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

TL;DR

A 53-year-old woman with coexisting NOTCH3 and HTRA1 mutations shows unique symptoms of cerebral small vessel disease.

Contribution

Reports a novel case of coexisting heterozygous NOTCH3 and HTRA1 mutations in cerebral small vessel disease.

Findings

The patient exhibited early-onset spastic paraparesis, frequent urination, cognitive impairment, and baldness.

The case suggests potential synergistic effects of coexisting NOTCH3 p.R75P and HTRA1 p.R166L mutations.

Clinical features were compared with known CADASIL and HTRA1-related CSVD phenotypes.

Abstract

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.

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