Littérature scientifique sur le sujet « HTRA1, small vessel disease, cerebral small vessel disease, CARASIL »

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.

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.

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.

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.

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.

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.

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.

High temperature requirement A1 (HTRA1) belongs to heat shock-induced serine proteases and is ubiquitously expressed in normal human adult tissues. HTRA1 plays a modulatory role in various cell processes, particularly regulates the transforming growth factor-β (TGF-ß) signalling. Biallelic mutations in HTRA1 lead to cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), a rare cerebral small vessel disease (CSVD). Nowadays, fifteen HTRA1 mutations have been identified. Recent data reported that heterozygous HTRA1 mutations seem to be linked to familial CSVD of unknown aetiology, which is characterized by a later age at onset. These data suggest that HTRA1 mutation could behave as autosomal recessive or dominant mutation. Our aim is to obtain further data about the pathogenic effect of various heterozygous HTRA1 mutations. We compared expression profiles of HTRA1 and intermediaries of TGF-β signalling proteins both in heterozygous carriers, with missense and stop codon HTRA1 mutations, and in heterozygous and homozygous mouse embryonic fibroblasts harbouring HTRA1-R274Q mutation. Moreover, we used heterozygous and homozygous murine models harbouring HTRA1-R274Q in order to evaluate in vivo the effects of mutant HTRA1. Further, we performed supplementary studies to evaluate the possibility of a dominant negative effect on HTRA1-WT by HTRA1-mutants, and the possibility torescue HTRA1-protease activity in homozygous HTRA1-R274Q carriers. The cell lysates and culture medium of cultured cells were used to analyse the expression pattern of both HTRA1 and intermediaries of TGF-β signalling proteins by western blot and immunofluorescence analysis. RNAs extracted from cultured cells and from mice tissues were used to analyse HTRA1-RNA and CTGF-RNA expression level by RT-qPCR. We found a ∼50% reduction in HTRA1 expression in human fibroblasts carrying heterozygous HTRA1-mutations compared to control. RT-qPCR analysis confirmed these data for two of the analysed subjects, whilst showed no significant reduction in the remaining carriers compared to control. Analysis of the murine models showed that there is no alteration of HTRA1-RNA expression nor in heterozygous nor in homozygous HTRA1-R274Q mice. No significant alteration of Smad2/3 phosphorylation and CTGF expression, down- and up-stream intermediaries of TGF-β signalling pathway, respectively, were found, suggesting that dysfunction of TGF-β signalling in fibroblasts might not contribute to the pathogenesis of CARASIL and CSVD linked to heterozygous HTRA1 mutations reported in this study. Heterozygous and homozygous HTRA1-R274Q murine cells displayed an increased fibronectin accumulation of 10-fold and 40-fold, respectively, than HTRA1-WT cells, suggesting that even the heterozygous HTRA1-mutations could be enough to cause deleterious phenotypic alterations in brain small vessels. HTRA1-WT protease activity did not display any remarkable alteration in presence of HTRA1-mutants.These findings seem to rule out a dominant negative effect in HTRA1 mutations we investigated. Finally, MEFs transfected with the rescue protein give an outcome similar to that obtained with MEFs transfected with HTRA1-WT, opening actual possibility to rescue the functionality of HTRA1-mutants. In conclusion, our results seem to suggest that CSVD, linked to heterozygous HTRA1 mutations, may occur in the presence of ~50% expression of the protein. Progressive tissue damage accumulation in small vessels leading to delayed and milder clinical expression with later onset with respect to classical CARASIL phenotype may be hypothesized. Moreover, data collection on heterozygous HTRA1 mutants is still limited, so investigation on the HTRA1 expression and activity, in cells from a wider number of subjects harboring different heterozygous HTRA1 missense mutations, could be helpful to verify a possible correlation between specific aminoacidic variations and particular protein alterations.

Screening genetico di pazienti affetti da small vessel disease che sono risultati negativi a mutazioni nei geni NOTCH3 e HTRA1, causativi di CADASIL e CARASIL, le forme di SVD più comuni. Mai prima d'ora il gene CTSA è stato associato a questo tipo di malattia.