NOTCH3 variants of unknown significance underpin vascular dysfunction in neurodegenerative disease: a case series of three nfvPPA-FTD patients

Introduction: The NOTCH3 gene encodes for an evolutionarily conserved protein, whose functions encompass both embryonic cell proliferation and adult tissue-specific differentiation. Among others, a pivotal role in maintaining functional integrity of neurovascular unit (NVU) is supported by the association of several NOTCH3 gene mutations with neuroimaging markers of cerebral small vessel disease (SVD). Indeed, a pathogenic role of NOTCH3 is recognised in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, an increasing number of NOTCH3 variants with unclear pathogenic role have been identified in patients suspected of having CADASIL. The following case series describes three patients under the age of 65 with clinical diagnosis of nonfluent-variant of primary progressive aphasia (nfvPPA), whose genetic analysis revealed the presence of three distinct novel variants of unknown significance (VUS) in NOTCH3 gene. Results: The diagnostic work-up revealed common features among the patients: clinical presentation -nfvPPA at neuropsychological evaluation with consistent extrapyramidal symptoms; neuroimaging -low brain MR burden of SVD and FDG-PET impairment of cortical areas involved in speech production network; and biomarkers –Cerebrospinal fluid (CSF) analysis negative for Alzheimer’s Disease (AD), corroborating suspicion of underlying Frontotemporal Lobe Degeneration (FTLD). Discussion and Conclusion: The retrieved VUS in NOTCH3 suggest that the involvement of Notch signalling in pathophysiology of neurodegenerative disease is more complex and needs to be fully explored. Rare variants in SVD-associated genes may influence progression of neurodegeneration via the dysfunction of several vascular pathways.