexterity but their rate of change on this measure did not differ from the other two groups. Pm converters performed better than Pm nonconverters on visual attention and planning overall but showed a significantly greater rate of decline on planning. In contrast, manual movement speed was significantly slower in Pm converters than in Pm nonconverters, and Pm converters became slower over time (p = .055). None of these significant effects survived multiple comparison correction (11 test domains, 22 slope comparison p values).

Table 5 Parameter estimates from age-based mixed models (matched trios)

Discussion

Here, we present the results of the first longitudinal study of aging FMR1 premutation carriers, with a focus on neuropsychological functioning. The primary importance of this study’s cohort and design is its emphasis on enrollment prior to the onset of FXTAS and the subsequent tracking of changes in functioning during the emergence of disease. The results demonstrate (a) that age-related declines in executive functions including visual working memory and inhibitory control, as well as manual movement speed, appear to be greater in male premutation carriers than controls without an FMR1 mutation, and (b) that the onset of the FXTAS disease process (“conversion”) is marked by subtle bradykinesia (slowing of movement) and possibly by changes in frontal-lobe mediated planning ability and working memory. Prior cross-sectional studies have suggested that changes in executive function [21, 37,38,39,40] and movement [40] may be key early indicators of imminent or emerging FXTAS; the present longitudinal study documents accelerated changes in these parameters over time, providing key support for these initial observations.

Findings of a greater rate of decline in working memory in FXTAS converters are in line with neuroimaging results we have reported in cross-sectional studies of FMR1 premutation carriers compared to controls. Using functional MRI, we have reported reduced hippocampus activation during recall [18], altered hippocampal-prefrontal function during memory encoding [41], reduced activation in the right ventral inferior frontal cortex and left premotor/dorsal inferior frontal cortex during a verbal working memory task [21], and dysfunctions in the “when” pathway (right temporoparietal junction) during a working memory task requiring temporal order judgments [22]. Using structural neuroimaging, we have also reported significant reductions of fractional anisotropy in multiple white matter tracts, including the middle and superior cerebellar peduncle, cerebral peduncle, and the fornix and stria terminalis—areas that transmit information from the hippocampus and integrate limbic information and monitor valence [42].

Findings in the present study of a significantly greater rate of decline in motor planning, and significantly slower manual movement speed in converters than in the non-converters is also in line with past structural neuroimaging findings. In these cross-sectional studies, we have reported weaker structural connectivity in motor fiber tracts: middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum [43]. In addition, we have reported involvement of subcortical gray structures: thalamus, caudate nucleus, putamen, and globus pallidus (which serve the functions of relaying motor signals to the cerebral cortex, planning and execution of movement, and regulation of voluntary movements) in FXTAS [44]. Finally, in a report of early longitudinal neuroimaging findings from the same cohort described here, we found that decreasing width of the middle cerebellar peduncle (MCP) appeared to be sensitive to early structural changes associated with FXTAS development [11]. The MCP is a structure through which passes the predominant afferent fiber of the corticopontocerebellar pathway—a pathway involved in the communication between the cerebellum and the prefrontal cortex for the coordination and planning of motor responses.

Among our matched trios of controls, Pm converters, and Pm nonconverters, there were two domains in which the converters performed better than nonconverters overall, but the rate of change over time showed a sharper decline in performance among converters compared to nonconverters: visual working memory and planning/problem solving. The trio sample sizes were small, and because we examined multiple domains of function, correction for multiple comparisons made differences hard to confirm. If these findings are upheld with greater numbers and/or replication, they would align with those from a previous study of neuroimaging abnormalities in premutation carriers, in which executive dysfunction and cognitive processing scores were decreased in correlation with white matter changes in the frontocerebellar region of the brain [19]. Interestingly, increased cognitive “load” during standardized walking protocols significantly impairs gait in premutation carriers [45, 46], further highlighting the role of changes in frontocerebellar pathways and functional connectivity in the development of cognitive and motor symptom decline in this population.

An important finding in this study is the motor and executive function changes that occur before and during the onset of FXTAS. These results suggest that prophylactic treatments for molecular abnormalities that have been reported such as oxidative stress and mitochondrial dysfunction [47,48,49] could be initiated in patients thus identified at high risk, before the onset of FXTAS, to try to stall disease progression. Future targeted treatments for FXTAS and other neurological and neuropsychological symptoms associated with the premutation will need to rely on a well-validated and scalable battery of outcome measures to track treatment response across research and clinical centers. The research presented here points to several neuropsychological domains that may be important to capture in such studies, especially those capturing specific executive functions and cognitive tasks mediated by frontocerebellar activity. Future work should focus on comparing psychometric properties and sensitivity of various outcome measures for premutation carriers and FXTAS in order to refine and then establish a harmonized battery to facilitate collaboration across centers and prepare for future clinical trials.

