title: Clinicopathological description of two cases with SQSTM1 gene mutation associated with frontotemporal dementia.
abstract: There is a strong genetic influence on the clinicopathological phenotypes associated with frontotemporal lobar degeneration (FTLD) and frontotemporal dementia (FTD). Intracellular deposition of TDP-43 is the phenotypical hallmark of a frequent subgroup of cases. Mutations in the sequestosome 1 (SQSTM1) gene have rarely been found in individuals with FTD. Here we provide a comprehensive clinicopathological description of two cases with a SQSTM1 mutation. The clinical phenotype of patient 1 (mutation p.Glu396*) was compatible with the behavioural variant (bv) of FTD. TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology. However, prominent neuronal granular cytoplasmic TDP-43 immunoreactivity and abundant oligodendroglial inclusions, proven by colocalization with the oligodendroglial-marker TPPP/p25, were also seen. The clinical phenotype of patient 2 was compatible with bvFTD associated with parkinsonism and bulbar symptoms in the later stage. Genetic testing of patient 2 identified a C9orf72 repeat expansion mutation together with a missense mutation (p.Arg212Cys) in SQSTM1. TDP-43 pathology was characterized by neuritic profiles compatible mostly with type A. In contrast to patient 1, p62 pathology was seen to a greater extent as TDP-43 immunoreactivity in neurons. Using an antibody that detects poly(GP) peptides produced via repeat associated non-ATG translation associated with expanded hexanucleotide repeat in the C9orf72 gene, we confirmed the presence of pathognomonic inclusions. The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology. The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations. Oligodendroglial TDP-43 pathology is considerable in some forms of FTLD-TDP, thus their evaluation might be considered to be included in classification systems.
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, Antwerp, VIB, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Memory Disorders Clinic, Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Hort
authors.affiliation: Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, SMZ-Ost- Donauspital, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kristoferitsch
authors.affiliation: Department of Nuclear Medicine, SMZ-Ost-Donauspital, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Leitha
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ströbel
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, Antwerp, VIB, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic.|Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Radoslav
authors.initials: R
authors.lastname: Matej
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001519:Behavior; D000073885:C9orf72 Protein; D004252:DNA Mutational Analysis; D042622:DNA Repeat Expansion; D018450:Disease Progression; D057180:Frontotemporal Dementia / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D016501:Neurites / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D011506:Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D000071456:Sequestosome-1 Protein; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: FTD; SQSTM1; TDP-43; amyotrophic lateral sclerosis; p62