Diagnosis Of CADASIL Research Articles

Abstract Number: LBA11 CADASIL revealed by COVID‐19: A case report and systematic review

Introduction Cerebral Autosomal Dominant Arteriopathy with subcortical Infarcts and leuko‐encephalopathy (CADASIL) is a genetic condition characterized by migraine, ischemic strokes, mood disturbances, and cognitive impairment. Since COVID‐19 pandemic started in late 2019, six patients (including our case) were reported to present with neurological symptoms associated with CADASIL mutation and four of them were diagnosed while hospitalized for COVID‐19 illness. Methods A case report anda systematic literature review done via PubMed search that was performed up to Oct 15, 2022. Studies reporting on CADASIL and COVID‐19 infection were included. Results In addition to our case report, 5 case‐reports were identified, and full articles were reviewed and summarized. Including our case, the mean age of patients was 45.44 years, and all of them were females. The diagnosis of CADASIL was established after COVID‐19 infection in four of the cases including ours, while the diagnosis of CADASIL was established in the other two patients after neurological symptoms and prior strokes warranting investigations and stroke workup. CADASIL diagnosis was confirmed with genetic testing in all of them. Two cases had history of migraines with aura, three cases had hypertension, and two patients had unremarkable past medical history. Four cases reported dysarthria as one of the initial symptoms at presentation. The initial MRI brain reported involvement of corona radiata in two cases, centrum semiovale in two cases, cerebellum in one case. All cases reported bilateral changes on imaging. Aspirin, clopidogrel, statins, intravenous immunoglobulins, and steroids were the medical treatment modalities used amongst those patients. Four cases had mild‐complete recovery of symptoms, one case was reported to have partial resolution of deficits, and one patient had complete resolution of motor deficit and persistent mild neurocognitive dysfunction. Conclusions COVID‐19 infection might be a triggering factor forCADASIL flare. Although it is unclear whether CADASIL mutations would be the only etiology behind the neurological deficits in these patients, as COVID‐19 infection has been reported to be associated with many neurological manifestations, the reported imaging findings along with the genetic confirmation weighs more towards COVID‐19 infection acting as a trigger for CADASIL flare.

Recurrent generalized seizures as the prominent manifestation in a patient with CADASIL: a case report and literature review

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arteriopathy typically caused by mutations in the NOTCH-3 gene. Few detailed descriptions of recurrent generalized seizures in CADASIL has been reported.Case presentationThis article details a case of recurrent generalized seizures, which eventually be diagnosed as CADASIL with a heterozygous variant, c.1630 C > T (p. Arg544Cys), in exon 11 of the Notch 3 gene. Here, we discussed the possible pathogenesis underlying the epilepsy associated with CADASIL through the brain magnetic resonance imaging changes and the captured epileptiform waves in the electroencephalography during the patient’s follow-up period. Related literatures were also reviewed to discuss the etiology of the epilepsy.ConclusionsRecurrent generalized seizures may be a presenting neurological manifestation of CADASIL in the absence of other discernible causes. Clinicians should comprehensively seek the possible etiology of patients with recurrent generalized seizures, considering the possible diagnosis of CADASIL.

A Chinese CADASIL Family with a Novel Mutation on Exon 10 of Notch3 Gene

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by the Notch3 gene mutation, has its unique clinical and imaging characteristics. Here we present a Chinese family with a novel mutation on exon 10 of Notch3 gene. MethodsClinical and MRI data of the three patients in the family during the 7-year follow-up were collected. The CADASIL Scale Score was calculated to evaluate the disease risk of the three patients at their first admission or clinic visit. Five family members underwent genetic test. ResultsGenetic test confirmed the diagnosis of CADASIL in this family. A novel mutation of p.C533S on exon 10 of Notch3 gene was detected. The CADASIL score of the proband and her sister was both 17 and that of her brother was 14. ConclusionsOur report not only expands the mutation spectrum of Notch3 gene in CADASIL, but also shows the distinct heterogeneity of CADASIL patients in the same family with the same mutation.

