Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.0.0
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: NOTCH3
• Condition: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukocenphalopathy, type 1
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• NOTCH3 ⇔ 0000914 (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1): Limited Actionability

Actionability Rationale

The experts were unanimous in asserting limited actionability given available intervention is not effective in reducing the risk for stroke in individuals with CADASIL. There is limited evidence that avoidance of thrombolysis or anti-platelet therapies is effective in reducing secondary iatrogenic harm in the acute setting of CADASIL.

Final Consensus Scores

Gene Condition Pairs: NOTCH3 ⇔ 0000914 (OMIM:125310)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality from stroke / Specialist care and management, including monitoring and controlling vascular risk factors	2	2A	1D	3	8AD

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The exact prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is not known and is probably underdiagnosed. Multiple small and national registries have estimated the minimum prevalence between 2-5 per 100,000. Epidemiological data on the prevalence of CADASIL in different racial and ethnic groups are incomplete. Data on individuals of European and Asian ancestry is more common, whereas identification of CADASIL in people of African ancestry remains rare. The differences in disease prevalence may be accounted for, in part, by underreporting as a result of resource limitations, under-recognition, and undertesting.
Based on a recent report that NOTCH3 pathogenic variants in the general population is 100-fold higher than current estimates of the minimum prevalence of CADASIL, CADASIL is thought to be much more prevalent than previously suspected. [1, 2, 3, 4]

Clinical Features

CADASIL is a disease of the small to medium-sized arteries, mainly affecting the brain. Classically, it is characterized by mid-adult onset of recurrent ischemic stroke (related to small vessel pathology), cognitive decline progressing to dementia, migraine with aura, mood disturbances/psychiatric disorders (variable, from personality changes to severe depression), and apathy (may be independent of depression). Less common signs include reversible acute encephalopathy, epilepsy, motor disability, and gait disorders. Intracerebral hemorrhage (ICH) can occur. Neuropsychiatric complications such as adjustment disorders, dysthymia, and pseudobulbar palsy are the most common and lead to worse quality of life. Impaired cognition can range from mild cognitive impairment to vascular dementia. The classic CADASIL phenotype consists of migraines, subcortical strokes, and ultimately vascular dementia.
Diffuse white matter lesions and subcortical infarcts are present on neuroimaging. Magnetic resonance imaging (MRI) features include symmetrical and progressive subcortical white matter hyperintensities (WMHs), lacunes, microbleeds, enlarged perivascular spaces, and cerebral atrophy. Anterior temporal lobe WMHs are often considered a radiological hallmark for CADASIL but are not sensitive or specific for the condition. [1, 2, 3, 4, 5, 6]

Natural History

The presenting symptoms, age at onset, and disease progression in CADASIL are variable. Migraine with aura occurs in many individuals with CADASIL. When present, it can be the first symptom, with a mean age of onset of 26-30 years (age range 6-80 years). Over half of those with migraine with aura have experienced an atypical migraine attack: prolonged, basilar or hemiplegic aura, confusion, fever, or coma. In one third of individuals, migraine may be severe and refractory. Transient ischemic attacks and ischemic stroke, the most frequent presentations, are present in a large majority of individuals. They occur at a mean age of 47 years (age range 20-70 years), in most cases without conventional vascular risk factors. Ischemic episodes are often recurrent, leading to severe progression including severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy. Cognitive decline, the second most frequent feature, may start as early as 35, with over two thirds of individuals developing dementia. Cognitive decline usually manifests initially with executive dysfunction, decreased verbal fluency, and inattention (mild cognitive impairment), slowly progressing to a multidomain cognitive impairment and dementia after 60 years of age. Concurrently, stepwise deterioration occurs due to recurrent strokes. Impaired cognition may be the sole symptom in some individuals. ICH, with occurrence rates being much higher in Asians than in Europeans. Epilepsy occurs in a small percentage of individuals and presents in middle age, usually secondary to stroke.
Brain imaging abnormalities evolve as the disease progresses. MRI WMHs, although sometimes very subtle, can present between 20-40 years of age, often first appearing in the anterior temporal lobes. In the course of the disease, the load of WMH lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable.
Prognosis of CADASIL is poor, with severe progression to being unable to speak and get out of bed occurring 10–20 years after stroke onset. However, individuals with milder disease are increasingly reported. Based on a study of 411 individuals, the median age at onset of inability to walk without assistance was approximately 60 years old and the median age at which individuals became bedridden was 64 years. The median age at death was 68 years with a more rapid disease progression in men than in women. The most common cause of death was pneumonia, followed by sudden unexpected death and asphyxia. [1, 2, 3, 4, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

