AI Article Synopsis
- Pathogenic variants in the STUB1 gene are linked to autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia, with cognitive impairment seen in 54% of carriers.
- In a study of 440 cases of cerebellar ataxia, variants were identified in 50 patients, with significant variability in onset age and severity; a notable number of patients were women.
- Additionally, findings suggest that STUB1 variant effects may be influenced by other genetic variants and the patient’s sex, highlighting a 7% involvement of STUB1 in dominantly inherited cerebellar ataxias.
Article Abstract
Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).
Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.
Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.
Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.
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| http://dx.doi.org/10.1038/s41436-020-0899-x | DOI Listing |
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