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

Masahiro Uemura,Akira Hanazono,Ikuko Mizuta,Hiroaki Nozaki,Taisuke Kato,Toshiki Mizuno,Arata Abe,Yoshinori Nishimoto,Shoichiro Ando,Daisuke Kuzume,Masato Kanazawa,Aki Sato,Akihiro Shindo,Takeshi Ikeuchi,Naoko Sakai,Mari Yoshida,Osamu Onodera,Kiran Polavarapu,Atchayaram Nalini,Nozomi Hishikawa,Mohammad El‐Ghanem ,Akira Koyama

doi:10.3389/fneur.2020.00545

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 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.

Highlights

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL, OMIM 600142) is a hereditary cerebral small vessel disease (CSVD) caused by biallelic loss-of-function mutations in high-temperature requirement A serine peptidase 1 (HTRA1), which upregulates the transforming growth factor β1 (TGF-β1) signal [1]
We have shown that the mutant HTRA1s, which are found in symptomatic carriers, are characterized by either an inability to form a trimer or a mutation in the loop 3 (L3)/loop D (LD) domain [18]
We found that the clinical symptoms/signs of symptomatic carriers were milder than those of CARASIL patients, a result that was supported by prior work

Summary

Introduction

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL, OMIM 600142) is a hereditary cerebral small vessel disease (CSVD) caused by biallelic loss-of-function mutations in high-temperature requirement A serine peptidase 1 (HTRA1), which upregulates the transforming growth factor β1 (TGF-β1) signal [1]. Most parents of CARASIL patients are asymptomatic [1, 3, 5, 11,12,13,14,15,16,17] It remains unclear why certain mutations cause CSVD in HTRA1 carriers. We reported that either a deficiency in trimerization or an amino-acid mutation located in the loop D (LD) or loop 3 (L3) domain was common in missense HTRA1 proteins identified in symptomatic carriers [18]. We speculated that these mutations in the HTRA1 gene may inhibit wild-type (WT) protease activity [7]. We reviewed the literature that describes symptomatic carriers and CARASIL to clarify the molecular and clinical features of HTRA1-related CSVD

Methods

Results

Discussion

Conclusion