A case of coexisting heterozygous NOTCH3 and HTRA1 mutations in cerebral small vessel disease

• Published in: Human genome variation Vol. 12; no. 1; pp. 13 - 3
• Main Authors: Yamashiro, Masataka, Yasutomi, Daigo, Ohya, Yuichiro, Ohyama, Satoshi, Takashima, Hiroshi, Tokashiki, Takashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.07.2025; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/378/2583; Age; Baldness; Biomedical and Life Sciences; Biomedicine; Blood vessels; Case reports; Data Report; Families & family life; Gait; Gene Expression; Gene Function; Gene Therapy; Genetic testing; Hereditary spastic paraplegia; Heterozygotes; Human Genetics; Ischemia; Leukoencephalopathy; Magnetic resonance imaging; Molecular Medicine; Mutation; Notch protein; Phenotypes; Stroke; Urination; Vascular diseases
• ISSN: 2054-345X; 2054-345X
• DOI: 10.1038/s41439-025-00317-z

Hereditary cerebral small vessel diseases (CSVDs) include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 , cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy caused by biallelic HTRA1 , and heterozygous HTRA1 -related CSVD. Here we report a case of a 53-year-old Japanese woman with coexisting NOTCH3 p.R75P and HTRA1 p.R166L mutations, each in the heterozygote. She presented with early-onset spastic paraparesis, frequent urination, cognitive impairment and baldness. We compared the clinical features of this case with known phenotypes of CADASIL caused by p.R75P, HTRA1 -related CSVD. We reported cases with heterozygous HTRA1 p.R166L to discuss the potential synergistic effects of the coexisting variants.