Headache and NOTCH3 Gene Variants in Patients with CADASIL

Area of Science:

• Genetics
• Neurology
• Vascular Diseases

Background:

• Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic vascular disorder.
• CADASIL is characterized by strokes, cognitive decline, psychiatric issues, and headaches, including migraine with aura (MA).
• Mutations in the NOTCH3 gene are the known cause of CADASIL.

Purpose of the Study:

• To investigate the association between NOTCH3 genetic variants and headache types in CADASIL patients.
• To identify novel NOTCH3 variants and assess their clinical significance in relation to headache presentation.

Main Methods:

• Genetic analysis of the NOTCH3 gene in 30 CADASIL patients using PCR-HRM and sequencing.
• Classification of identified NOTCH3 variants as pathogenic/likely pathogenic or benign.
• Correlation of genetic findings with patient-reported headache characteristics.

Main Results:

• Three pathogenic/likely pathogenic NOTCH3 variants (p.Tyr189Cys, p.Arg153Cys, p.Cys144Arg) and two benign variants (p.Ala202=, p.Thr101=) were identified.
• A previously undescribed NOTCH3 variant (chr19:15192258 G>T) was also reported.
• Patients with pathogenic/likely pathogenic variants exhibited similar headache patterns, while those with benign variants showed more varied clinical presentations.

Conclusions:

• NOTCH3 gene variants appear to influence the differential presentation of headaches in CADASIL.
• Headache characteristics may hold diagnostic and prognostic value in managing CADASIL.
• Further research into genotype-phenotype correlations can enhance understanding and treatment of CADASIL.