PT  - JOURNAL ARTICLE
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 <em>STUB1</em> mutation
AID  - 10.1212/NXG.0000000000000417
DP  - 2020 Jun 01
TA  - Neurology Genetics
PG  - e417
VI  - 6
IP  - 3
4099  - http://ng.neurology.org/content/6/3/e417.short
4100  - http://ng.neurology.org/content/6/3/e417.full
SO  - Neurol Genet2020 Jun 01; 6
AB  - Objective To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 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 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.Conclusions 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.AD=Alzheimer disease; CHIP=C-terminus of Hsp70-interacting protein; CI=cytoplasmic inclusion; DNS=diffuse nuclear staining; FTD=frontotemporal dementia; GATK=Genome Analysis Toolkit; NII=neuronal intranuclear inclusion; PSP=progressive supranuclear palsy; SCA=spinocerebellar ataxia; STR=short tandem repeat; WES=whole-exome sequencing; WGS=whole-genome sequencing