Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leukoencephalopathy Syndrome Research Articles

Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines. The pathogenic role of cysteine-sparing NOTCH3 mutations with typical clinical CADASIL syndrome is still debated. This review aimed to characterize NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL. Articles on NOTCH3 cysteine-sparing mutations with clinical suspicion of CADASIL were reviewed. Clinical and radiological cerebral phenotypes data were extracted and characterized across regions and compared with phenotypes of typical CADASIL patients. We screened 298 NOTCH3 cysteine-sparing mutation individuals from 20 publications, and mutations in exon 3 were the most frequently reported (21.46%). Gait impairment (76.47%), cognitive impairment (67.47%), and stroke (62.37%) were the three most common clinical phenotypes; the most frequent radiological cerebral phenotypes were lacunes (74.29%) and cerebral microbleeds (72.73%). Compared with CADASIL patients, cognitive impairment and cerebral microbleed frequencies were significantly higher in patients with NOTCH3 cysteine-sparing mutations, while the white matter hyperintensities in anterior temporal polar and external capsule were rarely observed. Compared with Western patients, radiological phenotypes were more common than clinical phenotypes in cysteine-sparing Asian patients. More than half of cysteine-sparing patients had positive granular osmiophilic material deposits. NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL mainly manifested with gait and cognitive impairment but rare white matter hyperintensities in anterior temporal pole and external capsule. Further studies are warranted to pay attention to atypical NOTCH3 variants, which could guide specific diagnosis and help unravel underlying mechanisms.

Autonomic Dysfunction in the Setting of CADASIL Syndrome.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited cause of stroke. A female patient aged > 50 years with genetically proven CADASIL syndrome and an extensive stroke/transient ischemic attack (TIA) history experienced a bradycardic episode following hospitalization for new strokelike symptoms. The literature of cardiac involvement in CADASIL syndrome is limited, with no definitive recommendations for surveillance and screening. This case report postulates that cardiac surveillance and screening may be indicated for patients with CADASIL syndrome.

Mood symptoms Associated with CADASIL Syndrome: A Case Report

To discuss the psychiatric symptoms that are associated with CADASIL syndrome Abstract Cerebral:Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare type of hereditary disease involving the small cerebral vessels. The clinical symptoms are various and include recurrent ischemic strokes, migraine with aura, seizures with epilepsy, psychiatric problems such as mood disturbances, and progressive cognitive decline leading to dementia. This disease needs awareness amongst the psychiatrists even though it is discussed much more in neurology literature. Psychiatric symptoms are seen in 20-41% of patients with CADASIL syndrome (1, 2). Psychiatric symptoms are actually the initial presentation in 15% of the cases. (3) The psychiatric disturbance most reported are mood disturbances (9-41%) especially depression. Here a 42-year-old African American female was brought to the hospital emergency room after she was found wandering in the streets. Psychiatry was consulted for altered mental status. Upon evaluation by the psychiatric consult service she was only oriented to person, depressed, anxious and complaining of headaches. Initial CT scan showed marked small vessel disease and old lacunar infarcts in the basal ganglia and right corona radiata. Magnetic Resonance Imaging (MRI) of the brain showed acute infarcts in the right posterior frontal and right parietal lobes along with old infarcts. Her symptoms and findings on imaging were consistent with CADASIL syndrome. Once the diagnosis was confirmed and prior records were obtained patient was resumed on an antidepressant and anxiolytic. The purpose of this case report was to discuss psychiatric symptoms associated with CADASIL syndrome. Although there has been research showing a relationship between vascular disease and depression, a review of the literature suggests that there needs to be more research done to explore other psychiatric disturbances that may be seen with this syndrome. Psychiatric symptoms that are untreated can have the potential to further impact the quality of life therefore psychiatrists need to be aware of this syndrome in order to treat these patients promptly. 1 https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0778-8 2 http://dx.doi.org/10.32474/OJNBD.2018.01.000101 3 https://pdfs.semanticscholar.org/47f6/5952ee3c5dcf2a61345f704914b17fa8dc0d.pdf.