Among male premutation carriers, it is estimated that approximately 75% will develop FXTAS by the ninth decade of life, with variable ages of onset and severity of course. Thus, the penetrance of the mutation is incomplete and a variety of environmental or secondary genetic factors are likely to affect outcomes. To date, we have limited information about how to predict which carriers will develop FXTAS and when. Limited studies suggest that CGG repeat length is associated with age of symptom onset and age of death among FXTAS carriers [50], but this molecular marker is not an especially powerful predictor. The prodrome of FXTAS, or the early signs or symptoms indicating the imminent onset of the disease, is not yet fully defined. This is an important area of investigation to better identify carriers in need of intervention, prophylactic treatment or lifestyle changes, and monitoring.

A potential weakness of the current investigation is the reliance on touch-screen technology to measure cognition in a population affected by tremor and movement disorder. However, several CANTAB tests (OTS, SWM) are unaffected by reaction time or manual movement accuracy and were sensitive to cognitive changes. Also, the CANTAB has been implemented to detect mild cognitive impairment (MCI) in Parkinson’s disease [51], and it is sensitive to differences between patients with MCI versus those with Alzheimer’s disease [52], demonstrating its broad utility in the assessment of cognitive neurodegeneration. This battery also provides a highly standardized and objectively quantified method that may be scalable for future multi-center studies or clinical trials. We did not include balance or gait measures in this report, whereas ataxia is a primary clinical feature of FXTAS. Detailed gait and balance metrics have been collected and will be reported elsewhere. This study presents the only longitudinal neuropsychological data from premutation carriers in the literature to date. However, because we examined multiple neuropsychological domains in the protocol, requiring multiple comparison adjustments, some group differences in change over time were difficult to confirm. This study focused on male premutation carriers, as fragile X-associated disorders are X chromosome linked, and thus males are more likely to be affected. However, female carriers do develop FXTAS and other neurological symptoms [9, 53], and future longitudinal studies should enroll females to examine phenotypic effects and identify individuals most at risk for neurodegenerative changes, as well as protective factors. Finally, it is important to be aware that individuals identified as “non-converters” might present with signs and symptoms of FXTAS after the period of follow-up in this study, as an average period of 5 years might not be adequate to determine clinical conversion.

Conclusions

In this prospective longitudinal study, we show that compared to controls, men with the FMR1 premutation have accelerated decline in manual dexterity and certain domains of executive functioning, including visual working memory, inhibitory control, and that conversion to FXTAS is associated with deterioration in inhibitory control, planning and problem solving, and slowing of manual movement. The findings, in conjunction with prior brain imaging literature, provide critical support for the hypothesis that the prodrome of FXTAS is characterized by executive dysfunction mediated by white matter changes in frontocerebellar pathways. Additional research is needed to select and validate a set of standardized outcome measures that can be used in future multicenter clinical trials of targeted treatments for FXTAS and prophylactic interventions of fragile X carriers who are at increased risk for neurodegeneration.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

FXTAS:

Fragile X-associated tremor/ataxia syndrome

Pm:

Premutation

Nc:

Normal control

CANTAB:

Cambridge Neuropsychological Test Automated Battery

CGG:

Cytosine-guanine-guanine

RAN:

Repeat-associated non-AUG

IRB:

Institutional Review Board

ADL:

Activities of daily living

UPDRS:

Unified Parkinson’s Disease Rating Scale

ICARS:

International Cooperative Ataxia Rating Scale

CRST:

Clinical Rating Scale for Tremor

SARA:

Scale for the Assessment and Rating of Ataxia

MRI:

Magnetic resonance imaging

BDS-2:

Behavioral Dyscontrol Scale, Second Edition

PAL:

Paired Associates Learning

RTI:

Simple and Five Choice Reaction Time

RVP:

Rapid Visual Processing

SWM:

Spatial Working Memory

SST:

Stop Signal Task

OTS:

One Touch Stockings of Cambridge

PCR:

Polymerase chain reaction

mRNA:

Messenger ribonucleic acid

MCP:

Middle cerebellar peduncle

MCI:

Mild cognitive impairment

References

  1. Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome (FXTAS): pathophysiology and clinical implications. Int J Mol Sci. 2020;21(12):4391.