Initial evaluation of all individuals should include:
• Neurologic evaluation
• Psychological evaluation of cognitive disorders
• Brain MRI for overall assessment and follow-up, irrespective of signs or symptoms
• Cervical and transcranial echodoppler for examination for associated atheromatous lesions
• Resting electrocardiogram (ECG)
• Holter blood pressure
• Biochemical evaluation: complete blood count, C-reactive protein, fasting blood glucose, exploration of lipid abnormality (cholesterol, triglycerides, HDL, calculated LDL) (Tier 2) [4, 7]

Individuals should be followed up by specialized centers and/or an expert neurologist. (Tier 2) [4, 7]

There are no available curative therapies for CADASIL. Therefore, treatment should focus on symptomatic management and management of vascular risk factors, which mainly center around prevention, avoidance, and cessation of specific/potential triggers. Some management approaches lack a clear evidence base, and as a consequence, there are inconsistencies in treatment and preventive care regimens. (Tier 2) [4, 5]

Addressing vascular risk for sporadic vascular disease may delay onset, modify severity or prolong the course for individuals with CADASIL. (Tier 2) [5]

Avoid antiplatelet therapy for primary stroke prevention. Extrapolating from general guidelines, physicians have treated many individuals with CADASIL with antiplatelet agents. However, there is no evidence to support the use of antiplatelet agents in individuals with CADASIL without prior ischemic stroke, or for preventing recurrent stroke. (Tier 2) [4, 5]

Anticoagulants are not recommended for stroke prophylaxis in CADASIL due to the risk of ICH, but they are not contraindicated if there is another strong indication (e.g. atrial fibrillation, pulmonary embolus). (Tier 2) [4]

Individuals with CADASIL should not receive thrombolysis for an acute small-vessel ischemic stroke, as its safety and efficacy are unknown in individuals with CADASIL. Thrombolysis should only be considered for acute ischemic stroke if it is due to a large-artery occlusion secondary to a concurrent cause, which is very uncommon. (Tier 2) [4, 5]

Intensive control of blood pressure is recommended in CADASIL. At a minimum, controlling blood pressure will help prevent cognitive decline and stroke attributed to vascular risk factors, which would only add to those inherent to CADASIL. Several observational studies have reported a high prevalence of hypertension in CADASIL, and that in CADASIL, hypertension has been shown to be associated with incident dementia, disability due to dementia, overall disability, incident stroke, and ICH. (Tier 2) [5]

Because vascular risk factors have been shown to increase the severity of CADASIL, vascular risk factor profile should be carefully evaluated and lifestyle changes such as smoking cessation, healthy diet, and physical exercise should be advised. Given reported associations between tobacco smoking and earlier onset of stroke in individuals with CADASIL, smoking cessation should be strongly encouraged. One study of 200 individuals with CADASIL (101 of which identified as an ever-smoker) reported that stroke was associated with pack-years of smoking (odds ratio [OR] =1.05; 95% CI, 1.01 to 1.10; P=0.029). (Tier 2) [4, 5, 7]

Recommendations for migraine prophylaxis are conflicting. One guideline suggests the use of beta-blockers for the prevention of migraine headache with aura, while a more recent guideline recommends avoiding beta-blockers and states that acetazolamide and sodium valproate may be preferred for prophylaxis. (Tier 2) [5, 7]

A meta-analysis of prophylactic medications for migraine in CADASIL included 123 individuals (from 13 studies) with a median age of 53 years (range: 23-83 years). Simple analgesics (35.8%, 44/123) and beta-blockers (22.0%, 27/123) were the most common abortive and prophylactic strategies, respectively. Over half (54.4%) of all individuals had used more than one medication sequentially or concomitantly. The most common prophylactic medications used were equivocal in terms of response. (Tier 1) [8]

Individuals should be offered psychological support and psychotherapy if needed. (Tier 2) [4, 7]

Consider referral to a psychiatrist for evaluation and treatment of mood/behavioral disorders. (Tier 4) [1]

Consider treatment with the cholinesterase inhibitor, donepezil 10 mg/day, to improve impaired executive function. (Tier 2) [5]

