Clinical and pathologic phenotype of a large family with heterozygous <i>STUB1</i> mutation
Merel O. Mol, Jeroen van Rooij, Esther Brusse, Annemieke J.M.H. Verkerk, Shamiram Melhem, Wilfred F.A. den Dunnen, Patrizia Rizzu, Chiara Cupidi, John C. van Swieten, Laura Donker Kaat
Abstract
OBJECTIVE: mutation causing SCA48. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.