Enfermedad de CADASIL: ictus familiares / Cadasil disease: Family strokes

El CADASIL es una microangiopatía cerebral de herencia autosómica dominante. Si bien su epidemiologia y patogénesis son poco conocidas, se sabe que está causada por una mutación del gen NOTCH3. Su expresión clínica es variable, dominada por episodios de migraña con aura seguido de episodios isquémicos cerebrales recurrentes, demencia y trastornos neuropsiquiátricos. El diagnóstico final se hace fundamentalmente con resonancia magnética desde la fase presintomática. El manejo del CADASIL es multidisciplinar. A continuación, exponemos el caso de un paciente que presenta múltiples accidentes cerebrovasculares. En la resonancia magnética se observa extensa afectación de sustancia blanca en ambos hemisferios cerebrales y en el estudio genético mutación compatible con enfermedad de CADASIL. (AU)

CADASIL is a brain microangiopathy with autosomal dominant inheritance. Although its epidemiology and pathogenesis are poorly understood, it is known to be caused by a mutation of the Notch3 gene. Its clinical expression is variable, dominated by episodes of migraine with aura followed by recurrent cerebral ischemic episodes, dementia and neuropsychiatric disorders. Final diagnosis is made fundamentally with magnetic resonance imaging from the pre-symptomatic phase. CADASIL is managed in a multidisciplinary way. Below, we report a case of a patient who presented multiple cerebrovascular accidents. Magnetic resonance imaging revealed extensive white matter involvement in both cerebral hemispheres and in the genetic study mutation compatible with CADASIL disease. (AU)

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association.

Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the most common inherited cerebral small vessel disease. Individuals with the disease show variability in the nature and onset of symptoms and rates of progression, which are only partially explained by differences in pathogenic mutations in the NOTCH3 gene. Recognizing the disease early in its course and securing a molecular diagnosis are important clinical goals, despite the lack of proven disease-modifying treatments. The purposes of this scientific statement are to review the clinical, genetic, and imaging aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, contrasting it with other inherited small vessel diseases, and to provide key prevention, management, and therapeutic considerations with the intent of reducing practice variability and encouraging production of high-quality evidence to support future treatment recommendations.

Pathogenesis and therapeutic advances of cerebral autosomal- dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease in adults. Many CADASIL cases were reported after NOTCH3 was identified as the causative gene of CADASIL. However, there is still no specific and effective therapies for CADASIL. In this review, we summarize recent research progress on disease models, symptomatic treatments and potential therapies for CADASIL, thereby providing a reference for follow-up CADASIL treatment research.

Management of Coronary Artery Disease in CADASIL Patients: Review of Current Literature.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia in adults. It is well-established that CADASIL results in neurocognitive dysfunction and mood disturbance. There is also cumulative evidence that CADASIL patients are more susceptible to ischemic heart disease. The aim of this study is to review the current literature regarding the incidence of coronary artery disease in CADASIL patients with a focus on the various management options and the clinical challenges associated with each of these treatment strategies. We conducted a literature search using Cochrane, MEDLINE, and EMBASE for papers that reported the occurrence of coronary artery disease in patients with CADASIL. We supplemented the search with a manual search in Google Scholar. Only case reports, case series, and original articles were included. The search resulted in six reports indicating the association between coronary artery disease and CADASIL and its management. Evidence suggests that extracranial manifestations of CADASIL may include coronary artery disease, presenting as a more extensive burden of disease in younger patients. Surgical and percutaneous revascularization strategies are feasible, but the incidence of peri-procedural stroke remains significant and should be weighed against the potential benefit derived from either of these strategies. A multidisciplinary approach to therapy, with perspectives from neurologists, cardiologists, and cardiac surgeons, is needed to provide the appropriate treatment to the CADASIL patient with severe coronary artery disease. Future studies should be directed toward the development of targeted therapies that may help with the early detection and prevention of disease progress in these patients.

Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease; no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study, we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C150 mice with aggregates composed of CADASIL-R133C mutated and wild-type EGF1-5 repeats for a total of 4 months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior, the number and integrity of vascular smooth muscle cells in the retina, neuronal survival, or inflammation or the renal system, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of NOTCH3 accumulation in a CADASIL mouse model supporting further development towards clinical application for the benefit of CADASIL patients.

Modeling the Cognitive Trajectory in CADASIL.

BACKGROUND: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition. OBJECTIVE: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL. METHODS: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared. RESULTS: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity. CONCLUSION: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies.