A systematic review of cholinesterase inhibitors included one RCT of donepezil in individuals with CADASIL and documented cognitive impairment (n=161). After 18 weeks of treatment, no significant differences were found between the treatment and placebo groups on primary cognitive or dementia scales. Improvements were noted on secondary outcome measures of executive function and processing speed, but the clinical relevance of these findings was not clear. (Tier 1) [3]

Cerebral catheter angiography should be avoided in individuals with CADASIL, unless being used therapeutically for a known symptomatic acute large vessel occlusion. In a review of individuals with CADASIL undergoing diagnostic cerebral catheter angiography, 69% (11/16) experienced neurological symptoms lasting hours to weeks after the procedure. (Tier 2) [5]

Anesthetic procedures maintaining hemodynamic stability and avoiding hypotension are recommended for individuals with CADASIL undergoing surgery. (Tier 2) [4]

Surgical management should include maintaining tight control of intraoperative mean arterial pressure, and head-down positioning should be restricted or avoided. (Tier 2) [5]

In the context of anesthesia, both hypo- and hypercapnia should be avoided because of the limits of autoregulation of the diseased vessels are not known. (Tier 2) [7]

Surveillance

Individuals should have a yearly evaluation of their vascular risk factor profile. (Tier 2) [4]

Individuals should be monitored for subjective and objective cognitive impairment. (Tier 2) [4]

The interval at which individuals with CADASIL should be seen for follow up depends on the severity and type of symptoms and the needs of individuals and their caregivers. Routine follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis onward. (Tier 4) [1]

Circumstances to Avoid

Most management recommendations focus on strategies such as avoidance, and cessation of specific/potential triggers. These are listed in the management section above. (Tier 2) [4, 5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [1, 2]

Prevalence of Genetic Variants

More than 95% of individuals with CADASIL have pathogenic variants (PVs) in NOTCH3. (Tier 3) [1, 3]

The frequency of NOTCH3 cysteine-altering PVs is 1:300 in the general population worldwide (gnomAD database), with the highest frequency in people who are of Asian descent (1:100). (Tier 3) [1]

Approximately 70% of European individuals with a clinical CADASIL diagnosis have a PV in one of the exons encoding epidermal growth factor-like repeat (EGFr) domains 1-6. PVs in EGFr domains 7-34 are less frequently seen in diagnosed individuals (~30%) but have a high frequency in the general population (gnomAD). (Tier 3) [1]

Penetrance

Penetrance of CADASIL is close to 100%. (Tier 4) [1, 6]

Frequency among symptomatic individuals with CADASIL:
Transient ischemic attacks and strokes = 85%
Dementia = 60-75%
Migraine = 30-75% (80-90% of which have migraine with aura)
Mood disturbances = 30%
Apathy = 40%
Epilepsy = 10% (Tier 3) [1, 3, 5]

In a study of 125 affected individuals with CADASIL, cerebral microbleeds were present in 34%. The majority of these microbleeds were located in three specific regions of the brain. (Tier 3) [1]

A meta-analysis including 13 studies (N=1310 individuals with CADASIL) reported the pooled prevalence of ICH in CADASIL of 10.1% (95% CI: 5.6-18.0%), with 17.7% (95% CI=11.0-28.5%) and 2.0% (95% CI=0.4%–10.8%) within the Asian and European subgroups, respectively. (Tier 1) [9]

In a systematic review of ICH in CADASIL, comprising 129 individuals and 142 ICH events in total, ICH was the first manifestation of the disease in 32 individuals (38.1%), recurrence occurred in 16 (12.4%), and 11 individuals died acutely of ICH. (Tier 1) [10]

Recent large prospective studies, ranging from 50-290 individuals with CADASIL, have reported that between 19.0-53.2% of their cohort had hypertension. (Tier 3) [5]

Episodes of fever, confusion, and reduced arousal, called CADASIL coma, may occur in up to 8.5% (6/70) of individuals with CADASIL. (Tier 3) [5]

Relative Risk

Information on relative risk was not available.

