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.
Neuropathol Appl Neurobiol. 2023 Feb;49(1):e12865. doi: 10.1111/nan.12865.
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.
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).
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.
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.
成人多聚糖体病（APBD）是一种进行性神经遗传疾病，由 1,4-α-葡聚糖分支酶 1（GBE1）突变引起，其特征是中枢和周围神经系统中多聚糖体（PBs）的积累。在这里，我们报告了一个家族中的两个兄弟姐妹，他们患有 GBE1 突变，表现为额颞叶变性伴 TAR DNA 结合蛋白 43（FTLD-TDP）和与年龄相关的 tau 星形胶质病（ARTAG）共病，中枢神经系统中有 PBs。
对一个家族中被诊断为家族性额颞叶痴呆的三个受影响和两个未受影响的兄弟姐妹进行全基因组测序（WGS）和 Sanger 测序（SS）。在受影响的兄弟姐妹中，对两个病例进行了尸检，并使用脑样本进行了生化和组织学分析。脑切片用苏木精和伊红染色，并免疫染色针对泛素、tau、淀粉样β、α-突触核蛋白、TDP-43 和融合肉瘤（FUS）的抗体。
发现了 GBE1 中的一个新的单核苷酸缺失，c.1280delG，预计会导致阅读框移位，p.Gly427Glufs*9。该变体在家族中与疾病分离，不存在于人群数据库中，预计会导致功能丧失，这是 APBD 的一种已知遗传机制。受影响的兄弟姐妹的 GBE 蛋白水平下降超过 50%。免疫组织化学分析显示，两个进行尸检的受影响兄弟姐妹的大脑中存在广泛的 FTLD-TDP（A型）和 ARTAG 病理学以及 PBs。
这是第一个报告有几个个体具有 FTD 临床表型和潜在的 APBD、FTLD-TDP 和 ARTAG 共病的家族，受影响的兄弟姐妹中存在 GBE1 功能丧失突变。APBD 和 FTLD-TDP 的共病发现表明这些过程可能共享由该 GBE1 突变引起的疾病机制。
