Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.
Mendelics Genomic Analyses, São Paulo, Brazil.
Ann Neurol. 2021 Aug;90(2):239-252. doi: 10.1002/ana.26136. Epub 2021 Jun 14.
Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11).
We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls.
Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions).
These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021;90:239-252.
蛋白质错误折叠不仅在肌萎缩侧索硬化症（ALS）中起核心作用，而且在其他疾病中也起核心作用，例如额颞叶痴呆（FTD）、包涵体肌病（hIBM）或 Pagets 骨病。多系统蛋白病（MSP）的概念是为了说明那些罕见的家族，这些家族在同一个家系中至少有 2 种以上的这些 4 种疾病分离。最近发现钙依赖性磷脂结合蛋白 annexin A11 与欧洲家系的 ALS 有关。在此，我们详细描述了 3 个巴西家族，这些家族存在 hIBM（单独存在或与 ALS/FTD 同时存在），由编码 annexin A11（ANXA11）的基因中的新型 p.D40Y 变化引起。
我们收集了 11 名受影响个体的临床、遗传、病理学和骨骼肌影像学资料。还从 8 名患者和 8 名匹配的对照中获得了神经影像学资料。
这种新型 hIBM 的临床-放射学表型显示出缓慢进展的主要肢体带综合征，但也经常涉及轴向（上睑下垂/垂头）和远端（内侧腓肠肌）。肌肉病理学发现了大量带有阳性 annexin A11、TDP-43 和 p62 包涵体的边缘空泡，但没有炎症。中枢神经系统也受到影响：2 名患者患有 FTD，但弥散张量成像在整个组中发现了多个脑白质损伤区域（包括皮质脊髓束和额下皮质区域）。
这些发现扩展了与 ANXA11 相关的表型谱。该基因应被认为是一种新型多系统蛋白病（MSP 型 6）的原因，而不仅仅是 ALS。神经病学年鉴 2021；90:239-252.