Coronavirus disease 2019 in a patient with CADASIL syndrome: a case report

We present a case report of a patient with a previously identified cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), who was admitted due to coronavirus disease 2019 (COVID-19), confirmed by polymerase chain reaction and computed tomography. Examination and treatment of these patients presents certain difficulties due to the large number of thromboembolic complications caused by a combination of congenital and infectious angiopathies. CADASIL syndrome and COVID-19 were manifested by the progression of neurological symptoms and increasing cognitive impairment. During therapy, there was a positive change with a gradual regression of these disorders.

Genetic diagnosis of CADASIL in three Hong Kong Chinese patients: A novel mutation within the intracellular domain of NOTCH3

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary stroke syndrome characterized by recurrent stroke and progressive cognitive impairment caused by NOTCH3 mutations. We report here the clinical and molecular findings of three unrelated Hong Kong Chinese families with CADASIL syndrome. Sanger sequencing of genomic DNA revealed a novel heterozygous variant NM_000435.2(NOTCH3):c.[5903_5904insATAA];[5903_5904=] NP_000426.2:p.(Asp1969∗);(Asp1969=) and two previously reported heterozygous mutations NM_000435.2(NOTCH3):c.[328C>T];[328C=] NP_000426.2:p.[(Arg110Cys)];[(Arg110=)] and NM_000435.2(NOTCH3):c.[580T>A];[580T=] NP_000426.2:p.(Cys194Ser);(Cys194=) in the three families respectively. Molecular basis of CADASIL in these three patients were further established. Genetic analysis provides a reliable method for confirming the diagnosis of CADASIL and enables proper genetic counseling and cascade testing.

Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL.

A Report of Accelerated Coronary Artery Disease Associated with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia and it is caused by mutations in the NOTCH3 gene. The neurologic manifestations of CADASIL syndrome have been well characterized; however, here we report one of the first de novo cases of CADASIL-associated coronary artery disease. A 45-year-old woman with a history of CADASIL and remote tobacco use presented with unstable angina. She was found to have diffuse and irregular narrowing of the left anterior descending artery and a drug eluting stent was deployed. Months later, she developed two subsequent episodes of unstable angina, requiring stent placement in the distal left anterior descending artery and the right coronary artery. Though the neurologic manifestations of CADASIL have been well described, these patients may also be predisposed to developing premature coronary artery disease. Patients with CADASIL and their physicians should be aware of this possible association because these patients may not be identified as high risk by traditional cardiovascular risk estimators. These patients may benefit from more aggressive interventions to reduce cardiac risk.

Neuroscience and Symptoms Related to the CADASIL Disease

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease belongs to the group of rare diseases. It is well established that Notch3 protein is primarily responsible for the development of the CADASIL syndrome. Herein, we attempt to shed light to the actual molecular mechanism underlying CADASIL syndrome via insights that we have from preliminary in silico and proteomics studies on the Notch3 protein, which is involved in many cancers and in particular lung and ovarian cancer. In this disease we always see accumulation of Granular Osmiophilic Material (GOM), which has been a hallmark for the final diagnosis based on electron microcopy (EM). Consequently, we present the regions of the brain that get affected by the disease and their functions. Finally, the symptoms of CADASIL are examined with reference to the neurological analysis that has preceded.

