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Journal articles on the topic 'HTRA1, small vessel disease, cerebral small vessel disease, CARASIL'

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Author: Grafiati

Published: 10 March 2023

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1

Müller, Sebastian J., Eya Khadhraoui, Ibrahim Allam, Loukas Argyriou, Ute Hehr, Jan Liman, Gerd Hasenfuß, Mathias Bähr, Christian H. Riedel, and Jan C. Koch. "CARASIL with coronary artery disease and distinct cerebral microhemorrhage: A case report and literature review." Clinical and Translational Neuroscience 4, no. 1 (January 1, 2020): 2514183X2091418. http://dx.doi.org/10.1177/2514183x20914182.

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Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL, Maeda syndrome) is an extremely rare autosomal-recessive genetic disorder with a serious arteriopathy causing subcortical infarcts and leukoencephalopathy. In less than 20 cases, a genetic mutation was proven. Patients suffer from alopecia, disc herniations, and spondylosis. Between the age of 30 and 40, the patients typically develop severe cerebral infarcts. Clinical symptoms, genetic study, magnetic resonance imaging (MRI), and coronary angiography of a patient with proven CARASIL are presented. The patient showed the typical phenotype with cerebral small-vessel disease, cerebral infarcts, spondylosis, and abnormal hair loss. Additionally, distinct cerebral microhemorrhage and a severe coronary artery disease (CAD) were found, which have not been reported before for CARASIL. Mutation screening revealed the presence of a homozygous c.1022G > T substitution in the HTRA1 gene. Evidence from other publications supports a pathogenetic link between the HTRA1 mutation and CAD as a new feature of CARASIL. This is the first report about CARASIL with a concomitant severe CAD. Thus, in patients with CARASIL, other vessel diseases should also be considered.

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Oluwole, Olusegun John, Heba Ibrahim, Debora Garozzo, Karim Ben Hamouda, Saly Ismail Mostafa Hassan, Ahmed Metwaly Hegazy, and Abdul Karim Msaddi. "Cerebral small vessel disease due to a unique heterozygous HTRA1 mutation in an African man." Neurology Genetics 6, no. 1 (December 26, 2019): e382. http://dx.doi.org/10.1212/nxg.0000000000000382.

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ObjectiveTo describe the case of an African patient who was diagnosed with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).MethodsCase report and literature review.ResultsWe present a 39-year-old Gabonese man who developed progressive gait difficulty at the age of 32, followed by insidious tetraparesis, urinary sphincter disturbance, spastic dysarthria, cognitive dysfunction, and seizures. Brain imaging was performed many years after disease onset and revealed diffuse confluent white matter lesions and lacunar infarcts. He tested negative for acquired white matter disease, but genetic screening detected a genetic variant of HTRA1 gene (G283R), which has not been previously reported.ConclusionsCARASIL is a disease that usually affects Asian patients. This case report describes a unique case of an African patient diagnosed with CARASIL and a novel genetic mutation in HTRA1 that has not been previously described in the literature.

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Bougea, Anastasia, George Velonakis, Nikolaos Spantideas, Evangelos Anagnostou, George Paraskevas, Elisabeth Kapaki, and Evangelia Kararizou. "The first Greek case of heterozygous cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy: An atypical clinico-radiological presentation." Neuroradiology Journal 30, no. 6 (April 12, 2017): 583–85. http://dx.doi.org/10.1177/1971400917700168.

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) was previously considered a rare, early-onset recessive form of small-vessel disease (SVD) caused by biallelic mutations in the serine protease gene HTRA1 with subsequent loss of its activity. However, very recently, there is growing interest of research showing heterozygous HTRA1 mutations as causes of SVD with a dominant inheritance pattern. This first Greek heterozygous CARASIL case with unusual clinico-radiological presentation extends our very recent knowledge on how heterozygous CARASIL mutations may be associated with cerebral SVD. Our findings highlight heterozygous HTRA1 mutations as an important cause of familial SVD, and that screening of HTRA1 should be considered in all patients with a hereditary SVD of unknown aetiology.

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Yao, Tingyan, Junge Zhu, Xiao Wu, Xuying Li, Yongjuan Fu, Yuan Wang, Zhanjun Wang, et al. "HeterozygousHTRA1Mutations Cause Cerebral Small Vessel Diseases." Neurology Genetics 8, no. 6 (December 2022): e200044. http://dx.doi.org/10.1212/nxg.0000000000200044.

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Background and ObjectivesCerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebrovascular disease caused by homozygous or compound heterozygous variations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. However, several studies in recent years have found that some heterozygousHTRA1mutations also cause cerebral small vessel disease (CSVD). The current study aims to report the novel genotypes, phenotypes, and histopathologic results of 3 pedigrees of CSVD with heterozygousHTRA1mutation.MethodsThree pedigrees of familiar CSVD, including 11 symptomatic patients and 3 asymptomatic carriers, were enrolled. Whole-exome sequencing was conducted in the probands for identifying rare variants, which were then evaluated for pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Sanger sequencing was performed for validation of mutations in the probands and other family members. The protease activity was assayed for the novel mutations. All the participants received detailed clinical and imaging examinations and the corresponding results were concluded. Hematoma evacuation was performed for an intracerebral hemorrhage patient with the p.Q318H mutation, and the postoperative pathology including hematoma and cerebral small vessels were examined.ResultsThree novel heterozygousHTRA1mutations (p.Q318H, p.V279M, and p.R274W) were detected in the 3 pedigrees. The protease activity was largely lost for all the mutations, confirming that they were loss-of-function mutations. The patients in each pedigree presented with typical clinical and imaging features of CVSD, and some of them displayed several new phenotypes including color blindness, hydrocephalus, and multiple arachnoid cysts. In addition, family 1 is the largest pedigree with heterozygousHTRA1mutation so far and includes homozygous twins, displaying some variation in clinical phenotypes. More importantly, pathologic study of a patient with p.Q318H mutation showed hyalinization, luminal stenosis, loss of smooth muscle cells, splitting of the internal elastic lamina, and intramural hemorrhage/dissection-like structures.DiscussionThese findings broaden the mutational and clinical spectrum of heterozygousHTRA1-related CSVD. Pathologic features were similar with the previous heterozygous and homozygous cases. Moreover, clinical heterogeneity was revealed within the largest single family, and the mechanisms of the phenotypic heterogenetic remain unclear. Overall, heterozygous HTRA1-related CSVD should not be simply taken as a mild type of CARASIL as previously considered.

