Headache and NOTCH3 Gene Variants in Patients with CADASIL

Abstract

Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular disease characterized by recurrent strokes, cognitive impairment, psychiatric symptoms, apathy, and migraine. Approximately 40% of patients with CADASIL experience migraine with aura (MA). In addition to MA, CADASIL patients are described in the literature as having migraine without aura (MO) and other types of headaches. Mutations in the NOTCH3 gene cause CADASIL. This study investigated NOTCH3 genetic variants in CADASIL patients and their potential association with headache types. Genetic tests were performed on 30 patients with CADASIL (20 women aged 43.6 ± 11.5 and 10 men aged 39.6 ± 15.8). PCR-HRM and sequencing methods were used in the genetic study. We described three variants as pathogenic/likely pathogenic (p.Tyr189Cys, p.Arg153Cys, p.Cys144Arg) and two benign variants (p.Ala202=, p.Thr101=) in the NOTCH3 gene and also presented the NOTCH3 gene variant (chr19:15192258 G>T), which has not been previously described in the literature. Patients with pathogenic/likely pathogenic variants had similar headache courses. People with benign variants showed a more diverse clinical picture. It seems that different NOTCH3 variants may contribute to the differential presentation of a CADASIL headache, highlighting the diagnostic and prognostic value of headache characteristics in this disease.

SNP and Structural Study of the Notch Superfamily Provides Insights and Novel Pharmacological Targets against the CADASIL Syndrome and Neurodegenerative Diseases

“…The accumulation of mutations appears to be different between EGF-like repeats 1 and 34, and these mutations were significantly increased in key amino acids in each EGF-like repeat such as in cysteine, glycine, and arginine (Figures 9 and 10). Today, with the increasing number of experimental data from patients with CADASIL syndrome, it is possible to create a mathematical model through which we will be able to relate the order and the series of mutations in different EGF-like repeats based on a specific phenotype of the disease, as well as based on sex and age [38,50,60,61]. Some studies also have made this observation [39].…”

“…The study of the Notch family has increased, significantly, the availability of biological data on polymorphisms and mutations that are related with neurodegenerative diseases [15,21,[37][38][39]. The initial purpose of this work was to gather all the cases and link them between nucleotides and protein sequences.…”

“…Today, the scientific research seems to be focused on understanding the way the EGF region functions due to the significant mutagenesis it presents through a series of scientific publications [39][40][41][42][43]. The ultimate goal of this study is the holistic study of all mutations occurring in Notch3, with an emphasis on the EGF region and the CADASIL syndrome, in order to identify specific patterns of mutagenesis in the EGF-repeats that may be related to the clinical phenotype, sex, and age data of the various patients [38,39,[44][45][46]. The study and analysis of all mutations can additionally open new horizons thus contributing to the identification of new pharmacological targets as well as contributing to the identification of a candidate treatment against CADASIL syndrome and, generally, neurodegenerative diseases.…”

Correction: Szymanowicz et al. Headache and NOTCH3 Gene Variants in Patients with CADASIL. Neurol. Int. 2023, 15, 1238–1252

“…In the original publication [ 1 ], there was a mistake in the legend for Figure 1 . Heterozygous variant in the NOTCH3 gene, chr19:15192257 T>G.…”

“…In the original publication [ 1 ], Coto, E.; Menéndez, M.; Navarro, R.; García-Castro, M.; Alvarez, V. A new de novo Notch3 mutation causing CADASIL. European Journal of Neurology 2006, 13 , 628–631 was not cited.…”