To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 mutation causing SCA48.

We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members.

Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with prominent cognitive decline and behavioral changes. Whole-exome sequencing identified a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3. Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was present in 1 case.

This study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48 and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark of the disease. Future studies will provide more insight into its pathologic heterogeneity.

描述具有引起 SCA48 的杂合STUB1突变的新谱系的临床和病理特征。

我们报告了大量荷兰体面的血统书。回顾临床和病理数据，并对多个家庭成员进行遗传分析（全外显子组测序、全基因组测序和连锁分析）。

患者出现成人起病的步态障碍（共济失调或帕金森症），并伴有明显的认知衰退和行为改变。全外显子组测序在 STUB1 中鉴定出一种新的杂合移码变体 c.731_732delGC (p.C244Yfs*24)，与疾病分离。该变体存在于染色体 16p13.3 上的连锁峰中。3 例的神经病理学检查显示小脑、新皮质和脑干中存在一致的泛素/p62 阳性神经元包涵体。此外，1 例出现 tau 病变。

该研究证实了先前发现的杂合STUB1突变是 SCA48 的原因，并强调了其突出的认知参与，除了小脑共济失调和运动障碍作为主要特征。核内包涵体的存在是该疾病的病理标志。未来的研究将更深入地了解其病理异质性。