5-year Progression of CADASIL: A Case Report

A female patient in her 40’s of mixed Chinese-Indian ancestry was referred to our neurology clinic for frequent migraine with aura and CADASIL. She had been treated for acute encephalopathy in 2014. The incident led to her CADASIL diagnosis and later retinitis pigmentosa, both rare conditions. Initial clinical assessment showed moderate severity of migraine and normal cognitive function. As there is no specific treatment recommended for CADASIL, the patient was maintained on pharmacological therapies for secondary prevention of ischaemic stroke, treatment of seizure, symptomatic treatment for migraine and a cholesterol-lowering drug. A supplement containing Vitamin E (tocotrienols) was recommended. During the ensuing 5-years, there were no further neurovascular incidents and her migraine went into full remission.

A-074 Evidence of Cognitive Decline in a Patient with CADASIL Without Major Stroke Event

Abstract Objective Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic disease that impacts small arteries in the brain and can result in ischemic strokes, seizures, and cognitive decline. This case study of a 61-year-old male illustrates the cognitive profile of an individual with CADASIL who has not suffered a major stroke event. Neuroimaging shows subcortical compromise in a diffuse manner. Methods The patient was assessed in an out-patient institutional practice. The individual was assessed with a clinical interview and comprehensive Neuropsychological Battery. The battery included cognitive and psychological measures with free-standing and imbedded validity measures. Results Cognitive testing demonstrated significant impairment in visuo-motor processing speed, executive planning, cognitive flexibility, verbal fluency, decision making, and visual memory, and suggests that the patients abilities show deterioration of subcortical regions, and is consistent with his CADASIL diagnosis. The patient was diagnosed with Mild Neurocognitive Disorder, due to medical condition. Conclusion Individuals with CADASIL often suffer from ischemic strokes and cognitive impairment. This study suggests that despite no major stroke event, individuals with CADASIL may still exhibit cognitive decline especially in subcortical regions. This case supports the theory that progressive cognitive decline in CADASIL patients does not begin as a result of a major stroke and can continue as a distinct cause of vascular neurocognitive disorder.

Novel dot-blot assay for detection of vascular Notch3 aggregates in patients with CADASIL

To detect vascular Notch3 extracellular domain aggregates in CADASIL, we developed a novel dot-blot assay with both autopsy and biopsy skin samples. We obtained samples from 11 patients with CADASIL and 12 control patients, and we performed dot-blot analyses by using sequential biochemical tissue extractions with three different antibodies against specific regions of the Notch3 extracellular domain. We also analyzed clinical features and vascular accumulations of Notch3 by immunohistochemistry. Via the dot-blot assay with the antibody against the C-terminal region of the Notch3 extracellular domain, we successfully detected Notch3 extracellular domain aggregates in skin tissue homogenates obtained from patients with CADASIL. Our novel method may therefore aid the diagnosis of CADASIL.

Homozygous NOTCH3 p.R587C mutation in Chinese patients with CADASIL: a case report

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations.Case presentationWe recruited two affected individuals with CADASIL from a mainland Chinese family. The proband (Patient 1), a 60-year-old male, presented with slow progressive gait instability, severe cognitive impairment, and emotional disorder for more than 2 years with a history of ischemic stroke and hypertension. His younger brother (Patient 2) presented with apparent gait difficulties, dysarthria as well as cognitive decline at 59 years old. Brain magnetic resonance imaging (MRI) showed diffused white matter lesions involving bilateral periventricular white matter, semioval center region, and anterior temporal lobes. Molecular genetic testing identified a homozygous variant, c.1759C > T (p.R587C), in NOTCH3 gene in both patients. Pathological analysis revealed granular osmiophilic material (GOM) deposits in small arterial walls of skin from the proband. The diagnosis of CADASIL was confirmed.ConclusionsOur cases of CADASIL with homozygous mutation c.1759C > T (p.R587C) in NOTCH3 share similar manifestation to the patients with heterozygous same mutation reported previously. Other than genetic factors, vascular risk factors or environmental factors might contribute to the phenotypic variation of CADASIL.