  2. Hall DA, Robertson E, Shelton AL, Losh MC, Mila M, Moreno EG, et al. Update on the clinical, radiographic, and neurobehavioral manifestations in FXTAS and FMR1 premutation carriers. Cerebellum. 2016;15(5):578–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Glineburg MR, Todd PK, Charlet-Berguerand N, Sellier C. Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in fragile X tremor ataxia syndrome. Brain Res. 2018;1693(Pt A):43–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004;291(4):460–9.

    Article  CAS  PubMed  Google Scholar 

  5. Famula JL, McKenzie F, McLennan YA, Grigsby J, Tassone F, Hessl D, et al. Presence of middle cerebellar peduncle sign in FMR1 premutation carriers without tremor and ataxia. Front Neurol. 2018;9:695.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome. Ann N Y Acad Sci. 2015;1338:58–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhao C, Liu Y, Wang Y, Li H, Zhang B, Yue Y, et al. A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor:case report and literature review on tremor in FXTAS. BMC Neurol. 2020;20(1):145.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, Xuncla M, Badenas C, Kulisevsky J, et al. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet. 2009;17(10):1359–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schneider A, Summers S, Tassone F, Seritan A, Hessl D, Hagerman P, et al. Women with fragile X-associated tremor/ataxia syndrome. Mov Disord Clin Pract. 2020;7(8):910–9.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Renaud M, Perriard J, Coudray S, Sevin-Allouet M, Marcel C, Meissner WG, et al. Relevance of corpus callosum splenium versus middle cerebellar peduncle hyperintensity for FXTAS diagnosis in clinical practice. J Neurol. 2015;262(2):435–42.

    Article  PubMed  Google Scholar 

  11. Shelton AL, Wang JY, Fourie E, Tassone F, Chen A, Frizzi L, et al. Middle cerebellar peduncle width-a novel MRI biomarker for FXTAS? Front Neurosci. 2018;12:379.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zafarullah M, Palczewski G, Rivera SM, Hessl DR, Tassone F. Metabolic profiling reveals dysregulated lipid metabolism and potential biomarkers associated with the development and progression of Fragile X-associated tremor/ataxia syndrome (FXTAS). FASEB J. 2020;34(12):16676–92.

    Article  CAS  PubMed  Google Scholar 

  13. Zafarullah M, Tang HT, Durbin-Johnson B, Fourie E, Hessl D, Rivera SM, et al. FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS). Sci Rep. 2020;10(1):11099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. J Investig Med. 2009;57(8):830–6.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Robertson EE, Hall DA, McAsey AR, O'Keefe JA. Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders. Clin Neuropsychol. 2016;30(6):849–900.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bacalman S, Farzin F, Bourgeois JA, Cogswell J, Goodlin-Jones BL, Gane LW, et al. Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia. J Clin Psychiatry. 2006;67(1):87–94.

    Article  PubMed  Google Scholar 

  17. Grigsby J, Brega AG, Engle K, Leehey MA, Hagerman RJ, Tassone F, et al. Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome. Neuropsychology. 2008;22(1):48–60.

    Article  PubMed  Google Scholar 

  18. Koldewyn K, Hessl D, Adams J, Tassone F, Hagerman PJ, Hagerman RJ, et al. Reduced hippocampal activation during recall is associated with elevated FMR1 mRNA and psychiatric symptoms in men with the fragile X premutation. Brain Imaging Behav. 2008;2(2):105–16.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Filley CM, Brown MS, Onderko K, Ray M, Bennett RE, Berry-Kravis E, et al. White matter disease and cognitive impairment in FMR1 premutation carriers. Neurology. 2015;84(21):2146–52.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wang JY, Hessl D, Hagerman RJ, Simon TJ, Tassone F, Ferrer E, et al. Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation. Neurobiol Aging. 2017;55:11–9.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hashimoto R, Backer KC, Tassone F, Hagerman RJ, Rivera SM. An fMRI study of the prefrontal activity during the performance of a working memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FXTAS). J Psychiatr Res. 2011;45(1):36–43.

