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. 2020 Mar 23;6(3):e417.
doi: 10.1212/NXG.0000000000000417. eCollection 2020 Jun.

Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation

Merel O Mol  1 , Jeroen G J van Rooij  1 , Esther Brusse  1 , Annemieke J M H Verkerk  1 , Shamiram Melhem  1 , Wilfred F A den Dunnen  1 , Patrizia Rizzu  1 , Chiara Cupidi  1 , John C van Swieten  1 , Laura Donker Kaat  1
Affiliations

Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation

Merel O Mol et al. Neurol Genet. .

Abstract

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.

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Figures

Figure 1
Figure 1. Pedigree of the family
Filled black symbols represent patients who were personally examined by the researchers. Filled gray symbols are affected individuals based on medical records (III-2 and III-3) or on reports from family members (II-2, III-1, III-5, and III-6). Individuals III-7, III-14, III-15, III-16, and III-17 were clinically unaffected and all deceased >75 years of age. Individual II-3 is an obligate carrier but did not have neurologic symptoms according to the family. Individual III-4 was diagnosed with Alzheimer disease without motor symptoms and without cerebellar atrophy and not considered to have the same phenotype. The numbers inside the symbols represent the number of individuals. Sex is not specified to protect anonymity. Transmission was independent of sex (including male to male transmission). + = mutated allele; – = wild type.
Figure 2
Figure 2. Histopathologic features of affected cases III-13 (A–H) and III-10 (I and J)
(A and B) Nearly complete loss of Purkinje cells, loss of neurons, and spongiosis in the cerebellar granular layer of the patient (A) compared with the control brain (B) in H/E staining; (C and D) NII in the cerebellar granular layer with ubiquitin (C) and p62 staining (D); (E) NII in the occipital cortex with p62 staining; (F) DNS in the occipital cortex with 1C2 staining; (G) DNS in the inferior olive with 1C2 staining; (H) granular CI in the hypoglossal nucleus with 1C2 staining; (I) AT8-positive neurons, neurites, and glial staining in the thalamic nuclei; (J) AT8-positive tufted astrocyte in the putamen. The arrowheads indicate NII, which are magnified in figure 2C-F. CI = cytoplasmic inclusion; DNS = diffuse nuclear staining; H/E = hematoxylin and eosin staining; NII = neuronal intranuclear inclusion.
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