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Tan, Rhea YY, Anna M. Drazyk, Kathryn Urankar, Clare Bailey, Stefan Gräf, Hugh Markus, and Nicola J. Giffin. "Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)." Practical Neurology 21, no. 5 (August 25, 2021): 448–51. http://dx.doi.org/10.1136/practneurol-2021-003058.

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A 44-year-old Caucasian man presented with seizures and cognitive impairment. He had marked retinal drusen, and MR brain scan showed features of cerebral small vessel disease; he was diagnosed with a leukoencephalopathy of uncertain cause. He died at the age of 46 years and postmortem brain examination showed widespread small vessel changes described as a vasculopathy of unknown cause. Seven years postmortem, whole-genome sequencing identified a homozygous nonsense HTRA1 mutation (p.Arg302Ter), giving a retrospective diagnosis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.

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Kondo, Yasufumi, Tsuneaki Yoshinaga, Katsuya Nakamura, Tomomi Yamaguchi, Masumi Ishikawa, Tomoki Kosho, and Yoshiki Sekijima. "Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant ofHTRA1." Neurology Genetics 9, no. 1 (December 15, 2022): e200047. http://dx.doi.org/10.1212/nxg.0000000000200047.

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ObjectiveTo investigate the clinical effect of a heterozygous missense variant ofHTRA1on cerebral small vessel disease (CSVD) in a large Japanese family with a p.A252T variant.MethodsWe performed clinical, laboratory, radiologic, and genetic evaluations of members of a previously reported family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).ResultsTwo family members were previously reported patients with CARASIL. Among 6 uniallelic p.A252T carriers, 2 had neurologic symptoms with brain MRI abnormalities, 2 showed CSVD on the MRI only, and the other 2 were unaffected. Clinical phenotypes of 2 heterozygous patients were comparable with those of patients with CARASIL, whereas the other 3 heterozygous patients had developed milder and later-onset CSVD. One heterozygous carrier was asymptomatic.DiscussionPrevious studies have suggested that uniallelic p.A252T causes disease. However, our study revealed that patients with uniallelic p.A252T can have severe and young-onset CSVD. The clinical manifestations of uniallelic variant carriers were highly variable, even within the same family. Male and atherosclerotic risk factors were considered to be additional factors in the severity of neurologic symptoms in uniallelic p.A252T carriers, suggesting that strict control of vascular risk factors can prevent vascular events in uniallelicHTRA1carriers.

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Tan, Rhea, and Hugh Markus. "NEXT GENERATION SEQUENCING IN FAMILIAL CEREBRAL SMALL VESSEL DISEASE - AN ONGOING STUDY." Journal of Neurology, Neurosurgery & Psychiatry 86, no. 11 (October 14, 2015): e4.106-e4. http://dx.doi.org/10.1136/jnnp-2015-312379.194.

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Cerebral small vessel disease (SVD) is the most common form of stroke and vascular dementia. CADASIL (notch3 mutations) is most frequent but other monogenic causes more recently identified include CARASIL (HTRA1 gene), RVCL (TREX1 gene) and COL4A1 and 2. Diagnostic tests for these are often inaccessible and expensive and there are families with clinical monogenic SVD in whom no known variants are detected.Next generation sequencing offers the potential to screen for these diseases, which present with similar phenotypes, more cost-effectively and rapidly in a single test. It could also identify novel genes underlying SVD. As part of the NHS GEL and NIHR BRIDGE projects, whole genome sequencing is being applied to SVD. Individuals with younger onset SVD and a family history, with negative notch3 screening, are being recruited from centres throughout England.Data (blood sample and phenotypic information) can be collected by phone and blood sent through the post, or participants seen at a research clinic in one of the seven recruitment sites. Testing is provided free of charge. Any SVD causative mutations are fed back to the patient via the referring clinician. We are interested in receiving potential recruits who can be referred to Rhea Tan yyrt2@medschl.cam.ac.uk.

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Nozaki, H., A. Koyama, M. Uemura, T. Kato, and O. Onodera. "The prevalence estimates of HTRA1-associated cerebral small vessel disease." Journal of the Neurological Sciences 381 (October 2017): 635. http://dx.doi.org/10.1016/j.jns.2017.08.1790.

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Hara, Kenju, Atsushi Shiga, Toshio Fukutake, Hiroaki Nozaki, Akinori Miyashita, Akio Yokoseki, Hirotoshi Kawata, et al. "Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease." New England Journal of Medicine 360, no. 17 (April 23, 2009): 1729–39. http://dx.doi.org/10.1056/nejmoa0801560.

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Liao, Y. C., N. C. Chao, P. C. Tsai, B. W. Soong, and Y. C. Lee. "Heterozygous HTRA1 mutations in Taiwanese patients with cerebral small vessel disease." Journal of the Neurological Sciences 381 (October 2017): 456. http://dx.doi.org/10.1016/j.jns.2017.08.3496.

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Grigaitė, Julija, Kamilė Šiaurytė, Eglė Audronytė, Eglė Preikšaitienė, Birutė Burnytė, Erinija Pranckevičienė, Aleksandra Ekkert, Algirdas Utkus, and Dalius Jatužis. "Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia—A Case Study." Genes 12, no. 12 (December 7, 2021): 1955. http://dx.doi.org/10.3390/genes12121955.

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Biallelic mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene are known to cause an extremely rare cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which belongs to the group of hereditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient’s phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

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Thaler, Franziska S., Cihan Catak, Maximilian Einhäupl, Susanna Müller, Klaus Seelos, Frank A. Wollenweber, and Tania Kümpfel. "Cerebral small vessel disease caused by a novel heterozygous mutation in HTRA1." Journal of the Neurological Sciences 388 (May 2018): 19–21. http://dx.doi.org/10.1016/j.jns.2018.02.043.

