title: Sequence variants in eukaryotic translation initiation factor 4-gamma (eIF4G1) are associated with Lewy body dementia.
abstract: We recently reported a missense mutation and four variants in eukaryotic translation initiation factor 4-gamma (EIF4G1) associated with parkinsonism, dementia or both. In those with a positive family history, the mode of inheritance was autosomal dominant. Detailed neuropathologic descriptions of individuals with EIF4G1 genetic variants have not been reported. Herein, we report neuropathologic findings of three individuals from two American families with EIF4G1 variants. The patients had initial clinical presentations of dementia or parkinsonism and all had dementia at the time of autopsy. One family carried an EIF4G1 double variant, c.2056G>T (p.G686C) and c.3589C>T (p.R1197 W), and one family carried variant c.1505C>T (p.A502V). All three patients also carried at least one ε4 allele of apolipoprotein E. One individual presented with cognitive impairment without significant parkinsonism; one presented with memory problems followed by bradykinesia; and the third presented with cardinal signs of Parkinson's disease, followed more than a year later by cognitive dysfunction. Pathological examination showed diffuse cortical Lewy bodies and Lewy neurites in all patients. A small subset of Lewy bodies and Lewy neurites were immunopositive for eIF4G1. All patients had moderate to frequent non-neuritic, cortical amyloid plaques, mostly medial temporal neurofibrillary pathology (Braak neurofibrillary tangle stages of II to IV), and minimal or no TDP-43 pathology. The results suggest that in some patients variants in EIF4G1 can be associated with pathology that has a high likelihood of association with clinical features of dementia with Lewy bodies.
authors.affiliation: Departments of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Fujioka
authors.forename: Christina
authors.initials: C
authors.lastname: Sundal
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Strongosky
authors.forename: Monica Case
authors.initials: MC
authors.lastname: Castanedes
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Carles
authors.initials: C
authors.lastname: Vilariño-Güell
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics*; D005192:Family Health; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D020961:Lewy Body Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged
chemical_list: C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D007381:Intermediate Filament Proteins; C430456:desmuslin