A Novel Heterozygous Variant in Exon 19 of NOTCH3 in a Saudi Family with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; OMIM #125310) is the most common cause of monogenic familial cerebral small vessel disease. It typically manifests at middle adulthood with highly variable clinical features including migraine with aura, recurrent transient ischemic attacks or ischemic strokes, mood disorders, and progressive cognitive decline. It is caused by mutations in the NOTCH3 gene, which maps to the short arm of chromosome 19 and encode for epidermal growth factor-like repeats. In this article, we report a 40-year-old male patient who presented with a two-year history of progressive cognitive decline including impaired attention, memory, executive functions, and processing speed whose family history was strongly positive for young-onset ischemic stroke and memory impairment. His father, uncle, and grandfather died due to ischemic strokes and cognitive impairment (similar condition). A whole exome sequencing to the patient (proband II-1) revealed a novel heterozygous missense variant c.3009G>T, p.(Trp1003Cys) (chr19;15291625; hg19) in exon 19 of the NOTCH3 gene. Sanger sequencing was used to confirm the variant in other family members. This variant has not been described in the literature so far. The novel mutation described in the present study widened the genetic spectrum of NOTCH3-associated diseases, which will benefit studies addressing this disease in the future. CADASIL remains a disabling disorder leading to medical retirement in our patient due to late clinical presentation, lack of family history taking prior to joining the military, and lack of curative therapy. Further research for therapeutic options is needed including stem cell therapy .

Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology.

BACKGROUND AND PURPOSE: Guidelines on monogenic cerebral small-vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and type IV collagen (COL4)A1/2. METHODS: We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. RESULTS: We have proposed 'red-flag' features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus. CONCLUSIONS: The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.

NOTCH3 Gene Mutation in a Chilean Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Family.

INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke disorder caused by mutations in the NOTCH3 gene. We report the first Chilean CADASIL family with complete radiological and histological studies. METHODS: The family tree was constructed from an autopsy-confirmed confirmed patient, and includes 3 generations. We performed clinical, pathologic, genetic, and radiologic examinations on members of a family with CADASIL. RESULTS: In the second generation, findings compatible with CADASIL were identified in 6 individuals, all of whom had a missense mutation in exon 3 (c.268C>T) resulting in an arginine to cysteine amino acid substitution at position 90 (R90C). In the third generation, a missense mutation was detected in one of the 4 asymptomatic individuals. CONCLUSIONS: There are similarities in clinical presentation between this family and previously described Asian and European series with R90C mutations. Detecting genotypes with a gain or loss of cysteine residues opens the door to future gene transfection-based therapies.

CADASIL: new advances in basic science and clinical perspectives.

PURPOSE OF REVIEW: Recent advances in genetic evaluation improved the identification of several variants in the NOTCH3 gene causing Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Despite improved diagnosis, the disease mechanism remains an elusive target and an increasing number of scientific/clinical groups are investigating CADASIL to better understand it. The purpose of this review is to summarize the current knowledge in CADASIL. RECENT FINDINGS: CADASIL is a genotypically and phenotypically diverse condition involving multiple molecular systems affecting small blood vessels. Cerebral white matter changes observed by MRI are a key CADASIL characteristic in young adult patients often before severe symptoms and trigger NOTCH3 genetic testing. NOTCH3 mutation locations are highly variable, correlate to disease severity and consistently affect the cysteine balance within extracellular Notch3. Granular osmiophilic material deposits around blood vessels are also a unique CADASIL feature and appear to have a role in sequestering proteins that are essential for blood vessel homeostasis. As potential biomarkers and therapeutic targets are being actively investigated, neurofilament light chain can be detected in patient serum and may be a promising circulating biomarker. SUMMARY: CADASIL is a complex, devastating disease with unknown mechanism and no treatment options. As we increase our understanding of CADASIL, translational research bridging basic science and clinical findings needs to drive biomarker and therapeutic target discovery.

Telemedicine for Follow-Up of Rare Neurological Disease.

Background and Purpose- Providing ongoing care for rare neurological conditions is challenging. Telemedicine can reduce patient travel. We set up and evaluated a telemedicine service for patients with a genetic form of stroke and dementia cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Methods- One hundred fourteen patients with mutation-positive cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (64 telemedicine and 50 face-to-face) were recruited. Patient and clinician satisfaction questionnaires rated the service to create a mean satisfaction score for both face-to-face and telemedicine follow-up appointments. Results- There was no difference in mean (SD) patient or clinician satisfaction scores between telemedicine and face-to-face appointments (patient: 4.57 [0.56] and 4.69 [0.42]; P=0.99; clinician: 4.55 [0.49] and 4.60 [0.43]; P=0.44). Conclusions- Telemedicine follow-up was suited to patients with stroke and dementia and offered satisfaction levels similar to that for face-to-face consultations.

A Novel NOTCH3 Gene Mutation in a Polish CADASIL Family.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetically determined disease of the cerebral vessels, characterized by recurrent ischemic strokes, dementia, and degeneration of the cerebral white matter. The condition is caused by a mutation in the NOTCH3 gene, whose product plays a great role in the development and physiology of the cardiovascular system. Magnetic resonance imaging reveals multiple hyperintensive lesions of the white matter in the T2-weighted images also in asymptomatic carriers of CADASIL and can be detected even 10-15 years prior to clinical signs. Diagnosis is confirmed by genetic testing. We present 2 patients (mother and daughter) carrying the same mutation p.Cys212Gly in 1 allele of the NOTCH-3 gene, which has not yet been recorded in the Human Gene Mutation Database for that gene and therefore described as a new one. The clinical manifestation of the disease differs between patients -the 63-year-old mother has been suffering from severe migraine headaches since her early youth and the first vascular event occurred when she was about 50 years old, she is now presenting with impaired cognitive functions, left facial palsy, bilateral pyramidal syndrome more prominent on the left side, and four-wheel support assisted walking. The neurological deficits that her 42-year-old daughter is afflicted with are discreet. Observation to date indicates a definitely less severe clinical course of the disease. This indicates that members of the same family carrying the same mutation may produce different clinical course of the disease.