Speech-language disorders in CADASIL: a case report

ABSTRACT The purpose of this study was to report the main speech-language disorders in a patient with CADASIL diagnosis, attending the Speech Therapy School Clinic of a Higher Education Institution from 2008 to 2013. Clinical evaluation of the speech organs was carried out, verifying reduced mobility and tonus of lips, tongue and cheeks, with major repercussions on deglutition in the last two years of care. Multiple swallowing were observed for pasty consistency, and coughing, for the liquid one, with "wet" vocal quality and cervical auscultation without alterations, after multiple swallowing. A hoarse vocal quality with asthenia, weak loudness, hypernasal resonance and imprecise articulation were observed regarding the patient’s voice. The speech therapy aimed at maintaining food intake and communication, improving the patient’s quality of life.

A large number of cerebral microbleeds in CADASIL patients presenting with recurrent seizures: a case report

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy associated with the NOTCH3 gene. Clinical manifestations include strokes, transient ischaemic events, psychiatric disturbances, dementia, and migraines. We report a case of a Thai man with a severe CADASIL phenotype who presented with recurrent seizures and acute ischaemic stroke and classic vascular risk factors.Case presentationA 50-year-old man with a history of mood disorder and progressive cognitive decline for 20 years as well as well-controlled diabetes mellitus and hypertension presented with recurrent generalized seizures and acute right-sided weakness. An MRI of the brain showed acute infarction of the left pons, a large number of cerebral microbleeds throughout the brain and white matter abnormalities without classic anterior temporal lobe lesions. Molecular genetic testing identified a homozygous pathologic variant, c.1672C > T (p. Arg558Cys), in the NOTCH3 gene. The diagnosis of CADASIL was confirmed. His clinical symptoms deteriorated, and he died of tracheobronchitis with secretion obstruction.ConclusionThis case raises awareness of an uncommon cause of acute ischaemic stroke in patients with classic vascular risk factors and emphasizes the need for a complete evaluation in cases with unexpected clinical presentation or unexpected diagnostic study results.

Corrigendum.

Corrigendum.

CADASIL: A Case Report with an Atypical Presentation and Novel Mutation

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL is a small vessel disease that commonly presents with ischemic episodes cognitive deficits migraine with aura and psychiatric disturbances It is caused by mutations in the NOTCH gene of which several specific point mutations have been identified We report a year old female with a confirmed CADASIL diagnosis an atypical presentation and an unreported NOTCH mutation She presented with stroke like symptoms and MRI was initially read as several subacute infarcts throughout the brain She denied any history of headaches A review of her imaging suggested CADASIL as a more likely diagnosis She underwent NOTCH testing which showed a pathogenic p Arg Cys mutation and a previously unreported p Pro Leu mutation

CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material.

IntroductionCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic vascular disorder. Granular osmiophilic material (GOM) is its ultrastructural marker. We reviewed tissue biopsies from CADASIL patients to establish whether ultrastructural observations help clarify the pathogenic mechanism of CADASIL. Given the resemblance of the GOM deposits to the immunoglobulin deposits seen in glomerulonephritis and focal segmental glomerulosclerosis (FSGS), their morphologies were investigated and compared.MethodsSkin, skeletal muscle, kidney, and pericardium tissue biopsies from 13 patients with a clinical and molecular diagnosis of CADASIL, and kidney biopsies from five patients with IgA nephropathy and five patients with primary FSGS were subjected to ultrastructural examination.ResultsIn CADASIL patients, several GOM deposits from all sites were partially or totally surrounded by an electron‐lucent halo. The deposits frequently had a more electron‐dense portion with a regular outline on the inner side and a less osmiophilic, looser outer side displaying a less regular profile. The uniformly dense deposits tended to be more osmiophilic if located close to the cell membrane and less osmiophilic if laid farther away from it. The immunoglobulin deposits from the glomerulonephritis and FSGS patients lacked both the granular pattern and the halo.ConclusionsThis study demonstrates that GOM deposits may have a nonuniform morphology and describes in detail an electron‐lucent halo surrounding several of them. It is conceivable that the halo is the morphological evidence and possibly the cause of an aberrant NOTCH3 processing, already suspected to be involved in CADASIL.