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13

Giau, Vo Van, Eva Bagyinszky, Young Chul Youn, Seong Soo A. An, and Sang Yun Kim. "Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome." International Journal of Molecular Sciences 20, no. 17 (September 3, 2019): 4298. http://dx.doi.org/10.3390/ijms20174298.

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Cerebral small vessel diseases (SVD) have been causally correlated with ischemic strokes, leading to cognitive decline and vascular dementia. Neuroimaging and molecular genetic tests could improve diagnostic accuracy in patients with potential SVD. Several types of monogenic, hereditary cerebral SVD have been identified: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), hereditary diffuse leukoencephalopathy with spheroids (HDLS), COL4A1/2-related disorders, and Fabry disease. These disorders can be distinguished based on their genetics, pathological and imaging findings, clinical manifestation, and diagnosis. Genetic studies of sporadic cerebral SVD have demonstrated a high degree of heritability, particularly among patients with young-onset stroke. Common genetic variants in monogenic disease may contribute to pathological progress in several cerebral SVD subtypes, revealing distinct genetic mechanisms in different subtype of SVD. Hence, genetic molecular analysis should be used as the final gold standard of diagnosis. The purpose of this review was to summarize the recent discoveries made surrounding the genetics of cerebral SVD and their clinical significance, to provide new insights into the pathogenesis of cerebral SVD, and to highlight the possible convergence of disease mechanisms in monogenic and sporadic cerebral SVD.

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Liu, Guiyou, Haihua Zhang, Bian Liu, and Xunming Ji. "Rs2293871 regulates HTRA1 expression and affects cerebral small vessel stroke and Alzheimer's disease." Brain 142, no. 11 (October 11, 2019): e61-e61. http://dx.doi.org/10.1093/brain/awz305.

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Lee, Yi-Chung, Chih-Ping Chung, Nai-Chen Chao, Jong-Ling Fuh, Feng-Chi Chang, Bing-Wing Soong, and Yi-Chu Liao. "Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease." Stroke 49, no. 7 (July 2018): 1593–601. http://dx.doi.org/10.1161/strokeaha.118.021283.

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Di Donato, Ilaria, Silvia Bianchi, Gian Nicola Gallus, Alfonso Cerase, Ilaria Taglia, Francesca Pescini, Serena Nannucci, et al. "Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease." CNS Neuroscience & Therapeutics 23, no. 9 (August 6, 2017): 759–65. http://dx.doi.org/10.1111/cns.12722.

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Ohta, Kentaro, Tetsuo Ozawa, Hidehiko Fujinaka, Kiyoe Goto, and Takashi Nakajima. "Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1." Internal Medicine 59, no. 10 (May 15, 2020): 1309–13. http://dx.doi.org/10.2169/internalmedicine.4041-19.

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Tateoka, Toru, Hideaki Onda, Kengo Hirota, Hidetoshi Kasuya, Toyoaki Shinohara, Hiroyuki Kinouchi, and Hiroyuki Akagawa. "Unusual case of cerebral small vessel disease with a heterozygous nonsense mutation in HTRA1." Journal of the Neurological Sciences 362 (March 2016): 144–46. http://dx.doi.org/10.1016/j.jns.2016.01.037.

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Zhang, Wen-ying, Fei Xie, and Pei-lin Lu. "Two novel heterozygous HTRA1 mutations in two pedigrees with cerebral small vessel disease families." Neurological Sciences 39, no. 3 (January 5, 2018): 497–501. http://dx.doi.org/10.1007/s10072-017-3231-z.

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Zhang, Haohan, Xiaoming Qin, Yingying Shi, Xinya Gao, Fengyu Wang, Huayuan Wang, Junkui Shang, Jingyi Zhao, Jiewen Zhang, and Fengmin Shao. "Genotype–phenotype correlations of heterozygous HTRA1-related cerebral small vessel disease: case report and systematic review." neurogenetics 22, no. 3 (May 8, 2021): 187–94. http://dx.doi.org/10.1007/s10048-021-00646-5.

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Ito, Junko, Hiroaki Nozaki, Yasuko Toyoshima, Takashi Abe, Aki Sato, Hideki Hashidate, Shuichi Igarashi, Osamu Onodera, Hitoshi Takahashi, and Akiyoshi Kakita. "Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation." Neuropathology 38, no. 4 (May 25, 2018): 428–32. http://dx.doi.org/10.1111/neup.12473.

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Kitahara, Sho, Shintaro Tsuboguchi, Masahiro Uemura, Hiroaki Nozaki, Masato Kanazawa, and Osamu Onodera. "Patients with heterozygous HTRA1-related cerebral small vessel disease misdiagnosed with other diseases: Two case reports." Clinical Neurology and Neurosurgery 223 (December 2022): 107502. http://dx.doi.org/10.1016/j.clineuro.2022.107502.

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Shiga, Atsushi, Hiroaki Nozaki, Akio Yokoseki, Megumi Nihonmatsu, Hirotoshi Kawata, Taisuke Kato, Akihide Koyama, et al. "Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1." Human Molecular Genetics 20, no. 9 (February 14, 2011): 1800–1810. http://dx.doi.org/10.1093/hmg/ddr063.

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Rannikmäe, Kristiina, Vhinoth Sivakumaran, Henry Millar, Rainer Malik, Christopher D. Anderson, Mike Chong, Tushar Dave, et al. "COL4A2 is associated with lacunar ischemic stroke and deep ICH." Neurology 89, no. 17 (September 27, 2017): 1829–39. http://dx.doi.org/10.1212/wnl.0000000000004560.

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Objective:To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.Methods:We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.Results:A locus in COL4A2 was associated (significance threshold p < 3.5 × 10−4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 × 10−8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 × 10−5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10−4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 × 10−4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.Conclusions:These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

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Shang, Ty, Marco Pinho, Debarti Ray, and Alka Khera. "Two Unique Mutations in HTRA1-Related Cerebral Small Vessel Disease in North America and Africa and Literature Review." Journal of Stroke and Cerebrovascular Diseases 30, no. 11 (November 2021): 106029. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106029.

