Age‐ and CGG repeat‐related slowing of manual movement in fragile X carriers: A prodrome of fragile X‐associated tremor ataxia syndrome?

Shickman, Ryan; Famula, Jessica; Tassone, Flora; Leehey, Maureen A.; Ferrer, Emilio; Rivera, Susan M.; Hessl, David

doi:10.1002/mds.27314

Cited by 14 publications

(20 citation statements)

References 45 publications

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“…Once there is significant white matter disease, the progression of further neurological dysfunction is thought to escalate, although the progression of FXTAS may be quite variable ( 33 ). A recent study by Shickman et al suggested that motor slowing may be measurable in asymptomatic premutation carriers before clinically observed motor or tremor symptoms arise in FXTAS ( 34 ). Future studies that examine white matter changes and subclinical motor signs of FXTAS may clarify which carriers are at greatest risk of developing clinical FXTAS symptoms.…”

Section: Discussionmentioning

confidence: 99%

Presence of Middle Cerebellar Peduncle Sign in FMR1 Premutation Carriers Without Tremor and Ataxia

et al. 2018

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Here we report five cases of male FMR1 premutation carriers who present without clinical symptoms of the fragile X-associated tremor/ataxia syndrome (FXTAS), but who on MRI demonstrate white matter hyperintensities in the middle cerebellar peduncles (MCP sign) and other brain regions, a rare finding. MCP sign is the major radiological feature of FXTAS; it is therefore remarkable to identify five cases in which this MRI finding is present in the absence of tremor and ataxia, the major clinical features of FXTAS. Subjects underwent a detailed neurological evaluation, neuropsychological testing, molecular testing, and MRI evaluation utilizing T2 imaging described here. Additional white matter disease was present in the corpus callosum in four of the five cases. However, all cases were asymptomatic for motor signs of FXTAS.

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Section: Discussionmentioning

confidence: 99%

Presence of Middle Cerebellar Peduncle Sign in FMR1 Premutation Carriers Without Tremor and Ataxia

et al. 2018

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“…While the results reported here are compelling, the study is not without limitations. Given the longitudinal aspect of this project, it is critically important that we continue to follow and track the progression of these biomarkers in conjunction with various neurological and neuropsychological symptoms, in particular motor control, balance and ataxia, and executive function (Shickman et al, 2018 ). Indeed, it will be critical to confirm whether or not the current group of non-converters remains asymptomatic, and if these findings remain in a larger cohort of Converters and Non-converters.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, it appears that atrophy of the midbrain and pons cross-sectional area may be a common phenotypic characteristic for FMR1 premutation carriers, while reductions in MCP width may be prognostic to FXTAS symptoms and progression. While we endeavor to assess to clinical viability of MCP width as a biomarker of FXTAS through our ongoing research, we compel clinicians to monitor and assess changes in the MCP, primarily for atrophy in width and hyperintensities, as well as other FXTAS radiological signs in premutation carriers at risk for FXTAS or with subtle non-specific clinical changes e.g., (Shickman et al, 2018 ). In sum, MCP width in FMR1 premutation carriers may be a candidate biomarker to clinically identify patients in prodromal and early stages of FXTAS to help guide candidates for treatment and perhaps monitor response.…”

Section: Discussionmentioning

confidence: 99%

Middle Cerebellar Peduncle Width—A Novel MRI Biomarker for FXTAS?

et al. 2018

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe neurodegenerative movement disorder affecting over 40% of male and 16% of female FMR1 premutation carriers over the age of 50. However, there is a lack of prognostic biomarkers to aid early diagnosis and treatment planning. Therefore, this study aimed to assess the utility of the Magnetic Resonance Parkinson Index (MRPI) as a potential MRI biomarker for FXTAS. The four measurements required for the MRPI were assessed in 45 male premutation carriers at risk of developing FXTAS (Mean age = 59.54 years), 53 male patients with FXTAS (Mean age = 66.16 years) and 61 male controls (Mean age = 60.75 years), of which 73 participants had follow-up visits on average 1.96 years later. Middle cerebellar peduncle (MCP) width as well as midbrain and pons cross-sectional area were reduced in patients with FXTAS compared to both premutation carriers without FXTAS and controls. While these measurements were not found to change over time in the three-group analysis, age was an important predictor of midbrain cross-sectional area and pons/midbrain ratio. MCP width was initially reduced in a subset of premutation carriers who developed FXTAS symptoms between their initial and follow-up visits, which also decreased between visits, compared to age-matched premutation carriers who did not show any FXTAS symptom development over time. Therefore, while the MPRI may not be a useful biomarker for FXTAS, decreased MCP width may be one of the first notable signs of FXTAS, and therefore the first biomarker with the potential to identify those most at risk for the disorder.

