Journal Article

DZNE-2020-01319

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation.

Mol, M. O. (Corresponding author) ; van Rooij, J. G. J. ; Brusse, E. ; Verkerk, A. J. M. H. ; Melhem, S. ; den Dunnen, W. F. A. ; Rizzu, P.DZNE* ; Cupidi, C. ; van Swieten, J. C. ; Donker Kaat, L.

2020
Minneapolis, Minn.

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Please use a persistent id in citations: doi:10.1212/NXG.0000000000000417

Abstract: 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.

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Contributing Institute(s):

1. Applied Genomics for Neurodegenerative Diseases (AG Rizzu)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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