Expressivity

CADASIL clinical expression varies in age of onset, severity of the clinical symptoms, and progression of the disease. Clinical presentation also varies among and within families. (Tier 4) [1]

There is variability in disease severity among individuals with CADASIL. A recent report found that the frequency of NOTCH3 cysteine-altering PVs in the general population is approximately 100-fold higher than current estimates of the minimum prevalence of CADASIL, suggesting that the NOTCH3 clinical spectrum must be considerably broader, ranging from classic CADASIL to a mild small-vessel disease, or possibly non-penetrance. (Tier 3) [1]

In this report, the PVs in EGFr domains 1-6 appear to be fully penetrant and are usually associated with the classic CADASIL phenotype. (Tier 4) [1]

Onset of stroke in CADASIL is reported to be influenced by classical vascular risk factors such as smoking and hypertension, as well as the presence of cysteine-altering pathogenic variants in NOTCH3 in specific EGFr domains (domains 1-6). (Tier 3) [1, 4, 6]

4. What is the Nature of the Intervention?

Nature of Intervention

Most interventions associated with CADASIL are avoidance of procedures, situations, and substances that could lead to cerebrovascular episodes, which are associated with minimal risk and burden. Cholinesterase inhibitors are associated with gastrointestinal side effects, including nausea, diarrhea, vomiting, leg cramps, abnormal dreams, dizziness, and weight loss. [3]

A meta-analysis that reviewed prophylactic medications for migraine in CADASIL, including 123 individuals (from 13 studies) found that individuals who received beta-blockers had significantly more unfavorable outcomes compared with individuals who did not, with the primary unfavorable response reported being worsened fatigue. [8]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

The first manifestations of CADASIL may be migraine, which may not lead to the diagnosis of CADASIL before the onset of cognitive decline. (Tier 4) [1, 2]

The phenotype observed in individuals with CADASIL can be indistinguishable from many other inherited disorders characterized by stroke and/or dementia. (Tier 4) [1]

The clinical characteristics and MRI abnormalities in multiple sclerosis, sporadic small vessel disease including Binswanger's disease, and primary angiitis of the nervous system, may resemble those of CADASIL. For example, corpus callosal involvement, typical of multiple sclerosis but rare in sporadic small vessel disease, can occur in CADASIL. (Tier 3) [1, 4]

While the presence and location of MRI WMHs have high discriminatory accuracy for CADASIL, other inherited microangiopathies and even sporadic cerebral small vessel disease can have similar patterns. (Tier 3) [5]

Hereditary cerebral amyloid angiopathies can mimic CADASIL, presenting with a CADASIL-like clinical and neuroimaging phenotype (progressive cognitive and motor decline, stroke, migraine and behavioral disorders, and leukoencephalopathy). (Tier 3) [5]

Date of Search: 07.28.2016 (updated 09.09.2024)

Reference List

1. J Rutten, SAJ Lesnik Oberstein. CADASIL. 2000 Mar 15 [Updated 2016 Jul 14]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1500

2. CADASIL. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=136

3. Li Y, Hai S, Zhou Y, Dong BR. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev. (2015)

4. Mancuso M, Arnold M, Bersano A, Burlina A, Chabriat H, Debette S, Enzinger C, Federico A, Filla A, Finsterer J, Hunt D, Lesnik Oberstein S, Tournier-Lasserve E, Markus HS. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur J Neurol. (2020) 27(1468-1331):909-927.

5. Meschia JF, Worrall BB, Elahi FM, Ross OA, Wang MM, Goldstein ED, Rost NS, Majersik JJ, Gutierrez J, American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Hypertension. Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association. Stroke. (2023) 54(1524-4628):e452-e464.

6. Guey S, Lesnik Oberstein SAJ, Tournier-Lasserve E, Chabriat H. Hereditary Cerebral Small Vessel Diseases and Stroke: A Guide for Diagnosis and Management. Stroke. (2021) 52(1524-4628):3025-3032.

7. Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. (1997) 56(0022-3069):947-64.

8. Glover PA, Goldstein ED, Badi MK, Brigham TJ, Lesser ER, Brott TG, Meschia JF. Treatment of migraine in patients with CADASIL: A systematic review and meta-analysis. Neurol Clin Pract. (2020) 10(2163-0402):488-496.

9. Lai QL, Zhang YX, Wang JJ, Mo YJ, Zhuang LY, Cheng L, Weng ST, Qiao S, Liu L. Occurrence of Intracranial Hemorrhage and Associated Risk Factors in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Systematic Review and Meta-Analysis. J Clin Neurol. (2022) 18(1738-6586):499-506.

10. Sukhonpanich N, Markus HS. Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review. J Neurol. (2024) 271(1432-1459):2423-2433.