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Chojdak-Łukasiewicz, Justyna, Edyta Dziadkowiak, and Sławomir Budrewicz. "Monogenic Causes of Strokes." Genes 12, no. 12 (November 23, 2021): 1855. http://dx.doi.org/10.3390/genes12121855.

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Strokes are the main cause of death and long-term disability worldwide. A stroke is a heterogeneous multi-factorial condition, caused by a combination of environmental and genetic factors. Monogenic disorders account for about 1% to 5% of all stroke cases. The most common single-gene diseases connected with strokes are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Fabry disease, mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) and a lot of single-gene diseases associated particularly with cerebral small-vessel disease, such as COL4A1 syndrome, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). In this article the clinical phenotype for the most important single-gene disorders associated with strokes are presented. The monogenic causes of a stroke are rare, but early diagnosis is important in order to provide appropriate therapy when available.

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Beaufort, Nathalie, Eva Scharrer, Elisabeth Kremmer, Vanda Lux, Michael Ehrmann, Robert Huber, Henry Houlden, David Werring, Christof Haffner, and Martin Dichgans. "Cerebral small vessel disease-related protease HtrA1 processes latent TGF-β binding protein 1 and facilitates TGF-β signaling." Proceedings of the National Academy of Sciences 111, no. 46 (November 4, 2014): 16496–501. http://dx.doi.org/10.1073/pnas.1418087111.

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Tan, Rhea Y. Y., Matthew Traylor, Karyn Megy, Daniel Duarte, Sri V. V. Deevi, Olga Shamardina, Rutendo P. Mapeta, et al. "How common are single gene mutations as a cause for lacunar stroke?" Neurology 93, no. 22 (November 12, 2019): e2007-e2020. http://dx.doi.org/10.1212/wnl.0000000000008544.

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ObjectivesTo determine the frequency of rare and pertinent disease-causing variants in small vessel disease (SVD)-associated genes (such as NOTCH3, HTRA1, COL4A1, COL4A2, FOXC1, TREX1, and GLA) in cerebral SVD, we performed targeted gene sequencing in 950 patients with younger-onset apparently sporadic SVD stroke using a targeted sequencing panel.MethodsWe designed a high-throughput sequencing panel to identify variants in 15 genes (7 known SVD genes, 8 SVD-related disorder genes). The panel was used to screen a population of 950 patients with younger-onset (≤70 years) MRI-confirmed SVD stroke, recruited from stroke centers across the United Kingdom. Variants were filtered according to their frequency in control databases, predicted effect, presence in curated variant lists, and combined annotation dependent depletion scores. Whole genome sequencing and genotyping were performed on a subset of patients to provide a direct comparison of techniques. The frequency of known disease-causing and pertinent variants of uncertain significance was calculated.ResultsWe identified previously reported variants in 14 patients (8 cysteine-changing NOTCH3 variants in 11 patients, 2 HTRA1 variants in 2 patients, and 1 missense COL4A1 variant in 1 patient). In addition, we identified 29 variants of uncertain significance in 32 patients.ConclusionRare monogenic variants account for about 1.5% of younger onset lacunar stroke. Most are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy variants, but the second most common gene affected is HTRA1. A high-throughput sequencing technology platform is an efficient, reliable method to screen for such mutations.

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Ferguson, Amy Christina, Sophie Thrippleton, David Henshall, Ed Whittaker, Bryan Conway, Malcolm MacLeod, Rainer Malik, et al. "Frequency and Phenotype Associations of Rare Variants in 5 Monogenic Cerebral Small Vessel Disease Genes in 200,000 UK Biobank Participants." Neurology Genetics 8, no. 5 (August 24, 2022): e200015. http://dx.doi.org/10.1212/nxg.0000000000200015.

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Background and ObjectivesBased on previous case reports and disease-based cohorts, a minority of patients with cerebral small vessel disease (cSVD) have a monogenic cause, with many also manifesting extracerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of putative pathogenic variants in cSVD genes in the UK Biobank (UKB), a large population-based study.MethodsWe used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in CTSA, TREX1, HTRA1, and COL4A1/2. We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in the UKB's linked health data from UK hospital admissions, death records, and primary care. Among 199,313 exome-sequenced UKB participants, we assessed the following: the proportion of participants carrying ≥1 variant(s); phenotype-of-interest penetrance; and the association between variant carrier status and phenotypes-of-interest using a binary (any phenotype present/absent) and phenotype burden (linear score of the number of phenotypes a participant possessed) approach.ResultsAmong UKB participants, 0.5% had ≥1 variant(s) in studied genes. Using hospital admission and death records, 4%–20% of variant carriers per gene had an associated phenotype. This increased to 7%–55% when including primary care records. Only COL4A1 variant carrier status was significantly associated with having ≥1 phenotype-of-interest and a higher phenotype score (OR = 1.29, p = 0.006).DiscussionWhile putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only approximately half of variant carriers have a relevant disease phenotype recorded in their linked health data. We could not replicate most previously reported gene-phenotype associations, suggesting lower penetrance rates, overestimated pathogenicity, and/or limited statistical power.

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Nozaki, Hiroaki, Masatoyo Nishizawa, and Osamu Onodera. "4. Detection of Novel Dementia-related Genes. 2) Dysregulation of TGF-^|^beta; Family Signaling and Hereditary Cerebral Small Vessel Disease: Insight into Molecular Pathogenesis of CARASIL." Nihon Naika Gakkai Zasshi 100, no. 8 (2011): 2207–13. http://dx.doi.org/10.2169/naika.100.2207.

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Rannikmäe, Kristiina, David E. Henshall, Sophie Thrippleton, Qiu Ginj Kong, Mike Chong, Nickrooz Grami, Isaac Kuan, et al. "Beyond the Brain." Stroke 51, no. 10 (October 2020): 3007–17. http://dx.doi.org/10.1161/strokeaha.120.029517.