More on Clinical Renal Genetics

The clinical heterogeneity of genetic diseases characterized by well identified mutations is a striking feature. The diseases related to COL4A1 mutations are a new example of this statement. The COL4A1 gene codes for the α1 chain of type IV collagen (α1(IV)), a major ubiquitous component of basement membranes. Mutations in this gene were first reported by neurologists in families with autosomal dominant forms of porencephaly. The porencephalic cavity is caused by cerebral hemorrhage that occurred during the intrauterine or neonatal period. A broad range of neurologic features have been reported, including infantile hemiplegia, mental retardation, and hemorrhagic strokes in children or in adults that are triggered by trauma or anticoagulation. In another group of patients, cerebral small vessel disease (CSVD) predominates, with leukoencephalopathy, lacunar infarcts, and micro- or macrobleeds without porencephaly. Various eye abnormalities may be found, including retinal arteriolar tortuosity, cataract, or anterior segment dysgenesis of the eye (Axenfeld–Rieger anomaly). This CSVD is reminiscent of the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of mutations in the NOTCH 3 receptor. Rare cases of CADASIL syndrome associated with renal involvement have been reported. Electron microscopic analysis showed pathognomonic granular osmiophilic material in cerebral, cutaneous, and intrarenal arteries. Immunohistochemistry using an antibody specific for the NOTCH 3 ectodomain showed positive granular staining in the same vessels, whereas no staining was found in a patient with common nephroangiosclerosis (1). In addition, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) was reported in 1997 and is caused by mutations in the TREX1 transcription factor (2). This represents a distinctive subtype of retinal vasculopathy with cerebral leukodystrophy. The third mode of presentation of COL4A1 mutations has been described by Plaisier et al., and the patients first presented with renal disease (3). This autosomal dominant entity has been named HANAC syndrome, or hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (3). Mutations affect glycine residues in close proximity in exons 24 and 25 within the triple-helix domain of the protein. The main phenotypic features encompass a nephropathy with hematuria or bilateral renal cysts, a muscular disease with cramps, and retinal arterial tortuosity. Skin and kidney biopsies show by electron microscopy abnormal thickening, multilamination, and/or focal disruption of the basement membranes. In their recent study, Alamovitch et al. collected data on the neurologic condition of 14 HANAC patients (ranging from 22 to 57 years of age) belonging to three unrelated families. Nine were interviewed and examined. For the four deceased subjects (ages at death ranging from 60 to 69 years), the causes of death were not neurologic. One patient declined to participate in this study. No patient had infantile hemiparesia, mental retardation, history of stroke, or spontaneous subarachnoid or intracerebral hemorrhage. Only two patients had a history of cerebrovascular injury: acute cerebellar ataxia in one and posttraumatic cerebromeningeal hemorrhage in the other. In nine patients, brain magnetic resonance imaging (MRI) was performed and all showed at least one abnormality. No porencephaly was observed. Multiple intracranial aneurysms (ICAs) were found in three patients; these ICAs were small, asymptomatic, and localized on the intracranial carotid at the level of the carotid siphon. Seven patients had MRI abnormalities consistent with CSVD dominated by leukoencephalopathy. No cortical involvement was detected. HANAC syndrome therefore constitutes a new monogenic cause of familial ICAs. Of interest, two other inherited diseases with syndromic ICAs have been identified: autosomal dominant polycystic kidney disease and Ehlers–Danlos syndrome type IV with mutations in COL3A1. Regarding diagnosis, skin vessels changes have been described in three autosomal dominant angiopathies: CADASIL, HERNS, and HANAC. Skin biopsy analysis may provide a cost-effective guide before practicing an expensive and time-consuming gene screening. These entities such as HANAC or CADASIL syndromes can be considered as “systemic basalopathies.” They also reopened the field of renal angiopathies/nephrosclerosis/nephroangiosclerosis by using new tools of investigation and by suggesting more pathophysiological heterogeneity than previously thought.

Is the increased expression of ubiquitin in CADASIL syndrome a manifestation of aberrant endocytosis in the vascular smooth muscle cells?

Ubiquitin is a highly conserved protein involved in many important cellular processes, such as cell surface receptor signaling, endocytosis and protein degradation. Since ubiquitin plays a key role in the pathomechanisms of many neurodegenerative diseases, we immunohistochemically analyzed its expression in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is a heritable vascular dementia characterized by degeneration of the vascular smooth muscle cells (VSMC) caused by mutations in the notch 3 gene. In CADASIL, there is abnormal accumulation of the Notch 3 extracellular domain on blood vessels, but the molecular pathways linking notch 3 mutations to degeneration of the VSMC are, as yet, poorly understood. We studied human brain and skin biopsy specimens, and observed increased ubiquitin expression on structures primarily affected by the pathological process in CADASIL: the VSMC and vascular lamina media, and also large ballooned macrophages. Ultrastructurally, we noted that pathognomonic CADASIL deposits of granular osmiophilic material were often located inside indentations in the VSMC membrane that resembled endocytic vesicles. We suggest that in CADASIL, damage to the VSMC may be associated with aberrant ubiquitin-dependent endocytosis of the Notch 3 ligand, and increased accumulation of ubiquitin on the vessel wall may be a manifestation of this aberration.

