Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders

Robertson, Erin; Hall, Deborah A.; McAsey, Andrew; O’Keefe, Joan A.

doi:10.1080/13854046.2016.1202239

Cited by 26 publications

(26 citation statements)

References 422 publications

(534 reference statements)

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“…Tremor is the most frequent symptom and is seen in 80 % of patients, cerebellar ataxia in 50 % and parkinsonism in 30 % (13). Most patients have mixed tremor, with tremors both at rest and during movement.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Dementia is also seen at advanced stages of the disease, and it is reported that as many as 50 % of male patients over the age of 55 fulfil criteria for dementia (13). Patients with fragile X-associated tremor/ataxia syndrome also have increased rates of anxiety and depression, with a lifetime prevalence of severe depression of 44 %, and of anxiety disorders of 52 % (14).…”

Section: Clinical Featuresmentioning

confidence: 99%

“…This also applies to cases with atypical development of other movement disorders. Table 1 provides a brief summary of the clinical similarities and differences between fragile X-associated tremor/ataxia syndrome and the movement disorders listed above (13). Table 1 Differential diagnoses of fragile X-associated tremor/ataxia syndrome (13).…”

Section: Clinical Differential Diagnosesmentioning

confidence: 99%

“…Cerebellar involvement also gives rise to slurred speech (dysarthria) and imprecise movements of the upper extremities (ataxia and dysmetria) in the majority of patients (13).…”

Section: Clinical Featuresmentioning

confidence: 99%

“…In 2016, Robertson et al published a systematic review in which they compared the phenotype of fragile X-associated tremor/ataxia syndrome to that of essential tremor, Parkinson's disease, autosomal dominant hereditary ataxias, multiple system atrophy, and progressive supranuclear palsy (13).…”

Section: Clinical Differential Diagnosesmentioning

confidence: 99%

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Fragilt X-assosiert tremor-ataksi-syndrom

Hoem¹,

Koht²

2017

Tidsskriftet

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Section: Clinical Featuresmentioning

confidence: 99%

Section: Clinical Featuresmentioning

confidence: 99%

Section: Clinical Differential Diagnosesmentioning

confidence: 99%

“…Cerebellar involvement also gives rise to slurred speech (dysarthria) and imprecise movements of the upper extremities (ataxia and dysmetria) in the majority of patients (13).…”

Section: Clinical Featuresmentioning

confidence: 99%

Section: Clinical Differential Diagnosesmentioning

confidence: 99%

See 3 more Smart Citations

Fragilt X-assosiert tremor-ataksi-syndrom

Hoem¹,

Koht²

2017

Tidsskriftet

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Neuropathology of FMR1‐premutation carriers presenting with dementia and neuropsychiatric symptoms

Dijkstra

Haify

Verwey

et al. 2020

Alzheimer's & Dementia

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Background CGG repeat expansions in the premutation range (55‐200) of the FMR1 gene can lead to Fragile‐X associated tremor/ataxia syndrome (FXTAS). Clinically, FXTAS is characterized by progressive tremor and ataxia, however psychiatric symptoms can also manifest as part of the syndrome, termed Fragile‐X associated neuropsychiatric disorders (FXAND) (1). Pathology of FXTAS/FXAND include ubiquitin‐positive intranuclear inclusions in both neurons and glia cells. Recently, FMRpolyG RAN‐translation product has been identified in the majority of the inclusions (2). Method Here, we describe two cases with predominantly FXAND symptoms with mild movement disturbances. One donor was diagnosed with vascular dementia and frontotemporal dementia during life carrying an 107 CGG repeat expansion in the FMR1 gene. Donor two, carrying an 77 repeat expansion, presented with dementia and behavior alterations, and suffered from several infarcts throughout the brain. Result Macroscopically, both donors showed no FXTAS‐characteristic white matter lesions on MRI, but vascular infarcts in cortical‐ and subcortical regions were identified. At microscopic level, vascular pathology was observed throughout the brain. A high number of p62‐positive intranuclear inclusions were observed predominantly in cortical regions in neuronal, glial, ependymal, choroid plexus and endothelial cells. The majority of these inclusions were positive for FMRpolyG as well. Dopaminergic neurons in the substantia nigra contained p62‐positive intranuclear inclusions, but were FMRpolyG negative. Conclusion We conclude that in these patients with FXAND, no characteristic MRI abnormalities are seen and that the inclusion pathology of FXAND also affects the vasculature of the brain. Inclusions were present in large numbers throughout the brain, and often positive for FMRpolyG. The described donors clinically resemble other types of dementia, and in absence of genetic testing or family history, FMRpolyG can be used post‐mortem to identify premutation carriersHagerman et al. Fragile X‐Associated Neuropsychiatric Disorders (FXAND) Front. Psychiatry. 2018. (2) Krans et al. Neuropathology of RAN translation proteins in fragile X‐associated tremor/ataxia syndrome Acta Neuropathol Commun. 2019.

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Cerebellum neuropathology and motor skill deficits in fragile X syndrome

Chen

Guo

Han

et al. 2022

Intl J of Devlp Neuroscience

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Fragile X syndrome (FXS) is a leading form of inherited intellectual disability and single‐gene cause of autism spectrum disorder (ASD) and is characterized by core deficits in cognitive flexibility, sensory sensitivity, emotion, and social interactions. Motor deficits are a shared feature of FXS and autism. The cerebellum has emerged as one of the target brain areas affected by neurodevelopmental diseases. Alterations in the cerebellar structure, circuits, and function may be the key drivers of impaired fine and gross motor skills in FXS and fragile X‐associated tremor/ataxia syndrome (FXTAS). In this review, we briefly examined recent findings in FXS and present a discussion on the literature supporting motor skill deficits in FXS. Subsequently, we focused on neuropathological alterations in the cerebellum in FXS and FXTAS. We highlight studies that have directly examined the function of fragile X mental retardation protein and related epigenetic variations in the cerebellum. Overall, we obtained considerable supporting evidence for the hypothesis that cerebellar dysfunction is evident in FXS and FXTAS; however, compared with studies on other ASD models, studies on motor skills related to fragile X disorders are particularly rare and inconclusive. Hence, future research should address FXS‐related motor and behavioral trajectories and examine the underlying mechanisms at both the cell and circuit levels.

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Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders

Abstract: Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.

Cited by 26 publications

References 422 publications

Fragilt X-assosiert tremor-ataksi-syndrom

Fragilt X-assosiert tremor-ataksi-syndrom

Neuropathology of FMR1‐premutation carriers presenting with dementia and neuropsychiatric symptoms

Cerebellum neuropathology and motor skill deficits in fragile X syndrome

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