Cerebral Hemorrhage in CADASIL: First Report in Entre Ríos

Introduction: CADASIL is a hereditary disease of the cerebral small blood vessels. We describe the case of a patient with diagnosis of CADASIL and intracerebral hemorrhage. Clinical case: A 47-year-old hypertensive male patient treated with antithrombotic agents, who was diagnosed with CADASIL by skin biopsy and admitted at the emergency department for sudden and intense headache. The MRI showed left occipital intracerebral hemorrhage. Conclusion: In patients diagnosed with CADASIL, a positive echo-time for microbleeds could avoid the use of antithrombotic agents given the high risk of ICH. Thus avoid further damage to patients with a disease that currently has no specific treatment.

John W.Stirling, AlanCurry and BrianEydenDiagnostic Electron Microscopy – A Practical Guide to Interpretation and Technique (RMS – Royal Microscopical Society)John Wiley & Sons, West Sussex, UK, 2013. 468 pages. Price £71.25 (Hardback, Amazon). ISBN 978‐1‐119‐97399‐7

I first came across a pre-publication copy of this book at a conference on a trade stand and instantly knew that I wanted to read it from just having a quick flick through. This new and exciting book covers a wide range of the most common areas in diagnostic pathology at the ultrastructural level, including chapters on muscle, nerve and CADASIL. There are also extremely informative and helpful chapters about the practicalities of processing, cutting and viewing different types of specimen. Each chapter is written by specialists in that particular field. The book itself has a very pleasing lay out and text which is clear, flowing and easily accessible. The electron micrographs are numerous and high in quality, with clear and concise figure legends which are well referenced within the main body of the text. It is easy to dip in and out of and find the particular area of interest. The editors of this book state that they have not attempted to reproduce previous encyclopaedic texts of TEM in diagnostic pathology. However for a relatively small book a lot of ground is covered. Chapters cover the ultrastructural pathology of renal disease, transplant renal biopsies, skeletal muscle, nerve, tumours, microbial ultrastructure, ciliary disorders and sperm centriolar abnormalities, lysosomal storage diseases, CADASIL, platelet disorders, congenital dyserythropoietic anaemia types I and II, Ehlers-Danlos Syndrome, and occupational and environmental lung disease. I like the fact that where appropriate many of the chapters start by describing and illustrating ‘normal’ tissue, something you never normally see in diagnostic electron microscopy. The book also covers the practical aspects of electron microscopy, including how to cut up and process samples in order to gain the maximum amount of information from them. Detailed protocols are included and, having had to do TEM on a histological section on a slide for the first time recently, I can speak from experience and say that the protocols are clear, easy to follow and really do work. There is also a section on trouble shooting problems with sectioning of blocks which is useful, and a discussion of hot topics in modern diagnostic electron microscopy. This includes chapters covering digital imaging in diagnostic EM, the uncertainly of measurement and the impact of microwave technology and telemicroscopy. From a neuropathological point of view the CADASIL chapter provides a logical and practical approach for how to screen the sample for the presence of the classical GOM deposits that confirm a positive diagnosis of CADASIL. The electron micrographs in this chapter show clear examples of the GOM deposits and also show that they should not be confused with other non-specific electron dense deposits often see in samples that are submitted as possible CADASIL. The chapters on skeletal muscle and nerve cover 64 pages in total and give a good but brief overview of these tissues. The chapters cover practical aspects of how to handle and process these tissues, the ultrastructure of normal tissue, possible artefacts, and pathological changes. The chapter on lysosomal storage diseases is particularly useful for those rare occasions when you see them in clinical practice. The chapter provides a good overview of these diseases, the majority of which have CNS involvement. The chapter contains an array of electron micrographs demonstrating the ultrastructural findings of some of these diseases in skin biopsies, which are the most cost effective first line diagnostic tool in these cases. Overall I feel that this book is a valuable and useful addition to the bookshelf of anyone involved in electron microscopy who works in a diagnostic setting, be they an electron microscopist or a pathologist. It covers a lot of ground in just 468 pages. Priced at £71.25 (http://www.amazon.co.uk), it offers excellent value for money. This book is also available as a kindle edition with a price of £49.88 (http://www.amazon.co.uk). The clear explanations, electron micrographs and practical advice (that really works) make this a good all round diagnostic EM reference book. I would highly recommend it.