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Background and Purpose: An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature. Methods: We performed a systematic review following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), searching Medline/Embase for publications describing individuals with pathogenic variants in COL4A1/2 , TREX1 , HTRA1 , ADA2 , and CTSA genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically relevant phenotype. We extracted individuals’ characteristics and information about associated extracerebral phenotypes and stroke/transient ischemic attack. We noted any novel extracerebral phenotypes and looked for shared phenotypes between monogenic cSVDs. Results: After screening 6048 publications, we included 96 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 COL4A2 (37 individuals), 119 ADA2 (209 individuals), and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1 , where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extracerebral phenotype (14% COL4A2 , 43% HTRA1 heterozygotes, 47% COL4A1 , 57% TREX1 , 91% ADA2 , 94% HTRA1 homozygotes, and 100% CTSA individuals). Indeed, for 4 of 7 genes, an extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD. Conclusions: Extracerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.

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Arnardottir, Snjolaug, Francesca Del Gaudio, Stefanos Klironomos, Eike-Benjamin Braune, Ariane Araujo Lombraña, Daniel V. Oliveira, Shaobo Jin, Helena Karlström, Urban Lendahl, and Christina Sjöstrand. "Novel Cysteine-Sparing Hypomorphic NOTCH3 A1604T Mutation Observed in a Family With Migraine and White Matter Lesions." Neurology Genetics 7, no. 3 (April 22, 2021): e584. http://dx.doi.org/10.1212/nxg.0000000000000584.

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ObjectiveTo conduct a clinical study of a family with neurologic symptoms and findings carrying a novel NOTCH3 mutation and to analyze the molecular consequences of the mutation.MethodsWe analyzed a family with complex neurologic symptoms by MRI and neurologic examinations. Exome sequencing of the NOTCH3 locus was conducted, and whole-genome sequencing was performed to identify COL4A1, COL4A2, and HTRA1 mutations. Cell lines expressing the normal or NOTCH3A1604T receptors were analyzed to assess proteolytic processing, cell morphology, receptor routing, and receptor signaling.ResultsCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease (SVD) and caused by mutations in the NOTCH3 gene. Most CADASIL mutations alter the number of cysteine residues in the extracellular domain of the NOTCH3 receptor, but in this article, we describe a family in which some members carry a novel cysteine-sparing NOTCH3 mutation (c.4810 G>A, p.Ala1604Thr). Two of 3 siblings heterozygous for the NOTCH3A1604T mutation presented with migraine and white matter lesions (WMLs), the latter of a type related to but distinct from what is normally observed in CADASIL. Two other members instead carried a novel COL4A1 missense mutation (c.4795 G>A; p.(Ala1599Thr)). The NOTCH3A1604T receptor was aberrantly processed, showed reduced presence at the cell surface, and less efficiently activated Notch downstream target genes.ConclusionsWe identify a family with migraine and WML in which some members carry a cysteine-sparing hypomorphic NOTCH3 mutation. Although a causal relationship is not established, we believe that the observations contribute to the discussion on dysregulated Notch signaling in cerebral SVDs.

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Olowu, Adeola, Spence Septien, Alka Khera, Worthy Warnack, and Ty Shang. "Abstract 38: New Mutations Linked to Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Africa and North America." Stroke 51, Suppl_1 (February 2020). http://dx.doi.org/10.1161/str.51.suppl_1.38.

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Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary disease. It is linked to mutations in the high-temperature requirement A serine peptidase 1 gene ( HTRA1 ). The clinical presentation is characterized by cerebral small vessel disease, alopecia, and spondylosis. CARASIL was initially thought to be a recessive disorder and exclusively exist in Asian populations. The paradigm of CARASIL has recently expanded. Genetically confirmed heterozygous mutations and manifestation in other ethnicities were reported. A few cases were reported in Hispanic and Caucasian populations but none in the African population. Here we report a new homozygous mutation in a Hispanic male and a known heterozygous mutation in an African female. Methods: Patients underwent routine ischemic stroke work up and risk factor management. MRI brain results were consistent with severe small vessel disease out of proportion to age. Genetic testing for vascular dementia for NOTCH-3 and HTRA1 in Patient 1 and only HTRA1 in Patient 2 were performed through Mayo Clinic. Results: Table 1. Patient Characteristics and HTRA1 Mutations Discussion: The prevalence of CARASIL is unknown but probably underestimated. Since the recognition of heterozygous HTRA1 mutation in CARASIL, more cases of heterozygous HTRA1 mutations have been reported. One of the clinical CARASIL triad -alopecia was not reported or observed in our cases. Cases of CARASIL without alopecia have been reported. Thus, CARASIL should still be suspected in the appropriate clinical presentation even if there is no classic triad or in non-Asian populations. Our cases expanded CARASIL mutations and affected populations. Being more aware of the broad clinical presentation of CARASIL can lead to early diagnosis.

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Nozaki, Hiroaki, Taisuke Kato, Megumi Nihonmatsu, Yohei Saito, Ikuko Mizuta, Tomoko Noda, Ryoko Koike, et al. "Abstract TP269: Distinct Molecular Mechanisms of Htra1 Mutants in Manifesting Heterozygotes With Carasil." Stroke 48, suppl_1 (February 2017). http://dx.doi.org/10.1161/str.48.suppl_1.tp269.

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Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an autosomal recessive inherited cerebral small vessel disease (CSVD), involves severe leukoaraiosis, multiple lacunar infarcts, early-onset alopecia, and spondylosis deformans. High-temperature requirement serine peptidase A1 (HTRA1) gene mutations cause CARASIL by decreasing HTRA1 protease activity. Although CARASIL is a recessive inherited disease, heterozygous mutations in the HTRA1 gene were recently identified in 11 families with CSVD. Because CSVD is frequently observed in elderly individuals, it is unclear which mutants truly contribute to CSVD pathogenesis. Here, we found heterozygous mutations in the HTRA1 gene in individuals with CSVD and investigated the differences in biochemical characteristics between these mutant HTRA1s and mutant HTRA1s observed in homozygotes. Methods: We recruited 113 unrelated index patients with clinically diagnosed CSVD. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. Results: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in CARASIL (A252T and V297M) did not inhibit wild- type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer- associated HTRA1 activation. Conclusions: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

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Chen, Mei-Jiao, Yi Zhang, Wen-Jiao Luo, Hai-Lin Dong, Qiao Wei, Juan Zhang, Qi-Qi Ruan, Wang Ni, and Hong-Fu Li. "Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease." Frontiers in Genetics 13 (August 10, 2022). http://dx.doi.org/10.3389/fgene.2022.909131.

