Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: NOTCH3
Condition: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukocenphalopathy, type 1
GENEDISEASE PAIRS: NOTCH3125310
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
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 and 4 per 100,000 in Europe.
1 2 3
Clinical Features
(Signs / symptoms)
CADASIL is a disease of the small to medium-sized arteries, mainly affecting the brain. 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). Diffuse white matter lesions and subcortical infarcts are present on neuroimaging. Less common signs include reversible acute encephalopathy and epilepsy.
1 2 3
Natural History
(Important subgroups & survival / recovery)
The presenting symptoms, age at onset, and disease progression in CADASIL are variable. Migraine with aura occurs in 30%-40% of individuals with CADASIL. When present, it can be the first symptom, with a mean age of onset of 30 years (age range 6-48 years). Of those with migraine, 90% have migraine with aura. Transient ischemic attacks and ischemic stroke, the most frequent presentation, are present in 85% of symptomatic 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 disability with gait disturbance, urinary incontinence, and pseudobulbar palsy. Cognitive decline, the second most frequent feature, may start as early as 35, with approximately 75% of affected individuals developing dementia. Cognitive decline usually manifests initially with executive dysfunction (mild cognitive impairment) and is progressive with a concurrent stepwise deterioration due to recurrent strokes. Mood disturbances/psychiatric disorders occur in about 30% of affected individuals, and apathy has been described in 40%. Epilepsy occurs in 10% of individuals and presents in middle age, usually secondary to stroke. Brain imaging abnormalities evolve as the disease progresses. MRI white matter hyperintensities, although sometimes very subtle, can be visualized from age 21 years onward. In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable.
 
Prognosis of CADASIL is poor. 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.
2 1
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Initial evaluation of all patients should include:
 
• Neurologic evaluation, therapeutic management, and follow-up
 
• Psychological evaluation of cognitive disorders
 
• Brain MRI for overall assessment and follow-up
 
• Cervical and transcranial echodoppler for examination for associated atheromatous lesions
 
• Resting 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
Antiplatelet therapy is frequently used, but has not been proven effective in CADASIL. (Tier 3)
1
Patients should maintain a balanced diet aimed at controlling possible factors such as vascular risk associated with the disease. (Tier 2)
4
During surgery requiring anesthesia, patients should be monitored for cerebral region oxygen saturation and with close ECG monitoring. Invasive arterial blood pressure is recommended in the most invasive surgical procedures or if major blood loss is expected. (Tier 2)
5
A systematic review of cholinesterase inhibitors included one RCT of donepezil in patients with CADASIL and documented cognitive impairment (n=161). After 18 weeks of treatment, no significant effects were found on primary cognitive scales and other measurements. However, some improvement was found on two secondary outcome measures of executive functioning. (Tier 1)
3
Psychological counseling should be offered to patients and their families in order to give emotional support. (Tier 4)
2 1
Surveillance
There are no standard international surveillance guidelines for CADASIL. However, yearly follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis. (Tier 4)
1
Family Management
Testing of at-risk asymptomatic adult relatives of individuals with CADASIL is possible after molecular genetic testing has identified the specific NOTCH3 pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling. (Tier 4)
1 2
Circumstances to Avoid
Angiography and anticoagulants are contraindicated in CADASIL as they may provoke cerebrovascular accidents. (Tier 3)
1
Smoking increases the risk of stroke of individuals with CADASIL and should be avoided. One study of 127 patients with CADASIL reported that smoking was associated with an earlier onset of stroke/TIA. (Tier 3)
1
Thrombolytic therapy (intravenous thrombolysis) is contraindicated because of the presumed increased risk for cerebral hemorrhage. (Tier 3)
1
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)
5
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
More than 95% of individuals with CADASIL have pathogenic variants in NOTCH3, and CADASIL is estimated to have close to 100% penetrance. Thus the prevalence of genetic mutations associated with CADASIL should be similar to the prevalence of CADASIL (estimated between 2 and 4 per 100,000). (Tier 3)
1 2 3
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Penetrance of CADASIL is probably 100%. (Tier 4)
1
Frequency among symptomatic individuals with CADASIL:
 
Transient ischemic attacks and strokes = 85%
 
Dementia = 75%
 
Migraine = 30-40%
 
Mood disturbances = 30%
 
Apathy = 40%
 
Epilepsy = 10%. (Tier 3)
1
Information on the prevalence of mutations was not available.
 
 
 
 
 
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. The clinical presentation also varies among and within families. (Tier 4)
1
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 cardiovascular episodes, which are associated with minimal risk and burden. Cholinesterase inhibitors are associated with gastrointestinal side effects, including nausea, diarrhea, and vomiting.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting 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)
2 1
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Stroke / Specialist care and management
2
3C
1A
3
9CA
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
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; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1500
3. Li Y, Hai S, Zhou Y, Dong BR. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev. (2015)
4. French National Authority for Health (HAS). List of services for a long-term condition cadasil (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy). Haute autorité de santé. Publisher: French National Authority for Health (HAS). (2011) Website: http://cadasilfoundation.net/National%20Diagnosis%20and%20Treatment%20Protocol%20for%20CADASIL%20%20%202011.pdf
5. C. Errando, F. Veyckermans, C. Andre. Orphananesthesia anesthesia recommendations for patients suffering from cadasil. (2013) Website: http://www.orphananesthesia.eu/en/component/docman/doc_download/119-cadasil-syndrome.html
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