Autosomal dominant cerebral small vessel disease associated with HTRA1 gene mutation in an Italian family

Introduction: Cerebral small vessel diseases (CSVDs) are an important cause of stroke, cognitive impairment, and mood disorders among the elderly. Usually CSVD is sporadic, but early-onset monogenic forms of CSVD have been reported. CADASIL is one of the most common hereditary CSVD caused by autosomal dominant NOTCH3 gene mutations, while CARASIL is a rare autosomal recessive CSVD caused by HTRA1 gene mutations. More than 200 mutations are known in NOTCH3 gene and only 12 HTRA1 mutated CARASIL families have been reported so far. Recently, heterozygous HTRA1 mutations have been described associated with an autosomal dominant form of CSVD with reduced penetrance, showing clinical features differing from those of CARASIL. Patients and methods: We report a family with three affected individuals, referred for stroke and cognitive impairment segregating as an autosomal dominant disorder. Mutations in NOTCH3 and HTRA1 genes have been screened by Sanger sequencing. In silico prediction tools PolyPhen and SIFT have been used to predict the pathogenicity of the variants found. Skin biopsy of one patient was examined with transmission electron microscope. Results: A heterozygous HTRA1 missense mutation segregating with the disease and predicted to be deleterious has been found. The mutation affects a highly conserved aminoacid, which, if mutated, strongly reduce the HTRA1 proteolytic activity. The biopsy showed deposits of osmophilic material in the arterial wall, very similar to those characterizing CADASIL. Conclusions: We confirm the dominant inheritance of some HTRA1 mutations, overlapping clinical, MRI and ultramicroscopic features of CADASIL, in absence of the typical CARASIL extra-neurological symptoms.