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

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) co-pathologies 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 2 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 co-pathologies of APBD, FTLD-TDP, and ARTAG with a segregating GBE1 loss-of-function mutation in affected siblings. The finding of co-pathologies of APBD and FTLD-TDP suggests these processes may share a disease mechanism resulting from this GBE1 mutation.