Cerebral hemorrhages in CADASIL: Report of four cases and a brief review

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease, clinically characterized by migraine, recurrent transient ischemic attacks or strokes, psychiatric disorders and cognitive decline. Strokes are typically ischemic, while hemorrhagic events have been only sporadically described. However, cerebral microbleeds have been found in 31–69% of CADASIL patients. MethodsWe describe four unrelated CADASIL patients who had hemorrhagic strokes. We also briefly review the literature on intracerebral hemorrhage (ICH) in CADASIL. ResultsThree patients had a thalamo-capsular hemorrhage (age at onset: 54, 67, 77) and one of these had a second hemispheric cerebellar hemorrhage. Another patient experienced an interpeduncular cistern subarachnoid hemorrhage when he was 39. None of these patients was receiving antiplatelets, anticoagulants or statins at the time of hemorrhage; all were hypertensive. NOTCH3 gene analysis revealed mutations on exons 14, 22 (two patients presenting the same mutation), and 24. MRI signs of previous hemorrhages were present in all these patients. ConclusionsHemorrhagic stroke can occur in CADASIL similarly to sporadic cerebral small vessel diseases; this finding expands the phenotype of the disease. A diagnosis of CADASIL should probably be considered also in patients with ICH. These data bear potential implications in terms of need of better control of risk factors, particularly hypertension, and raise relevant questions about the use of antiplatelets as prevention measures in CADASIL patients.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Two Siblings with Neuropsychiatric Symptoms

erebral autosomal dominant arteriopathy with subcorti-cal infarcts and leukoencephalopathy (CADASIL) is arare hereditary disease that presents with various neurologicaland/or psychiatric symptoms, such as stroke, migraine with aura,cognitive changes, mood disorders, and dementia. Mutations inthe Notch3 gene have been documented in most of the patients.Clinically, the most useful diagnostic tool is cranial magneticresonance (MR) imaging, which demonstrates widespread sub-cortical leukoencephalopathy associated with hyperintensities inbasal ganglia, thalamus, and brainstem. Psychiatric symptomsare seen in 20%–41% of the patients, and are rarely the initialpresenting symptom. Here we present two siblings in their 40swith prominent psychiatric complaints. Clinical diagnosis ofCADASIL was made years later, after a careful personal andfamily history combined with typical MR imaging findings.Both patients had a missense mutation in exon 4 of Notch3. Ifpatients with various psychiatric symptoms have a history ofheadache, stroke-like episodes, or cognitive changes, and a pos-itive family history of similar complaints, they should undergocranial MR imaging. In case the imaging demonstrates unex-plained leukoencephalopathy, patients should be investigated forCADASIL.Cerebral autosomal dominant arteriopathy with subcor-tical infarcts and leukoencephalopathy (CADASIL) is a rarehereditary brain disease that in most patients occurs due tomutations of the notch 3 gene on chromosome 19q12.