Notch3ECD immunotherapy improves cerebrovascular responses in CADASIL mice.

OBJECTIVE: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by dominant mutations in the NOTCH3 receptor, is the most aggressive small vessel disease of the brain. A key feature of its pathogenesis is accumulation of the extracellular domain of NOTCH3 receptor (Notch3ECD ) in small vessels, with formation of characteristic extracellular deposits termed granular osmiophilic material (GOM). Here, we investigated the therapeutic potential of a mouse monoclonal antibody (5E1) that specifically recognizes Notch3ECD . METHODS: The binding affinity of 5E1 toward purified NOTCH3 was assessed using Octet analysis. The ability of 5E1 to bind Notch3ECD deposits in brain vessels and its effects on disease-related phenotypes were evaluated in the CADASIL mouse model, which overexpresses a mutant rat NOTCH3. Notch3ECD and GOM deposition, white matter lesions, and cerebral blood flow deficits were assessed at treatment initiation (10 weeks) and study completion (30 weeks) using quantitative immunohistochemistry, electron microscopy, and laser-Doppler flowmetry. RESULTS: 5E1 antibody bound recombinant rat NOTCH3 with an average affinity of 317nM. A single peripheral injection of 5E1 robustly decorated Notch3ECD deposits in the brain vasculature. Chronic administration of 5E1 did not attenuate Notch3ECD or GOM deposition and was not associated with perivascular microglial activation. It also failed to halt the development of white matter lesions. Despite this, 5E1 treatment markedly protected against impaired cerebral blood flow responses to neural activity and topical application of vasodilators and normalized myogenic responses of cerebral arteries. INTERPRETATION: This study establishes immunotherapy targeting Notch3ECD as a new avenue for disease-modifying treatment in CADASIL that warrants further development. Ann Neurol 2018;84:246-259.

Multiple sclerosis or "inflammatory CADASIL?": Case Report and review of the literature.

BACKGROUND: Multiple sclerosis (MS) and CADASIL presenting together is exceedingly rare. As more cases of "inflammatory" CADASIL emerge, diagnostic challenges for clinicians increase. We report an individual with MS and CADASIL presenting with cognitive decline at age 25. She presented with gadolinium enhancing lesions on MRI and inflammatory cerebrospinal fluid raising the question of whether these patients should be given a diagnosis of "inflammatory CADASIL" or both MS and CADASIL. METHODS: A literature review was conducted on reports of inflammatory CADASIL or MS and CADASIL, clinical presentations including spinal cord lesions and CSF inflammatory markers. RESULTS: Nine cases in the literature of individuals with CADASIL and inflammatory presentations were found with treatment varying from intravenous steroids to MS immunomodulatory therapy. CONCLUSIONS: If individuals with CADASIL present with immune mediated inflammatory components they may benefit from immunomodulatory therapy. This is discussed with a review of the inflammatory CADASIL/MS cases in the literature and report of a case.

Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.

Pregnancy in CADASIL.

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease caused by NOTCH3 gene mutations. CADASIL women are frequently considered at high risk of systemic vascular events during pregnancy and often prescribed with antithrombotic drugs. This decision is not evidence-based considering the lack of data about pregnancy outcome in CADASIL. We describe our experience on pregnancy in CADASIL patients. MATERIALS AND METHODS: We reviewed records of 50 CADASIL females followed in our center, and we collected prospective information in six patients for a total of 93 pregnancies. RESULTS: No woman had the disease onset or suffered from cerebral vascular ischemic events during pregnancy. Sixteen miscarriages (17.2%) were recorded. There were 72 vaginal births, and five cesarean sections. Considering the six patients followed prospectively (for a total of eight pregnancies), data on fetal growth and newborns weight were in line with those from the general population. Considering gestational complications, we recorded mild proteinuria without hypertension in one patient and hyperinsulinemia and pre-eclampsia in another affected by a known nephropathy. Antithrombotic drugs were used in three patients, in one for an unrelated coexisting prothrombotic condition. CONCLUSIONS: CADASIL does not seem to be associated with an unfavorable outcome of pregnancy either for women and fetuses. Patients and treating physicians should be reassured that pregnancy can be safely initiated in CADASIL, as there is no evidence to support a specific preventive antithrombotic treatment during pregnancy in CADASIL. Larger studies are needed to definitively confirm these conclusions.