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

Anke Dijkstra (1) , Saif Haify (2) , Niek Verwey , Niels Prins (3) , Esmay van Der Toorn , Annemieke Rozemuller , Marianna Bugiani , Wilfred den Dunnen (4) , Peter Todd (5) , Nicolas Charlet-Berguerand (6) , Rob Willemsen , Renate Hukema , Jeroen Hoozemans (1)

1 Amsterdam UMC - Amsterdam University Medical Center
2 Erasmus MC - Erasmus University Medical Center [Rotterdam]
3 VU University Medical Center [Amsterdam]
4 UMCG - University Medical Center Groningen [Groningen]
5 University of Michigan [Ann Arbor]
6 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Domaines: Sciences du Vivant [q-bio]

Anke Dijkstra, Saif Haify, Niek Verwey, Niels Prins, Esmay van Der Toorn, et al.. Neuropathology of FMR1 -premutation carriers presenting with dementia and neuropsychiatric symptoms. Brain Communications, 2021, 3 (1), pp.fcab007. ⟨10.1093/braincomms/fcab007⟩. ⟨hal-03339489⟩