Department of Neuropathology, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Neurology. 2010 Aug 17;75(7):611-8. doi: 10.1212/WNL.0b013e3181ed9cde. Epub 2010 Jul 28.
Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a form of ALS characterized by protein deposits in motor neurons that are morphologically and tinctorially distinct from those of classic sporadic ALS. The nosologic position of this type of ALS in the molecular pathologic and genetic classification of ALS is unknown.
We identified neuropathologically 4 patients with juvenile ALS with basophilic inclusions and tested the hypothesis that specific RNA binding protein pathology may define this type of ALS. Immunohistochemical findings prompted us to sequence the fused in sarcoma (FUS) gene.
Motor symptoms began between ages 17 and 22. Disease progression was rapid without dementia. No family history was identified. Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43). Granular and compact FUS deposits were identified in glia and neuronal cytoplasm and nuclei. Ultrastructure of aggregates was in keeping with origin from fragmented rough endoplasmic reticulum. Sequencing of all 15 exons of the FUS gene in 3 patients revealed a novel deletion mutation (c.1554_1557delACAG) in 1 individual and the c.1574C>T (P525L) mutation in 2 others.
Juvenile ALS with basophilic inclusions is a FUS proteinopathy and should be classified as ALS-FUS. The FUS c.1574C>T (P525L) and c.1554_1557delACAG mutations are associated with this distinct phenotype. The molecular genetic relationship with frontotemporal lobar degeneration with FUS pathology remains to be clarified.
伴有嗜碱性包涵体的青少年肌萎缩侧索硬化症（ALS）是一种 ALS 形式，其特征在于运动神经元中的蛋白沉积物在形态和染色方面与经典散发性 ALS 不同。这种 ALS 在 ALS 的分子病理和遗传分类中的分类位置尚不清楚。
我们鉴定了 4 例伴有嗜碱性包涵体的青少年 ALS 患者，并检验了特定 RNA 结合蛋白病理学可能定义这种 ALS 的假说。免疫组织化学发现促使我们对融合肉瘤（FUS）基因进行测序。
运动症状始于 17 至 22 岁之间。疾病进展迅速，无痴呆。未发现家族史。嗜碱性包涵体对 FUS 蛋白呈强阳性，但对 TAR DNA 结合蛋白 43（TDP-43）呈阴性。在神经胶质细胞和神经元细胞质及核内发现颗粒状和致密状 FUS 沉积物。聚集物的超微结构与源自碎片状粗面内质网的起源一致。对 3 例患者的 FUS 基因的所有 15 个外显子进行测序，发现 1 例存在新的缺失突变（c.1554_1557delACAG），另外 2 例存在 c.1574C>T（P525L）突变。
伴有嗜碱性包涵体的青少年 ALS 是一种 FUS 蛋白病，应归类为 ALS-FUS。FUS c.1574C>T（P525L）和 c.1554_1557delACAG 突变与这种独特表型相关。与具有 FUS 病理学的额颞叶痴呆的分子遗传关系仍有待阐明。
