TY  - JOUR
AU  - Mol, Merel O
AU  - van Rooij, Jeroen G J
AU  - Brusse, Esther
AU  - Verkerk, Annemieke J M H
AU  - Melhem, Shamiram
AU  - den Dunnen, Wilfred F A
AU  - Rizzu, Patrizia
AU  - Cupidi, Chiara
AU  - van Swieten, John C
AU  - Donker Kaat, Laura
TI  - Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation.
JO  - Neurology / Genetics
VL  - 6
IS  - 3
SN  - 2376-7839
CY  - Minneapolis, Minn.
M1  - DZNE-2020-01319
SP  - e417
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32337344
C2  - pmc:PMC7164971
DO  - DOI:10.1212/NXG.0000000000000417
UR  - https://pub.dzne.de/record/153322
ER  -