Regulation of vascular morphogenesis by Notch signaling

The Notch pathway is a versatile regulator of cell fate specification, growth, differentiation, and patterning processes in metazoan organisms. In the vertebrate cardiovascular system, multiple Notch family receptors and several of their Jagged and Delta-like ligands are expressed during critical stages of embryonic and postnatal development. Functional studies in mice, fish, tumor models, and cell culture systems have shown that the angiogenic growth of the blood vessel network, the proliferation of endothelial cells, and the differentiation of arteries and veins are controlled by Notch signaling. Moreover, Notch pathway components play important roles in human pathological conditions involving the vasculature, namely CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and Alagille syndrome. Recent findings highlight the Notch ligand Delta-like 4 as a key regulator of tumor angiogenesis and suggest that this protein might be a promising target for cancer therapy.

The R110C mutation in Notch3 causes variable clinical features in two Turkish families with CADASIL syndrome

Mutations in Notch3 gene are responsible for the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). It is a late onset neurological disorder recognized by recurrent strokes and dementia. We describe here the clinical and molecular findings of three unrelated Turkish families with CADASIL syndrome. Two of the families were identified to have the same mutation, p.R110C (c.C328T), located in exon 3 of the Notch3 gene. Interestingly, the phenotypic expression of the disease in these two families was markedly different in severity and age of onset implicating additional genetic and/or non-genetic modulating factors involved in the pathogenesis. In addition, we identified the novel p.C201R (c.T601C) mutation in exon 4 of the Notch3 gene in a proband of the third family with two consecutive stroke-like episodes and typical MRI findings. Mutations described here cause an odd number of cysteines in the N-terminal of the EGF domain of Notch3 protein, which seems to have an important functional effect in the pathophysiology of CADASIL. The phenotypic variability in families carrying the same molecular defect as presented here makes the prediction of prognosis inconceivable. Although DNA analysis is effective and valuable in diagnosing approximately 90% of the CADASIL patients, lack of genotype–phenotype correlation and prognostic parameters makes the presymptomatic genetic counseling very difficult.

Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation

Notch signaling is essential for vascular patterning and response of the vasculature to injury and growth factor stimulation. Despite these findings, the molecular basis of Notch signaling in the vasculature is poorly understood. Here we report that activation of Notch signaling mediated through members of the HRT family of basic helix-loop-helix transcription factors represses smooth muscle cell (SMC) differentiation and expression of genes encoding smooth muscle cell contractile markers. Activation of Notch receptors by Jagged1 or forced expression of the constitutively active Notch1 intracellular domain in C3H10T1/2 fibroblasts inhibited myocardin-dependent transcription of SMC-restricted genes and activity of multiple SMC-restricted transcriptional regulatory elements. Consistent with these findings, forced expression of HRT2 inhibited myocardin-induced expression of SMC-restricted genes and activity of SMC-restricted transcriptional regulatory elements. Moreover, forced expression of HRT2 repressed transcription of multiple SMC-restricted transcriptional regulatory elements in A10 SMCs. The repressive function of HRT2 was not mediated via the capacity of HRT2 to bind SMC CArG elements or by disruption of myocardin-SRF protein complexes. Structure-function analyses of HRT2 indicated that repression required the basic DNA binding domain and additional C-terminal sequence. Taken together, these results demonstrate that Notch signaling represses myocardin-dependent SMC transcription. These data are consistent with a model wherein Notch signaling represses SMC differentiation and maintenance of the contractile SMC phenotype.

Mutations of the Notch3 Gene in Non-Caucasian Patients with Suspected CADASIL Syndrome

The Notch3 gene has been recently identified as a causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). To investigate the genetic contribution of Notch mutations in familial cases with vascular leukoencephalopathy, we screened 13 patients from 11 unrelated families, which were selected on the basis of magnetic resonance imaging findings and positive family history. We identified three different missense mutations in 5 patients from 4 families. Two (Arg90Cys and Arg133Cys) are the same as previously reported in Caucasian patients, the other (Cys174Phe) is a novel mutation causing a loss of a cysteine in epidermal-growth-factor-like repeats of Notch3. These data indicate that the CADASIL Notch3 mutations were found in approximately 35% of familial cases with leukoencephalopathy, suggesting genetic heterogeneity of the disease.