Heterozygous mutations of HTRA 1 gene in patients with familial cerebral small vessel disease

Summary Aims Cerebral small vessel disease ( SVD ) is the leading cause of vascular dementia. Although the most of cases are sporadic, familial monogenic causes have been identified in a growing minority of patients. CADASIL , due to mutations of NOTCH 3 gene, is the most common genetic SVD , and CARASIL , linked to HTRA 1 gene mutations, is a rare but well known autosomal recessive SVD . Recently, also heterozygous HTRA 1 mutations have been described in patients with familial SVD . To detect a genetic cause of familial SVD , we performed mutational analysis of HTRA 1 gene in a large cohort of Italian NOTCH 3 ‐negative patients. Methods We recruited 142 NOTCH 3 ‐negative patients and 160 healthy age‐matched controls. Additional control data were obtained from five pathogenicity prediction software. Results Five different HTRA 1 heterozygous mutations were detected in nine patients from five unrelated families. Clinical phenotype was typical of SVD , and the onset was presenile. Brain magnetic resonance imaging ( MRI ) showed a subcortical leukoencephalopathy, with involvement of the external and internal capsule, corpus callosum, and multiple lacunar infarcts. Cerebral microbleeds were also seen, while anterior temporal lobes involvement was not present. Conclusion Our observation further supports the pathogenic role of the heterozygous HTRA 1 mutations in familial SVD .