Abundant copathologies of polyglucosan bodies, frontotemporal lobar degeneration with TDP-43 inclusions and ageing-related tau astrogliopathy in a family with a GBE1 mutation.

Autor:	Uemura MT; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Suh ER; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Robinson JL; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Brunden KR; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Grossman M; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Irwin DJ; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Lee VM; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Trojanowski JQ; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Lee EB; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Van Deerlin VM; Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Jazyk:	angličtina
Zdroj:	Neuropathology and applied neurobiology [Neuropathol Appl Neurobiol] 2023 Feb; Vol. 49 (1), pp. e12865.
DOI:	10.1111/nan.12865
Abstrakt:	Aims: Adult polyglucosan body disease (APBD) is a progressive neurogenetic disorder caused by 1,4-alpha-glucan branching enzyme 1 (GBE1) mutation with an accumulation of polyglucosan bodies (PBs) in the central and peripheral nervous systems as a pathological hallmark. Here, we report two siblings in a family with a GBE1 mutation with prominent frontotemporal lobar degeneration with TAR DNA-binding protein 43 (FTLD-TDP) and ageing-related tau astrogliopathy (ARTAG) copathologies with PBs in the central nervous system. Methods: Whole-genome sequencing (WGS) followed by Sanger sequencing (SS) was performed on three affected and two unaffected siblings in a pedigree diagnosed with familial frontotemporal dementia. Out of the affected siblings, autopsies were conducted on two cases, and brain samples were used for biochemical and histological analyses. Brain sections were stained with haematoxylin and eosin and immunostained with antibodies against ubiquitin, tau, amyloid β, α-synuclein, TDP-43 and fused in sarcoma (FUS). Results: A novel single nucleotide deletion in GBE1, c.1280delG, was identified, which is predicted to result in a reading frameshift, p.Gly427Glufs*9. This variant segregated with disease in the family, is absent from population databases and is predicted to cause loss of function, a known genetic mechanism for APBD. The affected siblings showed a greater than 50% decrease in GBE protein levels. Immunohistochemical analysis revealed widespread FTLD-TDP (type A) and ARTAG pathologies as well as PBs in the brains of two affected siblings for whom an autopsy was performed. Conclusions: This is the first report of a family with several individuals with a FTD clinical phenotype and underlying copathologies of APBD, FTLD-TDP and ARTAG with a segregating GBE1 loss-of-function mutation in affected siblings. The finding of copathologies of APBD and FTLD-TDP suggests these processes may share a disease mechanism resulting from this GBE1 mutation. (© 2022 British Neuropathological Society.)
Databáze:	MEDLINE
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