Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48)

Abstract

ObjectiveTo describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA.MethodsThis is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3.ResultsSix patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT STUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function.ConclusionsWe report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

“…In our cohort, clinical phenotyping in 11 patients from eight kindred substantially confirms the SCA48 clinical picture described in previous reports [15,16]. Indeed, all of the newly identified patients manifest with adult-onset cerebellar ataxia and dysarthria, associated with a significant cerebellar atrophy, prevalently involving the vermis and lobules VI-VII.…”

“…The in‐depth characterization of the SCA48 patients from our study expands the spectrum of clinical, genetic and neuroimaging features associated with this autosomal dominant SCA variant, suggesting a more complex neurological phenotype than that illustrated in the original report .…”

“…Following the results of NGS and segregation studies, detailed clinical phenotyping was performed in the 11 heterozygous STUB1-positive patients, further supporting a pathogenic role of the identified mutations and thus a diagnosis of SCA48 (Table 1). Indeed, all of them showed various additional features, including parkinsonism, dystonia, chorea, neuropsychiatric symptoms or endocrine dysfunction, shared with both SCA48 [15,16] and SCAR16 patients [5][6][7][8][9][10][11][12][13].…”

“…In contrast to SCAR16 patients [5,7,8,10], none of our SCA48 patients had major pyramidal tract signs, nor evidence of peripheral neuropathy. Regarding the latter issue, lack of peripheral nervous system involvement also characterizes STUB1-mutated patients so far described in the literature [5][6][7][8][9][10][11][12][13]15,16]. Accordingly, immunohistochemical studies in mouse models have documented the expression of CHIP only in the central nervous system [5].…”

Extending the Phenotypic Spectrum Associated with STUB1 Mutations: A Case of Dystonia

“…High FSH and LH levels in our patient, consistent with menopause, normal puberty, and fertility, ruled out the possibility of Gordon Holmes syndrome. SCA48 is a newly described entity in 3 family members with ataxia and cognitive affective syndrome caused by a heterozygous mutation in STUB1 gene. As 1 of the 2 heterozygous variants in our patient was classified as a variant of unknown significance, a diagnosis of SCA48 could be considered; however, this would be unlikely as there was no autosomal‐dominant family history of ataxia.…”