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

Abstract

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.

Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain‐of‐function toxicity mechanism contributing to the pathogenesis of fragile X‐associated premature ovarian insufficiency

“…Next, we carried out immunostaining for p62, a marker of the proteasomal and autophagic degradation pathways and observed that some, but not all cells, positive for either CGG RNA or FMRpolyG expression were also positive for p62 at 48 h post transfection (Figure 2E). This suggests that the CGG RNA aggregates and FMRpolyG expression observed are not artefactual but biologically meaningful 40,41,54 . It is possible that the proportion of p62 positive CGG/FMRpolyG positive cells may increase at 72 h post transfection, however this was not explored further due to low cell viability at later time points.…”

“…This suggests that the CGG RNA aggregates and FMRpolyG expression observed are not artefactual but biologically meaningful. 40,41,54 It is possible that the proportion of p62 positive CGG/FMRpolyG positive cells may increase at 72 h post transfection, however this was not explored further due to low cell viability at later time points.…”

“…35,36 In the case of FMR1, expanded CGG repeats are predominantly translated into a polyglycinecontaining protein, named FMRpolyG, which forms ubiquitin-positive intranuclear inclusions and which expression is toxic for neurons in cell and animal models. [37][38][39] Intranuclear inclusions of FMRpolyG have been detected in the brains of FXTAS patients, 37,[39][40][41] as well as in non-CNS tissues, 42 including the ovarian stroma of a woman with FXPOI, 43 and in mural granulosa cells from six FMR1 premutation carriers. 44 Furthermore, FMRpolyG protein has been detected in the ovarian stroma of mice expressing expanded CGG repeats.…”