Clinical presentation of Y189C mutation of the NOTCH3 gene in the Polish family with CADASIL

Abstract

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary, progressive ischemic disease of small vessels of the brain characterized by migraine with aura (MA), recurrent subcortical ischemic episodes, cognitive decline and psychiatric disorders. CADASIL is caused by mutations in the NOTCH3 gene. We identified the NOTCH3 Y189C mutation as a genetic cause of CADASIL in a Polish family and provided its first clinical manifestation. Material and methods: The study included twelve subjects from one family. The NOTCH3 mutation, APOE and MTHFR polymorphisms were determined by high-resolution melting analyses (HRMA) and Sanger sequencing. Neuroimaging included CT and MRI. Ultrastructural examination of skin-muscle biopsy material of the proband was performed. Results: The NOTCH3 Y189C mutation was present in a 36-year-old woman and her two sisters (aged 40 and 27) from 6 siblings. The MA was found in all of them, and started or became more severe after childbirth. The numerous T2/FLAIR hyperintense lesions were shown in the brain MRI. The deposition of granular osmiophilic material in the wall of small vessels of the proband observed in histopathological analysis confirmed the high degree of CADASIL severity. Conclusions: Patients with the Y189C mutation of NOTCH3 from the same family display a similar phenotype of CADASIL.

Headache and NOTCH3 Gene Variants in Patients with CADASIL

“…The pathogenic variant p.Tyr189Cys (c.566A>G) of the NOTCH3 gene was identified in exon 4, representing a classic pathogenic CADASIL mutation involving a change in the number of cysteine residues from six to seven [ 49 ]. This variant was detected in three women belonging to one family.…”

“…Among the three people with the pathogenic p.Tyr189Cys variant of the NOTCH3 gene, we observed a common phenotype: MA (100%), onset at a young age (around 20 years old), onset of headaches after severe experiences (high stress, pregnancy, childbirth), attacks lasting about 2 days, 1–2 times or 3–4 times a month with changes of vascular origin in the MRI/CT image. A detailed clinical picture of this family was presented by Dorszewska et al [ 49 ]. However, it should be noted that knowledge about the role of the pathogenic p.Tyr189Cys variant of the NOTCH3 gene in MA and CADASIL remains limited, and further research on this variant is needed.…”

Mutations in NOTCH3 Gene may Promote the Clinical Presentation of Spinocerebellar Ataxia Type 37 Caused by Mutations in DAB1 Gene

“…Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is an autosomal dominant inherited vasculopathy characterized by migraine with aura, recurrent subcortical ischemic stroke, cognitive decline, and psychiatric disorders ( Chen et al, 2019 ; Dorszewska et al, 2020 ). CADASIL is caused by mutations in the NOTCH3 gene which is localized on chromosome 19p13 ( Joutel et al, 1997 ; Sari et al, 2019 ).…”