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“…The findings of subtle changes in the integrity of white matter in premutation male carriers without, or prior to, the occurrence of FXTAS [70][71][72], and of abnormal trajectories in cerebellar and brain stem volumes from early adulthood in these carriers [73] has provided direct evidence for preclinical brain changes. Indirect evidence for the pathological process relevant to neural involvement in non-FXTAS male carriers has also been obtained during the last decade [74,75], by observing the relationship between CGG expansion size and a modified combined measure of the three motor scales used individually in this study. However, there has been less evidence so far of neural involvement in non-FXTAS female carriers apart from a few reports of the presence of executive dysfunction [34], and early changes in postural stability [35].…”

Section: Discussionmentioning

confidence: 79%

Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways.

Storey

Bui

Stimpson

et al. 2020

Preprint

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Background Smaller expansions of CGG trinucleotide repeats in the FMR1 X-linked gene termed ‘premutation’ lead to a neurodegenerative disorder: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) in nearly half of aged carrier males, and 8-16% females. Core features include intention tremor, ataxia, and cognitive decline, and white matter lesions especially in cerebellar and periventricular locations. A ‘toxic’ role of elevated and expanded FMR1 mRNA has been linked to the pathogenesis of this disorder. The emerging issue concerns the trajectory of the neurodegenerative changes: is the pathogenetic effect confined to overt clinical manifestations? Here we explore the relationships between motor and cognitive scale scores in a sample of 57 asymptomatic adult female premutation carriers of broad age range. Methods Three motor scale scores (ICARS-for tremor/ataxia, UPDRS-for parkinsonism, and the Clinical Tremor) were related to 11 cognitive tests and two psychiatric pathology scores - DASS and SCL-90 - using Spearman’s rank correlations. Robust regression, applied in relationships between all phenotypic measures, and genetic molecular and demographic data, identified age and educational levels as common correlates of these measures, which were incorporated as confounders in correlation analysis. Results Cognitive tests demonstrating significant correlations with motor scores were those assessing psychomotor speed/visual attention (SDMT; TMT-A) and those dependent on various aspects of executive functioning for their execution: sequencing and alternation (TMTB-A); working memory (DS backwards); and non-verbal reasoning (MR). The largest number of motor x cognitive correlations involved ICARS and Tremor scales, which reflect the type of motor dysfunctions seen in FXTAS. Conclusions Subtle motor impairments correlating with cognitive deficits may occur in female premutation carriers not meeting diagnostic criteria for FXTAS. This pattern of cognitive deficits is consistent with those seen in other cerebellar disorders. Our results provide evidence that more than one category of clinical manifestation reflecting cerebellar changes – motor and cognitive - may be simultaneously affected by premutation carriage across a broad age range in asymptomatic carriers. Future longitudinal studies should determine whether cognitive dysfunction tracking motor impairments is driven by the premutation status common to all carriers, or only to a subset of carriers who will develop FXTAS in older age.

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Age‐ and CGG repeat‐related slowing of manual movement in fragile X carriers: A prodrome of fragile X‐associated tremor ataxia syndrome?

Abstract: Early-developing cerebellar or fronto-motor tract white matter changes, previously documented in MRI studies, may underlie motor slowing that occurs before clinically observable neurological symptoms associated with FXTAS. © 2018 International Parkinson and Movement Disorder Society.

Cited by 14 publications

References 45 publications

Presence of Middle Cerebellar Peduncle Sign in FMR1 Premutation Carriers Without Tremor and Ataxia

Presence of Middle Cerebellar Peduncle Sign in FMR1 Premutation Carriers Without Tremor and Ataxia

Middle Cerebellar Peduncle Width—A Novel MRI Biomarker for FXTAS?

Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways.

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