Abstract
AbstractBackgroundCGG 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).MethodHere, 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.ResultMacroscopically, 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.ConclusionWe 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.
Highlights
The Fragile X mental retardation 1 (FMR1) gene contains a CGG dynamic trinucleotide repeat sequence
We identified a novel pathological vascular phenotype with inclusions present in pericytes and endothelial cells. These results need to be confirmed in more cases, we propose that these vascular lesions in the brain could contribute to the complex symptomology of FMR1-premutation carriers
The patient was demented and atypical Alzheimer’s disease (AD) and frontotemporal dementia were added to the differential diagnosis
Summary
The Fragile X mental retardation 1 (FMR1) gene contains a CGG dynamic trinucleotide repeat sequence. Expansions of the repeat sequence to more than 200 CGG repeats result in the absence of the FMR1 protein, and in the Fragile X syndrome (Murray et al, 1997). Smaller expansions (55–200 CGG repeats) are in the premutation range (Brouwer et al, 2009) and can lead to Fragile X-associated diseases, including the neurodegenerative diseases Fragile X-associated tremor/ataxia syndrome (FXTAS) (Berry-Kravis et al, 2007a) and the Fragile X-associated neuropsychiatric disorders (FXAND) (Hagerman et al, 2018). CGG-repeats in the premutation range are transcribed and translated into a toxic polyglycine-containing protein, named FMRpolyG protein (Todd et al, 2013). FMRpolyG is considered to play a major role in the pathogenesis of FXTAS (Sellier et al, 2017; Boivin et al, 2018)
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