Abstract
CGG repeat expansions within the premutation range (55–200) of the FMR1 gene can lead to Fragile X-associated tremor/ataxia syndrome and Fragile X-associated neuropsychiatric disorders. These CGG repeats are translated into a toxic polyglycine-containing protein, FMRpolyG. Pathology of Fragile X-associated tremor/ataxia syndrome and Fragile X-associated neuropsychiatric disorders comprises FMRpolyG- and p62-positive intranuclear inclusions. Diagnosing a FMR1-premutation carrier remains challenging, as the clinical features overlap with other neurodegenerative diseases. Here, we describe two male cases with Fragile X-associated neuropsychiatric disorders-related symptoms and mild movement disturbances and novel pathological features that can attribute to the variable phenotype. Macroscopically, both donors did not show characteristic white matter lesions on MRI; however, vascular infarcts in cortical- and sub-cortical regions were identified. Immunohistochemistry analyses revealed a high number of FMRpolyG intranuclear inclusions throughout the brain, which were also positive for p62. Importantly, we identified a novel pathological vascular phenotype with inclusions present in pericytes and endothelial cells. Although 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. Overall, our report suggests that Fragile X-associated tremor/ataxia syndrome and Fragile X-associated neuropsychiatric disorders may present diverse clinical involvements resembling other types of dementia, and in the absence of genetic testing, FMRpolyG can be used post-mortem to identify premutation carriers.
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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