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Background: Homozygous and compound heterozygous mutations in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, heterozygous pathogenic variants in HTRA1 were described in patients with autosomal dominant cerebral small vessel disease (CSVD). Here, we investigated the genetic variants in a cohort of Chinese patients with CSVD.Methods: A total of 95 Chinese index patients with typical characteristics of CSVD were collected. Whole exome sequencing was performed in the probands, followed by Sanger sequencing. Pathogenicity prediction software was applied to evaluate the pathogenicity of the identified variants.Results: We detected five heterozygous HTRA1 pathogenic variants in five index patients. These pathogenic variants included four known variants (c.543delT, c.854C>T, c.889G>A, and c.824C>T) and one novel variant (c.472 + 1G>A). Among them, c.854C>T, c.824C>T, and c.472 + 1G>A have never been reported in China and c.889G>A was once reported in homozygous but never in heterozygous. Three of them were distributed in exon 4, one in exon 2, and another splicing variant in intron 1. Four out of five probands presented typical features of CARASIL but less severe. The common clinical features included lacunar infarction, cognitive decline, alopecia, and spondylosis. All of them showed leukoencephalopathy, and the main involved cerebral area include periventricular and frontal area, centrum semiovale, thalamus, and corpus callosum. Anterior temporal lobes and external capsule involvement were also observed. Three probands had intracranial microbleeds.Conclusion: Our study expanded the mutation spectrum of HTRA1, especially in Chinese populations, and provided further evidence for “hot regions” in exon 1–4, especially in exon 4, in heterozygous HTRA1 pathogenic variants. Our work further supported that patients with heterozygous HTRA1 pathogenic variants presented with similar but less-severe features than CARASIL but in an autosomal dominantly inherited pattern.

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Uemura, Masahiro, Hiroaki Nozaki, Yumi Sekine, Ikuko Mizuta, Tomoko Noda, Kazuhide Miyazaki, Muichi Kaito, et al. "Abstract TMP92: Characteristic Brain MRI Features of Manifesting Heterozygotes With Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy." Stroke 48, suppl_1 (February 2017). http://dx.doi.org/10.1161/str.48.suppl_1.tmp92.

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Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a cerebral small-vessel disease (CSVD). Mutations in the high-temperature requirement serine peptidase A1 gene ( HTRA1 ) cause CARASIL via a decrease in protease activity of HTRA1. Although most of the heterozygotes with the HTRA1 mutation are healthy, manifesting heterozygotes have been reported. We have elucidated that the mutant HTRA1s that develops CSVD in a heterozygote state have a distinct molecular mechanism, resulting in the dominant negative effect. These individuals showed mild phenocopy of CARASIL. However, it is not clear whether brain MRI findings in manifesting heterozygotes are different from those of CARASIL. In this study, we aimed to clarify the characteristic brain MRI features in manifesting heterozygotes by comparing them to those in CARASIL. Methods: We have evaluated 19 MRIs in eight manifesting heterozygotes and 21 MRIs in seven CARASIL patients and scored the MRIs by using a semi-quantitative scale for CARASIL, which scored white matter lesions (WMLs) (signal score) and atrophy (atrophy score) (Nozaki et al. Neurology 2015). Statistical analysis was conducted using software R 3.2.2. We obtained written informed consent from all individuals. Results: Signal score in manifesting heterozygotes was significantly lower than that in CARASIL (Mean ± SD; 14.6 ± 1.9 vs. 23.1 ± 5.0, p < 0.0001), however, there was no difference in atrophy score between the two groups (Mean ± SD; 5.5 ± 2.2 vs. 7.5 ± 5.5, p = 0.20). Atrophy score showed positive correlation with the disease duration in both groups (r 2 = 0.48, p = 0.0014 vs r 2 = 0.41, p = 0.0041), however signal score showed no correlation with the disease duration. Conclusion: WMLs is milder in manifesting heterozygote as compared with CARASIL. In contrast, the brain atrophy is not influenced by the HTRA1 mutation status but positively correlated with the disease duration. The rate of carriers for pathogenic HTRA1 mutations are higher than expected. These characteristic findings of brain MRIs might be useful to pick up the candidate for the genetic screening for HTRA1 .

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Chen, Weijie, Yuanyuan Wang, Shengwen Huang, Xiaoli Yang, Liwei Shen, and Danhong Wu. "Case report: Two unique nonsense mutations in HTRA1-related cerebral small vessel disease in a Chinese population and literature review." Frontiers in Neurology 13 (December 22, 2022). http://dx.doi.org/10.3389/fneur.2022.1069453.

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BackgroundHomozygous or compound heterozygous mutations in the high-temperature requirement A serine protease 1 gene (HTRA1) elicits cerebral autosomal recessive arteriopathy with subcortical infarcts and white matter lesions (CARASIL). The relationship between some heterozygous mutations, most of which are missense ones, and the occurrence of cerebral small vessel diseases (CSVD) has been reported. Recently, heterozygous HTRA1 nonsense mutations have been recognized to be pathogenic.Case presentationWe described two Chinese patients diagnosed with HTRA1-CSVD accompanied by heterozygous nonsense mutations. Their first clinical manifestations were symptoms due to ischemic stroke, and brain Magnetic Resonance Imaging (MRI) showed diffuse white matter lesions (WMLs) and microbleeds in both of them. Genetic sequencing revealed two novel heterozygous nonsense mutations: c.1096G>T (p.E366X) and c.151G>T (p.E51X).ConclusionThis case report expands the clinical, radiographic, and genetic spectrum of HTRA1-CSVD. Attention should be paid to young patients with ischemic stroke as the first clinical manifestation. Genetic screening for such sporadic CSVD is recommended, even if the symptoms are atypical.

