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Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment
Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment
- Source :
- Genetics in Medicine, Genetics in Medicine, Nature Publishing Group, 2020, 22 (11), pp.1851-1862. ⟨10.1038/s41436-020-0899-x⟩, Genetics in medicine
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- International audience; 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.
- Subjects :
- Male
Pathology
MESH: Ataxia
Purkinje cell
Medizin
MESH: Cognitive Dysfunction
0302 clinical medicine
spinocerebellar ataxia
ATP-Dependent Proteases
SCA48
Medicine
Genetics (clinical)
0303 health sciences
Penetrance
3. Good health
MESH: Cerebellar Ataxia
MESH: ATPases Associated with Diverse Cellular Activities
medicine.anatomical_structure
Spinocerebellar ataxia
Female
medicine.symptom
Frontotemporal dementia
medicine.medical_specialty
Ataxia
Cerebellar Ataxia
MESH: Spinocerebellar Ataxias
Ubiquitin-Protein Ligases
Neuropathology
03 medical and health sciences
MESH: ATP-Dependent Proteases
Atrophy
Humans
Spinocerebellar Ataxias
Cognitive Dysfunction
030304 developmental biology
cognitive impairment
SCAR16
STUB1
MESH: Humans
Cerebellar ataxia
business.industry
medicine.disease
MESH: Ubiquitin-Protein Ligases
MESH: Male
ATPases Associated with Diverse Cellular Activities
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Human medicine
business
MESH: Female
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 10983600
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine, Genetics in Medicine, Nature Publishing Group, 2020, 22 (11), pp.1851-1862. ⟨10.1038/s41436-020-0899-x⟩, Genetics in medicine
- Accession number :
- edsair.doi.dedup.....10c4642c4e5d177527da8016ea948e04
- Full Text :
- https://doi.org/10.1038/s41436-020-0899-x⟩