Shorter telomeres in patients with cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL)

CADASIL is a hereditary systemic vasculopathy which affects mainly small cerebral arteries and is caused by mutations in the Notch3 gene. Misfolding of Notch3 is linked to endoplasmic reticulum stress and increased reactive oxygen species, which may result in dysfunction of endothelial cells, inflammation and ischemia. Oxidative stress and inflammation may induce a rapid telomere shortening in peripheral blood leukocytes (PBLs). The aim of this study was to assess the telomere length in PBLs from 29 patients with a genetic diagnosis of CADASIL by using a modified quantitative real-time polymerase chain reaction based assay. PBL telomere length was significantly shorter in CADASIL patients (T/S ratio = 0.17, 95% CI, 0.14-0.20) than in the controls (T/S ratio = 0.31, 95% CI, 0.27-0.35, t-test p < 0.001). Moreover, patients with functional dependence displayed shorter telomeres than those with functional independence (p = 0.039). Our data provide the first evidence that PBL telomere length is shortened in CADASIL disease, and this may be a systemic oxidative stress indicator in CADASIL patients, providing a possible biomarker of disease progression and for future therapeutic strategies.

NOTCH3 gene mutations in subjects clinically suspected of CADASIL

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of relatives at risk is critical in mutation carriers. MethodsMutation analysis of the NOTCH3 gene was performed through direct sequencing in 140 patients with clinical suspicion of CADASIL. Patients underwent genetic counselling pre and post testing. The 2–23 exons containing all EGF-like domains were screened. Results14 familial forms of the disease have been identified with 14 different causative mutations in exons 2, 3, 4, 5, 7, 10, 14, 19, 20 and 22 of the NOTCH3 gene; no pathogenetic mutations have been identified in exons 6 and 8; several genetic variations both in coding as well as in intronic regions were identified too. ConclusionsOur data confirm the importance of screening the whole EGF-like domains region of NOTCH3 gene for the molecular diagnosis of CADASIL among the Italian population too. Moreover genetic variants different from loss or gain of a cysteine residue are identified and presented.

The pathomechanism and treatment of CADASIL

CADASIL has been reported notably in Europe, has recently been found to occur in Japan and, with the increase in the number of reported cases, has been attracting attention. Currently, the diagnosis of CADASIL is established clinically if the patient: (1) develops the condition at a relatively young age (40-50 years), (2) is not at risk for stroke, (3) has repeated attacks of lacunar infarction with gradual progression to pseudobulbar paralysis and dementia, and (4) has other family members with similar symptoms. The diagnosis is also established by imaging and laboratory studies if: (1) MRI reveals leukoaraiosis and multiple small infarcts in the deep white matter, basal ganglia, thalamus, and pons, with hyperintensities of the temporal pole and external capsule bilaterally; (2) electron microscopy demonstrates granular osmiophilic material (GOM) around vascular smooth muscles in the brain, skeletal muscle, and skin; and (3) DNA analysis shows notch3 mutations. The mechanism of development of CADASIL due to notch3 mutations is still unknown. However, a recent study revealed that Notch3 ectodomain is a major component of GOM. On binding to the ligand, Notch3 normally undergoes proteolytic cleavage, with the resulting clearance of the extracellular domain. However, in CADASIL, it accumulates as GOM and potentially inhibits normal metabolism in smooth muscle cells. It is necessary to suppress the production of GOM for fundamental therapy of CADASIL.

Right-to-Left Shunt in CADASIL Patients: A Comorbidity Factor?

To the Editor: In 2001 Angeli et al1 reported a remarkably high prevalence of right to left shunt (RLS) in a single CADASIL pedigree, suggesting “a possible association between CADASIL and RLS”. Surprisingly, and notwithstanding the large volume of data building up on CADASIL pathogenesis and diagnosis, no further data has followed this first and only publication on this topic up to now. This is why we read with much interest the article from Zicari et al,2 reporting on a very high prevalence of RLS (71%) in a sample of 21 patients with CADASIL. However, some concerns have to be issued. …