Neuropathology of FMR1‐premutation carriers presenting with dementia and neuropsychiatric symptoms: Human neuropathology/other. (7th December 2020)

• Record Type: Journal Article
• Authors: Dijkstra, Anke A.; Haify, Saif; Verwey, Nicolaas A.; Prins, Niels D.; van der Toorn, Esmay; Rozemuller, Annemieke J.M.; Bugiani, Marianna; den Dunnen, Wilfred; Todd, Peter K.; Charlet‐Berguerand, Nicolas; Willemsen, Rob; Hukema, Renate; Hoozemans, Jeroen J.M.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.044916
• Languages: English
• ISSNs: 1552-5260

Abstract

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.