Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases

Georgia Xiromerisiou; Chrysoula Marogianni; Katerina Dadouli; Christina Zompola; Despoina Georgouli; Antonios Provatas; Aikaterini Theodorou; Paschalis Zervas; Christina Nikolaidou; Stergios Stergiou; Panagiotis Ntellas; Maria Sokratous; Pantelis Stathis; Georgios P Paraskevas; Anastasios Bonakis; Konstantinos Voumvourakis; Christos Hadjichristodoulou; Georgios M Hadjigeorgiou; Georgios Tsivgoulis

doi:10.1212/NXG.0000000000000434

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases

Neurol Genet. 2020 May 11;6(3):e434. doi: 10.1212/NXG.0000000000000434. eCollection 2020 Jun.

Authors

Georgia Xiromerisiou¹, Chrysoula Marogianni¹, Katerina Dadouli¹, Christina Zompola¹, Despoina Georgouli¹, Antonios Provatas¹, Aikaterini Theodorou¹, Paschalis Zervas¹, Christina Nikolaidou¹, Stergios Stergiou¹, Panagiotis Ntellas¹, Maria Sokratous¹, Pantelis Stathis¹, Georgios P Paraskevas¹, Anastasios Bonakis¹, Konstantinos Voumvourakis¹, Christos Hadjichristodoulou¹, Georgios M Hadjigeorgiou¹, Georgios Tsivgoulis¹

Affiliation

¹ Department of Neurology (G.X., C.M., D.G., A.P., M.S., G.M.H.), University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece; Second Department of Neurology (C.Z., A.T., P.Z., A.B., K.V., G.T.), "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; Department of Neurology (G.M.H.), Medical School, University of Cyprus, Nicosia, Cyprus; Department of Hygiene and Epidemiology (K.D., C.H.), Faculty of Medicine, University of Thessaly, Larissa, Greece; Department of Medical Oncology (P.N.), University Hospital of Ioannina, Ioannina, Greece; Department of Neurology (P.S.), Mediterraneo Hospital, Glyfada, Athens, Greece; Histopathological Department (C.N., S.S.), Hippokration General Hospital Thessaloniki; and Department of Neurology (G.P.P.), School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece.

Abstract

Objective: The aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.

Methods: Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations.

Results: Our patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity.

Conclusions: The collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.

Publication types

Review