Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous <i>HTRA1</i> mutation

Itô, Junko; Nozaki, Hiroaki; Toyoshima, Yasuko; Abe, Takashi; Sato, Aki; Hashidate, Hideki; Igarashi, Shuichi; Onodera, Osamu; Takahashi, Hitoshi; Kakita, Akiyoshi

doi:10.1111/neup.12473

Cited by 17 publications

(28 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pathological findings for patients with HTRA1 -related CSVD (two symptomatic carriers and four with CARASIL) are summarized in Table 4 ( 1 , 7 , 15 , 31 , 43 – 46 ). All patients, besides one Pakistani patient, were Japanese ( 15 ).…”

Section: Resultsmentioning

confidence: 99%

“…Although there was no granular osmophilic material found in HTRA1-related CSVD samples, a characteristic findings of autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), electron microscopy did reveal some deposits in one CARASIL patient and in one symptomatic carrier (31,43). Electron-dense deposits were also found in the cytoplasm of smooth muscles cells in CARASIL patients (31) and in the outer layer of the elastic lamina in symptomatic carriers (43).…”

Section: Pathological Findingsmentioning

confidence: 86%

See 1 more Smart Citation

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Pathological Findingsmentioning

confidence: 86%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…HtrA1 is primarily located and functions in the ECM; hence, it helps to degrade certain substrates located in extracellular compartments (Beaufort et al, 2014). However, aberrations and mutations in the HTRA1 gene can lead to abnormally aggregated elastin, the main protein component of the elastic lamina, presumably being associated with its fragility (Ito et al, 2018). For example, during the secretion, the interaction of LTBP-1 with fibronectin (a matrix protein) helps facilitate the latent TGF-β to be incorporated into the ECM.…”

Section: Relevant Aspects On Systems Biologymentioning

confidence: 99%

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

et al. 2019

View full text Add to dashboard Cite

Cerebral small vessel disease (CSVD) refers to a spectrum of clinical and imaging findings resulting from pathological processes of various etiologies affecting cerebral arterioles, perforating arteries, capillaries, and venules. Unlike large vessels, it is a challenge to visualize small vessels in vivo, hence the difficulty to directly monitor the natural progression of the disease. CSVD might progress for many years during the early stage of the disease as it remains asymptomatic. Prevalent among elderly individuals, CSVD has been alarmingly reported as an important precursor of full-blown stroke and vascular dementia. Growing evidence has also shown a significant association between CSVD’s radiological manifestation with dementia and Alzheimer’s disease (AD) pathology. Although it remains contentious as to whether CSVD is a cause or sequelae of AD, it is not far-fetched to posit that effective therapeutic measures of CSVD would mitigate the overall burden of dementia. Nevertheless, the unifying theory on the pathomechanism of the disease remains elusive, hence the lack of effective therapeutic approaches. Thus, this chapter consolidates the contemporary insights from numerous experimental animal models of CSVD, to date: from the available experimental animal models of CSVD and its translational research value; the pathomechanical aspects of the disease; relevant aspects on systems biology; opportunities for early disease biomarkers; and finally, converging approaches for future therapeutic directions of CSVD.

show abstract

“…[ 2 ] HTRA1 gene encodes high-temperature requirement protease A1, a serine enzyme that mediates cell signaling and protein degradation, and plays an important role in vascular integrity, skeletal development, and osteogenesis. [ 3 – 5 ] CARASIL is considered to be caused by biallelic mutations of HTRA1 . Only 19 recessive mutations (17 homozygous, 2 compounds heterozygous) in the HTRA1 gene related to CARASIL have been reported worldwide to date.…”

Section: Introductionmentioning

confidence: 99%

HTRA1-related autosomal dominant cerebral small vessel disease

Liu

Zhu

Zhou

et al. 2020

Chinese Medical Journal

View full text Add to dashboard Cite

Background Homozygous 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. Methods We 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. Results Forty-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. Conclusions HTRA1 -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.

show abstract

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation

Cited by 17 publications

References 13 publications

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

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

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

HTRA1-related autosomal dominant cerebral small vessel disease

Contact Info

Product

Resources

About