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Liu, Jing-Yi, Yi-Cheng Zhu, Li-Xin Zhou, Yan-Ping Wei, Chen-Hui Mao, Li-Ying Cui, Bin Peng, and Ming Yao. "HTRA1-related autosomal dominant cerebral small vessel disease." Chinese Medical Journal Publish Ahead of Print (October 26, 2020). http://dx.doi.org/10.1097/cm9.0000000000001176.

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Whittaker, Ed, Sophie Thrippleton, Liza Y. W. Chong, Victoria G. Collins, Amy C. Ferguson, David E. Henshall, Emily Lancastle, et al. "Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease." Journal of the American Heart Association, June 14, 2022. http://dx.doi.org/10.1161/jaha.121.025629.

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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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Mahale, RohanR, Aakash Agarwal, Jyothi Gautam, Nibu Varghese, Jennifer Kovoor, Pooja Mailankody, Hansashree Padmanabha, and Mathuranath Pavagada. "Autosomal dominant cerebral small vessel disease in HTRA1 gene mutation." Annals of Indian Academy of Neurology, 2020, 0. http://dx.doi.org/10.4103/aian.aian_381_20.

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Wang, Yunchao, Changhe Shi, Yusheng Li, Wenkai Yu, Sen Wei, Yu Fan, Chengyuan Mao, et al. "Genetic Study of Cerebral Small Vessel Disease in Chinese Han Population." Frontiers in Neurology 13 (March 25, 2022). http://dx.doi.org/10.3389/fneur.2022.829438.

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Cerebral small vessel disease (CSVD) is a syndrome of clinical, neuroimaging, and neuropathological manifestations caused by disorders that affect small cerebral vessels. Although the pathogenesis of the disease remains unclear, some studies have demonstrated that genetic variants contribute to the development of CSVD. Our study aimed to explore the genetic characteristics of CSVD in the Chinese Han population. We enrolled 182 sporadic CSVD Chinese Han patients whose magnetic resonance imaging results showed grade 2-3 white matter lesions. Target region sequencing of seven monogenic CSVD-related genes, including NOTCH3, HTRA1, COL4A1, COL4A2, GLA, TREX1, and CTSA, was performed, and we identified pathogenic variants by screening the sequencing results and functional predictive analysis. All variants were predicted to be pathogenic by the SIFT Score, Polymorphism Phenotyping-2 score, Mutation Taster, Splice site score calculation, and MaxEntScan. All variants were validated in 300 healthy controls. In total, eight variants were identified in patients with CSVD, including five novel variants, c.1774C>T (NOTCH3), c.3784C>T (NOTCH3), c. 1207C>T (HTRA1), and c. 1274+1G> A (HTRA1), c.1937G>C (COL4A1) and three reported mutations. None of these variants were present in 300 healthy controls. No pathogenic variants in COL4A2, GLA, TREX1, and CTSA were detected. This study identified five novel variants in CSVD-related genes in Chinese Han patients with sporadic CSVD. Our results expand the genetic profile of CSVD.

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Uemura, Masahiro, Hiroaki Nozaki, Taisuke Kato, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, et al. "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature." Frontiers in Neurology 11 (July 3, 2020). http://dx.doi.org/10.3389/fneur.2020.00545.

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Samuel, Sneha Susan, Bharat Mishra, and Nadheem Muhammad Shajeef. "Carasil and htra1: an early adulthood syndrome." UPI Journal of Pharmaceutical, Medical and Health Sciences, September 30, 2021, 13–17. http://dx.doi.org/10.37022/jpmhs.v4i3.26.

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Cerebral Autosomal Recessive Arteriopathy Subcortical Infracts Leukoencephalopathy (CARASIL), is an autosomal recessive disorder inherited by two copies of an abnormal gene from some trait, one from each parent. Person with this disorder may have a change in deep white matter in brain; and this disorder can be characterized by damage to small blood vessels in brain. Increasing muscle tone, slurred speech, stiff movement of legs, gait disturbance, spondylosis, sparse hair are the major symptoms. But the ultimate cause of this disorder can lead to loss of memory, cognitive impairment. This disorder can be caused in early adulthood i.e., between 20-40 years of age. CARASIL has first reported in Japan, later occurred in China and Caucasian population. A neurological disorder named Binswanger’s disease (BD) and chronic immunological disorder multiple sclerosis are main different alternation of this disease. Mutation requires the high temperature resultant, A serine peptidase 1 causes CARASIL, so it is a serine protease. Serine protease HTRA1 is an enzyme that in humans is encoded by HTRA1 gene. HTRA1 protein is composed of four distinct protein domains. This is located on the long (q) arm of chromosome 10 in a region known as 10q26. This protein is a secreted enzyme that is proposed to regulate the availability of insulin like growth factors (IGF) by cleaving IGF binding proteins. HTRA1 enzyme helps breakdown many other kinds of proteins in this space surrounding cells (extracellular matrix). This is attached to protein in Transforming Growth Factor Beta (TGF-beta) and slows down their ability to send chemical signals. Variant known as rs11200638 is found in an area of gene called promoter region which starts the production HTRA1 enzyme. It is unclear how of polymorphism in the HTRA1 gene might be an age-related macular degeneration. So at last, we can conclude that CARASIL is related to brain inherited from the abnormal genes caused to small arteries and to the specific area of deep brain in higher function; tissue loss due to lack of oxygen where small arteries get blocked destruction to myelin an oily substance covers and protects the nerve fibers in CNS.

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Ragno, Michele, Luigi Pianese, Massimo Caulo, Francesco Logullo, Mario Angelini, Alex Incensi, Rocco Liguori, et al. "Cutaneous Sensory and Autonomic Small Fiber Neuropathy in HTRA1-Related Cerebral Small Vessel Disease." Journal of Neuropathology & Experimental Neurology, December 14, 2020. http://dx.doi.org/10.1093/jnen/nlaa150.

