SQSTM1 gene as a potential genetic modifier of CADASIL phenotype
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SQSTM1 gene as a potential genetic modifier of CADASIL phenotype Maria Rosário Almeida1 · Ana Rita Silva1 · Inês Elias1 · Carolina Fernandes2 · Rita Machado2 · Orlando Galego3 · Gustavo Cordeiro Santo1,2 Received: 20 August 2020 / Revised: 5 November 2020 / Accepted: 8 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease and is caused by mutations in the NOTCH3 gene. Interestingly, CADASIL patients present a large phenotypic variability even harboring the same pathogenic variant. We describe two CADASIL siblings with a particularly aggressive clinical phenotype characterized by early-onset stroke, gait disturbances and/or dementia, severe emotional dysregulation, and dysexecutive syndrome together with a severe white matter burden on MRI. The genetic analysis revealed the co-occurrence of NOTCH3 (p.Gly420Cys) and SQSTM1 (p.Ser275Phefs*17) pathogenic variants which might worsen the aggressiveness of disease progression in both siblings. Interestingly, to the best of our knowledge, mutations in SQSTM1 gene have never been described in CADASIL patients before. Curiously, both Notch3 and p62 encoded proteins have a key role in the autophagy-lysosomal pathway which is impaired in CADASIL patients. Thus, the contribution of SQSTM1 gene to the clinical heterogeneity of CADASIL patients, in particular for those who develop cognitive impairment or dementia at an early age, is certainly overlooked. Therefore, we advocate expanding the genetic analysis to other genes associated with the phenotype spectrum of CADASIL patients using NGS-customized gene panel. Keywords CADASIL · NOTCH3 · SQSTM1 · Dementia · Emotional dysregulation · White matter hyperintensities
Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM #125310) is the most common inherited cerebral small-vessel disease [1]. It affects middle-aged adults, and is clinically characterized by recurrent cerebral ischemic episodes, migraine with aura, psychiatric symptoms, and progressive white matter degeneration [2–4]. Indeed, white matter Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00415-020-10308-5) contains supplementary material, which is available to authorized users. * Maria Rosário Almeida [email protected] 1
CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marques de Pombal, 3004‑517 Coimbra, Portugal
2
Neurology Department, Coimbra University Hospital, Coimbra, Portugal
3
Neuroradiology Department, Coimbra University Hospital, Coimbra, Portugal
hyperintensities (WMH) and small subcortical infarcts are considered hallmarks of the disease, usually starting in their 40 s. Also, early vascular cognitive impairment progresses into dementia of subcortical type later in life, and may enc
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