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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 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.

SUBMITTER: Uemura M

PROVIDER: S-EPMC7351529 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Uemura Masahiro M Nozaki Hiroaki H Kato Taisuke T Koyama Akihide A Sakai Naoko N Ando Shoichiro S Kanazawa Masato M Hishikawa Nozomi N Nishimoto Yoshinori Y Polavarapu Kiran K Nalini Atchayaram A Hanazono Akira A Kuzume Daisuke D Shindo Akihiro A El-Ghanem Mohammad M Abe Arata A Sato Aki A Yoshida Mari M Ikeuchi Takeshi T Mizuta Ikuko I Mizuno Toshiki T Onodera Osamu O

Frontiers in neurology 20200703

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 ...[more]

PMID: 32719647

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Project description:BackgroundHomozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 (HTRA1) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. This study was aimed to analyze the genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD.MethodsWe presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1-related autosomal dominant CSVD included in PUBMED by the end of March 1, 2020. CARASIL probands with genetic diagnosis reported to date were also reviewed. The genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL.ResultsForty-four HTRA1-related autosomal dominant CSVD probands and 22 CARASIL probands were included. Compared with typical CARASIL, HTRA1-related autosomal dominant probands has a higher proportion of vascular risk factors (P < 0.001), a later onset age (P < 0.001), and a relatively slower clinical progression. Alopecia and spondylosis can be observed, but less than those in the typical CARASIL. Thirty-five heterozygous mutations in HTRA1 were reported, most of which were missense mutations. Amino acids located close to amino acids 250-300 were most frequently affected, followed by these located near 150∼200. While amino acids 250∼300 were also the most frequently affected region in CARASIL patients, fewer mutations precede the 200th amino acids were detected, especially in the Kazal-type serine protease domain.ConclusionsHTRA1-related autosomal dominant CSVD is present as a mild phenotype of CARASIL. The trend of regional concentration of mutation sites may be related to the concentration of key sites in these regions which are responsible for pathogenesis of HTRA1-related autosomal dominant CSVD.

Project description:Background Cerebral small-vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause. While NOTCH3 is the best-known gene, several others have been reported. We aimed to summarize the cerebral phenotypes associated with these more recent cSVD genes. Methods and Results We performed a systematic review (PROSPERO [International Prospective Register of Systematic Reviews]: CRD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2, TREX1, HTRA1, ADA2, or CTSA pathogenic variant carriers. We extracted data about individuals' characteristics and clinical and vascular radiological cerebral phenotypes. We summarized phenotype frequencies per gene, comparing patterns across genes. We screened 6485 publications including 402, and extracted data on 390 individuals with COL4A1, 123 with TREX1, 44 with HTRA1 homozygous, 41 with COL4A2, 346 with ADA2, 82 with HTRA1 heterozygous, and 14 with CTSA. Mean age ranged from 15 (ADA2) to 59 years (HTRA1 heterozygotes). Clinical phenotype frequencies varied widely: stroke, 9% (TREX1) to 52% (HTRA1 heterozygotes); cognitive features, 0% (ADA2) to 64% (HTRA1 homozygotes); and psychiatric features, 0% (COL4A2; ADA2) to 57% (CTSA). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% (ADA2) to 100% (HTRA1 homozygotes; CTSA). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischemic and hemorrhagic lesions dominated, respectively. Conclusions There appear to be differences in cerebral manifestations across cSVD genes. Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterization of associated phenotypes, as well as insights from population-based studies, should improve our understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.

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

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<i>HTRA1</i>-Related Cerebral Small Vessel Disease: A Review of the Literature.

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