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Schrader, Joseph M., Aleksandra Stanisavljevic, Feng Xu, and William E. Van Nostrand. "Distinct Brain Proteomic Signatures in Cerebral Small Vessel Disease Rat Models of Hypertension and Cerebral Amyloid Angiopathy." Journal of Neuropathology & Experimental Neurology, July 20, 2022. http://dx.doi.org/10.1093/jnen/nlac057.

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Abstract Cerebral small vessel diseases (CSVDs) are prominent contributors to vascular cognitive impairment and dementia and can arise from a range of etiologies. Cerebral amyloid angiopathy (CAA) and hypertension (HTN), both prevalent in the elderly population, lead to cerebral microhemorrhages, macrohemorrhages, and white matter damage. However, their respective underlying mechanisms and molecular events are poorly understood. Here, we show that the transgenic rat model of CAA type 1 (rTg-DI) exhibits perivascular inflammation that is lacking in the spontaneously hypertensive stroke-prone (SHR-SP) rat model of HTN. Alternatively, SHR-SP rats display notable dilation of arteriolar perivascular spaces. Comparative proteomics analysis revealed few shared altered proteins, with key proteins such as ANXA3, H2A, and HTRA1 unique to rTg-DI rats, and Nt5e, Flot-1 and Flot-2 unique to SHR-SP rats. Immunolabeling confirmed that upregulation of ANXA3, HTRA1, and neutrophil extracellular trap proteins were distinctly associated with rTg-DI rats. Pathway analysis predicted activation of TGF-β1 and TNFα in rTg-DI rat brain, while insulin signaling was reduced in the SHR-SP rat brain. Thus, we report divergent protein signatures associated with distinct cerebral vessel pathologies in the SHR-SP and rTg-DI rat models and provide new mechanistic insight into these different forms of CSVD.

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Coste, Thibault, Dominique Hervé, Jean Philippe Neau, Eric Jouvent, Fatoumata Ba, Françoise Bergametti, Matthias Lamy, et al. "Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic." Brain, July 16, 2021. http://dx.doi.org/10.1093/brain/awab271.

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Abstract Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known cerebral small vessel disease genes, including HTRA1, in 3,853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 messenger RNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases (gnomAD v3.1.1 (p = 3.12 x 10−17, OR = 21.9), TOPMed freeze 5 (p = 7.6 x 10−18, OR = 27.1) and 1000 Genomes (p = 1.5 x 10−5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counseling

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Uemura, Masahiro, Hiroaki Nozaki, Naoko Sakai, Shouichirou Ando, Masato Kanazawa, Hajime Kondo, Akira Iwanaga, et al. "Abstract TMP94: Frequencies of Hereditary Cerebral Small Vessel Diseases Among Patients With Adult-Onset Leukoencephalopathy." Stroke 51, Suppl_1 (February 2020). http://dx.doi.org/10.1161/str.51.suppl_1.tmp94.

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Introduction: Recently, various causative genes have been identified in adult-onset white matter disorders. Some of these genes cause cerebral small vessel disease (CSVD). However, the frequency of genetic CSVD is unknown in the group of adult-onset white matter disorders (leukoencephalopathy). The purpose of this study is to clarify the frequency of genetic CSVD in adult-onset leukoencephalopathy patients and to examine their clinical features. Methods: One hundred patients in the Japanese cohort were included. All patients had neurological symptoms/signs and white matter lesions of grade 3/III classified by Fazekas grade on magnetic resonance imaging. Initially, genetic tests for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), high-temperature requirement A serine peptidase 1 (HTRA1)- related CSVD and retinovasculopathy with cerebral leukoencephalopathy (RVCL) were performed by Sanger method. For the remaining samples, we preformed whole exome sequencing. Patients were divided into groups according to the age at onset of neurological signs/symptoms and family history. Results: In 40 of 100 patients with leukoencephalopathy, we identified genetic mutations that cause CSVD: twenty-five patients with CADASIL,10 patients with HTRA1 -related CSVD, 3 patients with pseudoxanthoma elasticum (PXE), 1 patient with RVCL, and 1 patient with a mutation in COL4A1 . More than 85% patients have mutations in NOTCH3 or HTRA1 . In addition, we identified 3 patients with vanishing white matter disease, and 1 patient with X-linked adrenoleukodystrophy. The hereditary CSVDs other than CADASIL or HTRA1 -related CSVD were identified in the groups of age at onset ≤ 40 years-old irrespective of family history or age at onset ≤ 55 years-old with family history. Conclusions: The frequencies of genetic CSVDs were quite high among patients with leukoencephalopathy with neurological signs/symptoms. Although the genetic tests for CADASIL and HTRA1- related CSVD are sufficient for the most patients, we should consider the other genetic diseases especially for the patients with younger age onset of neurological signs/symptoms or positive family history.

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Zhang, Chen, Honghua Zheng, Xin Li, Shaowu Li, Wei Li, Ziwei Wang, Songtao Niu, Xingao Wang, and Zaiqiang Zhang. "Novel mutations in HTRA1 ‐related cerebral small vessel disease and comparison with CADASIL." Annals of Clinical and Translational Neurology, September 2022. http://dx.doi.org/10.1002/acn3.51654.

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Zhuo, Zhong‐ling, Lu Cong, Jun Zhang, and Xiao‐tao Zhao. "A novel heterozygous HTRA1 mutation is associated with autosomal dominant hereditary cerebral small vessel disease." Molecular Genetics & Genomic Medicine 8, no. 6 (April 2, 2020). http://dx.doi.org/10.1002/mgg3.1111.

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Ke, Shaofa, Changzhu Wu, and Long Chen. "Novel heterozygous HTRA1 pathogenic variant found in a Chinese family with autosomal dominant cerebral small vessel disease." Annals of Indian Academy of Neurology, 2020, 0. http://dx.doi.org/10.4103/aian.aian_74_20.

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