A number sign (#) is used with this entry because of evidence that autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2) is caused by heterozygous mutation in the HTRA1 gene (602194) on chromosome 10q26.

Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 is a disorder of the small arterial vessels of the brain characterized by stroke, transient ischemic attacks (TIA), cognitive impairment, dementia, balance impairment, gait disturbance, headaches, and/or seizures associated with early confluent or confluent diffuse white matter hyperintensities and sometimes associated with multiple lacunar infarcts and microbleeds. Dilated perivascular spaces with a typical status cribrosum characterized by innumerable dilated Virchow-Robin spaces and resulting in a cribriform change in basal ganglia occur in most patients. CADASIL2 differs from CADASIL1 (125310) by a later age of onset (Verdura et al., 2015).

For a discussion of genetic heterogeneity of CADASIL, see 125310.

Verdura et al. (2015) described 11 unrelated probands with a disorder characterized by the association of subcortical ischemic events and cognitive decline with onset in most patients in their sixth decade. None of the patients had early-onset alopecia or early-onset spondylosis. Three of them suffered from a lumbar disc prolapse late in life. Typical neuroimaging findings included confluent or early confluent white matter hyperintensities on MRI T2-weighted and FLAIR images, with frequent involvement of the external and internal capsules, sometimes associated with multiple lacunar infarcts and microbleeds. Anterior temporal regions and U fibres were spared. Dilated perivascular spaces with a typical status cribrosum characterized by innumerable dilated Virchow-Robin spaces and resulting in a cribriform change in basal ganglia were observed in most patients. The clinical and MRI features of these patients were similar to those of patients with small vessel disease.

Verdura et al. (2015) used whole-exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently used high-throughput multiplex polymerase chain reaction and next-generation sequencing to screen all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown etiology. A heterozygous HTRA1 variant (R166L; 602194.0009), absent from the 1000 Genomes Project and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands (4.97%) of the 201 additional probands harbored a heterozygous HTRA1 mutation predicted to be damaging (see, e.g., 602194.0010-602194.0012). There was a highly significant difference in the number of likely deleterious variants in patients compared to controls (p = 4.2 x 10(-6); odds ratio = 15.4, 95% CI = 4.9-45.5), strongly suggesting causality. In vitro activity analysis of HTRA1 mutants demonstrated a loss-of-function effect.