Domoto-Reilly Kimiko, Distad B Jane, Miller Danny E, Lin Yi-Han, Ivanick David, Warren Andrew S, Jayadev Suman, Latimer Caitlin S
From the Department of Neurology (K.D.-R., B.J.D., Y.L., S.J.); Department of Laboratory Medicine and Pathology (D.E.M.); Department of Pediatrics (D.E.M.); Brotman Baty Institute for Precision Medicine (D.E.M.), University of Washington, Seattle, WA; Department of Neurology (D.I.), Swedish Medical Center, Seattle, WA; College of Osteopathic Medicine (A.S.W.), Pacific Northwest University of Health Sciences, Yakima, WA; Department of Laboratory Medicine and Pathology (S.J., C.S.L.); and Department of Medical Genetics (S.J.), University of Washington.
Neurol Genet. 2024 Jul 24;10(4):e200173. doi: 10.1212/NXG.0000000000200173. eCollection 2024 Aug.
Here, we report detailed clinicopathologic evaluation of 2 individuals with pathogenic variants in , including one novel likely pathogenic splice variant. We describe the striking diversity of clinical phenotypes among family members and also the brain and spinal cord neuropathology associated with these 2 distinct variants.
Two individuals with pathogenic variants in and their families were clinically characterized, and the probands subsequently underwent extensive postmortem neuropathologic examination of their brains and spinal cords.
Multiple affected individuals within a single family were found to carry a previously unreported c.358+3A>G variant, predicted to alter splicing. Detailed histopathologic evaluation of our 2 variant carriers demonstrated distinct TDP-43 pathologic subtypes, but shared argyrophilic grain disease (AGD) tau pathology.
Although all pathogenic variants are associated with TDP-43 pathology, the clinical and histologic features can be highly variable. Within one family, we describe distinct neurologic presentations which we propose are all caused by a novel c.358+3A>G variant. AGD is typically associated with older age, but it has been described as a copathologic finding in other variant carriers and may be a common feature in FTLD-TDP due to .
在此，我们报告了2例携带 致病变异的个体的详细临床病理评估，其中包括1种新的可能致病的剪接变异。我们描述了家庭成员之间临床表型的显著差异，以及与这2种不同的 变异相关的脑和脊髓神经病理学特征。
对2例携带 致病变异的个体及其家族进行临床特征分析，先证者随后接受了广泛的脑和脊髓死后神经病理学检查。
在一个家族中发现多个受累个体携带一种先前未报道的c.358+3A>G变异，预计会改变剪接。对我们的2例 变异携带者进行的详细组织病理学评估显示出不同的TDP-43病理亚型，但均有嗜银颗粒病（AGD）tau病理特征。
尽管所有致病的 变异均与TDP-43病理相关，但其临床和组织学特征可能高度可变。在一个家族中，我们描述了不同的神经系统表现，我们认为这些表现均由一种新的c.358+3A>G变异引起。AGD通常与老年相关，但在其他 变异携带者中也被描述为共同病理发现，并且可能是由 导致的额颞叶痴呆伴TDP（FTLD-TDP）的常见特征。