    Article  PubMed  Google Scholar 

  22. Kim SY, Hashimoto R, Tassone F, Simon TJ, Rivera SM. Altered neural activity of magnitude estimation processing in adults with the fragile X premutation. J Psychiatr Res. 2013;47(12):1909–16.

    Article  PubMed  Google Scholar 

  23. Hall DA, Birch RC, Anheim M, Jonch AE, Pintado E, O'Keefe J, et al. Emerging topics in FXTAS. J Neurodev Disord. 2014;6(1):31.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Movement Disorder Society Task Force on Rating Scales for Parkinson's D. The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord. 2003;18(7):738–50.

    Article  Google Scholar 

  25. Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997;145(2):205–11.

    Article  CAS  PubMed  Google Scholar 

  26. Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66(11):1717–20.

    Article  CAS  PubMed  Google Scholar 

  27. Wechsler D. Wechsler Adult Intelligence Scale, Third Edition. San Antonio: Pearson; 1997.

    Google Scholar 

  28. Wechsler D. Wechsler Adult Intelligence Scale, Fourth Edition. San Antonio: Pearson; 2009.

    Google Scholar 

  29. Wechsler D. Wechsler Memory Scale, Third Edition. San Antonio: Pearson; 1997.

    Google Scholar 

  30. Wechsler D. Wechsler Memory Scale, Fourth Edition. San Antonio: Pearson; 2009.

    Google Scholar 

  31. Grigsby J, Kaye K, Robbins LJ. Reliabilities, norms and factor structure of the Behavioral Dyscontrol Scale. Percept Mot Skills. 1992;74(3 Pt 1):883–92.

    Article  CAS  PubMed  Google Scholar 

  32. Filipovic-Sadic S, Sah S, Chen L, Krosting J, Sekinger E, Zhang W, et al. A novel FMR1 PCR method for the routine detection of low abundance expanded alleles and full mutations in fragile X syndrome. Clin Chem. 2010;56(3):399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tassone F, Pan R, Amiri K, Taylor AK, Hagerman PJ. A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn. 2008;10(1):43–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tassone F, Hagerman RJ, Loesch DZ, Lachiewicz A, Taylor AK, Hagerman PJ. Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA. Am J Med Genet. 2000;94(3):232–6.

    Article  CAS  PubMed  Google Scholar 

  35. SAS Institute I. SAS/STAT 14.1 User's Guide. Cary: SAS Institute, Inc.; 2015.

    Google Scholar 

  36. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57(1):289–300.

    Google Scholar 

  37. Cornish KM, Hocking DR, Moss SA, Kogan CS. Selective executive markers of at-risk profiles associated with the fragile X premutation. Neurology. 2011;77(7):618–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cornish KM, Kogan CS, Li L, Turk J, Jacquemont S, Hagerman RJ. Lifespan changes in working memory in fragile X premutation males. Brain Cogn. 2009;69(3):551–8.

    Article  PubMed  Google Scholar 

  39. Grigsby J, Cornish K, Hocking D, Kraan C, Olichney JM, Rivera SM, et al. The cognitive neuropsychological phenotype of carriers of the FMR1 premutation. J Neurodev Disord. 2014;6(1):28.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Shickman R, Famula J, Tassone F, Leehey M, Ferrer E, Rivera SM, et al. Age- and CGG repeat-related slowing of manual movement in fragile X carriers: A prodrome of fragile X-associated tremor ataxia syndrome? Mov Disord. 2018;33(4):628–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang JY, Hessl DH, Hagerman RJ, Tassone F, Rivera SM. Age-dependent structural connectivity effects in fragile x premutation. Arch Neurol. 2012;69(4):482–9.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hashimoto R, Srivastava S, Tassone F, Hagerman RJ, Rivera SM. Diffusion tensor imaging in male premutation carriers of the fragile X mental retardation gene. Mov Disord. 2011;26(7):1329–36.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wang JY, Hessl D, Schneider A, Tassone F, Hagerman RJ, Rivera SM. Fragile X-associated tremor/ataxia syndrome: influence of the FMR1 gene on motor fiber tracts in males with normal and premutation alleles. JAMA Neurol. 2013;70(8):1022–9.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wang JY, Hagerman RJ, Rivera SM. A multimodal imaging analysis of subcortical gray matter in fragile X premutation carriers. Mov Disord. 2013;28(9):1278–84.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kraan CM, Hocking DR, Georgiou-Karistianis N, Metcalfe SA, Archibald AD, Fielding J, et al. Age and CGG-repeat length are associated with neuromotor impairments in at-risk females with the FMR1 premutation. Neurobiol Aging. 2014;35(9):2179 e7-13.

