HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature

Abstract

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that Uemura et al. CSVD Caused by HTRA1 Mutation haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants

“…In contrast with CADASIL-1, anterior temporal lobes are spared in most reported cases, while external capsule involvement appears to be common in both conditions (Uemura et al, 2020). All but one patient in our cohort had confluent supratentorial white matter changes and brain stem infarcts, whereas sparing of anterior temporal lobe was seen in all four patients.…”

Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

“…Additional support for decreased level and activity of HtrA1 protein associated with human disease is exemplified by individuals with CARASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In CARASIL patients, autosomal-recessive mutations in HTRA1 result in decreased expression or activity, leading to cerebral artery pathologies (17,18,44). In CADASIL patients, autosomaldominant mutations in NOTCH3 lead to the formation of intermolecular aggregates and accumulation of protein deposits in the tunica media of small cerebral arteries (45,46).…”

Cerebral microbleeds: from depiction to interpretation

“…53 In such populations, around 5% of patients exhibit five or more CMBs. 56 57 CMB prevalence is also particularly high in patients with genetic diseases of small blood vessels (eg, CADASIL, 58 CARASIL, 59 hereditary Dutch type CAA, 60 COL4A1 mutations 61 or other vascular conditions (eg, Moyamoya disease) 62 and Fabry disease 63 . )…”