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Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL
Chen Zhang1, Honghua Zheng2, Xin Li2
1Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Insights
Most familial cerebral small vessel disease (CSVD) patients in China have heterozygous HTRA1 mutations. This study differentiates HTRA1-CSVD from CADASIL using distinct clinical and neuroimaging features.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Familial cerebral small vessel disease (CSVD) can be caused by heterozygous or homozygous mutations in the HTRA1 gene.
- Heterozygous HTRA1-related CSVD shares clinical and neuroimaging similarities with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
Purpose of the Study:
- To characterize the genotypic and phenotypic features of HTRA1-related CSVD in a Chinese cohort.
- To compare the clinical and neuroimaging characteristics of heterozygous HTRA1-related CSVD with CADASIL.
Main Methods:
- Genetic sequencing was performed on unrelated patients with suspected familial CSVD from China.
- Clinical and neuroimaging data of patients with heterozygous HTRA1-related CSVD and CADASIL were analyzed and compared.
Main Results:
- Nine heterozygous and one homozygous HTRA1 mutations were identified, with seven novel mutations.
- Heterozygous HTRA1-CSVD patients exhibited a higher prevalence of spine disorders and less anterior temporal lobe white matter hyperintensities compared to CADASIL patients (p < 0.001).
Conclusions:
- The majority of HTRA1-related CSVD cases in China are associated with heterozygous HTRA1 mutations.
- Distinct extra-neurological and neuroimaging findings help differentiate heterozygous HTRA1-CSVD from CADASIL.
- This research expands the known spectrum of HTRA1 mutations associated with CSVD.
Objective:
There is evidence showing both heterozygous HTRA1 and homozygous HTRA1 mutations as causal for familial cerebral small vessel disease (CSVD). The clinical and neuroimaging signs of heterozygous HTRA1-related CSVD can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to characterize the genotypic and phenotypic features of HTRA1-related CSVD, and we compared the features of heterozygous HTRA1-related CSVD and CADASIL.
Methods:
We carried out genetic sequencing in a series of unrelated patients with suspected familial CSVD from China. Clinical and imaging characteristics of heterozygous HTRA1-related CSVD and CADASIL were compared.
Results:
We identified nine heterozygous HTRA1 mutations and one homozygous HTRA1 mutation, seven of which are novel. Compared with CADASIL, patients with heterozygous HTRA1-related CSVD had a higher proportion of spine disorders and a lower proportion of white matter hyperintensities involving the anterior temporal lobe (p < 0.001).
Interpretation:
This study shows that most HTRA1-related CSVD patients in China carry heterozygous HTRA1 mutations. The specific extra-neurological features and neuroimaging features reveal informative differences between heterozygous HTRA1-related CSVD and CADASIL. We expand the mutational spectrum of HTRA1.