    Article  PubMed  Google Scholar 

  46. O'Keefe JA, Guan J, Robertson E, Biskis A, Joyce J, Ouyang B, et al. The effects of dual task cognitive interference and fast-paced walking on gait, turns, and falls in men and women with FXTAS. Cerebellum. 2021;20(2):212–21.

    Article  CAS  PubMed  Google Scholar 

  47. Napoli E, Flores A, Mansuri Y, Hagerman RJ, Giulivi C. Sulforaphane improves mitochondrial metabolism in fibroblasts from patients with fragile X-associated tremor and ataxia syndrome. Neurobiol Dis. 2021;157:105427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Polussa J, Schneider A, Hagerman R. Molecular advances leading to treatment implications for fragile X premutation carriers. Brain Disord Ther. 2014;3.

  49. Song G, Napoli E, Wong S, Hagerman R, Liu S, Tassone F, et al. Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor/ataxia syndrome: use of antioxidants in precision medicine. Mol Med. 2016;22:548–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tassone F, Adams J, Berry-Kravis EM, Cohen SS, Brusco A, Leehey MA, et al. CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet B Neuropsychiatr Genet. 2007;144B(4):566–9.

    Article  CAS  PubMed  Google Scholar 

  51. Lawson RA, Yarnall AJ, Duncan GW, Breen DP, Khoo TK, Williams-Gray CH, et al. Stability of mild cognitive impairment in newly diagnosed Parkinson's disease. J Neurol Neurosurg Psychiatry. 2017;88(8):648–52.

    Article  PubMed  Google Scholar 

  52. Hammers D, Spurgeon E, Ryan K, Persad C, Heidebrink J, Barbas N, et al. Reliability of repeated cognitive assessment of dementia using a brief computerized battery. Am J Alzheimers Dis Other Demen. 2011;26(4):326–33.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hagerman RJ, Hagerman P. Fragile X-associated tremor/ataxia syndrome - features, mechanisms and management. Nat Rev Neurol. 2016;12(7):403–12.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the participants and their families for their effort and dedication to this research. We also thank Drs. Corrisa Jacomini and Sundas Pasha for neuropsychological and psychiatric examinations of participants.

Funding

This work was supported by National Institute of Health Grants MH078041 and NS110100 to Drs. Hessl and Rivera; HD036071 and AG032115 to Dr. Hagerman; HD02274 to Dr. Tassone; 90DD0596 from Health and Human Services Administration of Developmental Disabilities; and by the MIND Institute Intellectual and Developmental Disabilities Research Center (P50 HD103526).

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Authors and Affiliations

Authors

Contributions

JF coordinated all participant screening, enrollment, and assessment activities and wrote the initial draft of the manuscript. EF contributed to the design of the study and completed all statistical analyses. RJH completed neurological and medical examinations of the majority of participants and determined participant FXTAS staging and diagnostic information. FT directed all molecular assays. AS assisted with design of the study and measure selection, completed neuropsychological assessments of participants, and contributed to interpretation of study results. SMR is a co-equal principal investigator (with DH) and obtained funding and wrote sections of the manuscript pertaining to integration of study findings with existing brain MRI literature. DH is a co-equal principal investigator and lead the design of the neuropsychological aspects of the project, obtained funding, directed assessment activities, wrote the discussion, and finalized the manuscript. The authors read and approved the final manuscript.

Corresponding author

Correspondence to David Hessl.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) at UC Davis (ID# 473010), and all participants gave informed consent.

Consent for publication

Not applicable.

Competing interests

Dr Hessl has received funding from the following, all of which is directed to UC Davis, in support of fragile X syndrome treatment programs, and he receives no personal funds and has no relevant financial interest in any of the commercial entities listed: Autifony, Ovid, Tetra, Healx, and Zynerba pharmaceutical companies to consult on outcome measures and clinical trial design. RJH has received funding from Zynerba and the Azrieli foundation for treatment studies in Fragile X syndrome and unrelated to this study.

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Famula, J., Ferrer, E., Hagerman, R.J. et al. Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome. J Neurodevelop Disord 14, 23 (2022). https://doi.org/10.1186/s11689-022-09436-y

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Keywords

  • CANTAB
  • Fragile X premutation
  • Tremor
  • Ataxia
  • Executive function
  • FXTAS