Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3 -negative patients

Background and Purpose-Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. Methods-In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. Results-The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, −0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. Conclusions-Sapropterin

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL

Maria

Campolo

Frontali

et al. 2014

“…Many previous studies have been retrospective on populations in whom there may be significant selection bias. [24][25][26] Although our study shows that using our algorithm we achieved a relatively high yield of positive cases, it does not evaluate the effectiveness of the algorithm in diagnosing all cases of monogenic strokes in a stroke population. This would have required genetic testing in patients in whom the algorithm did not suggest a high probability of monogenic stroke.…”

Section: 2mentioning

confidence: 83%

“…This study provides some of the most robust data to guide current clinical practice. 6,[24][25][26] Our strategy identified 7% of patients affected by monogenic diseases. Our criteria seem to be particularly efficient for CADASIL pregenetic screening because we detected disease-related mutations in 9% of our suspected cases.…”

Section: 2mentioning

confidence: 99%

Clinical Pregenetic Screening for Stroke Monogenic Diseases

Bersano

Markus

Quaglini

et al. 2016

Background and Purpose— Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease Methods— We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. Results— In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. Conclusions— In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.

“…13 The genetic analysis is costly and time-consuming because the NOTCH3 gene is long and mutations can be found in any of the 22 exons codifying for the epidermal growth factors-like repeats.…”

Section: Strokementioning

confidence: 99%

The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale

Pescini

Nannucci

Bertaccini

et al. 2012

Overall, the recognition of the disease before the development of the full clinical-neuroimaging picture may be challenging. Moreover, as we recently reported, none of the Background and Purpose-Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) phenotype is highly variable, and, although the full clinical-neuroimaging picture may be suggestive of the disease, no characteristic is pathognomonic. Thus, a genetic test remains the diagnostic gold standard, but because it is costly and time-consuming, a pregenetic screening appears desirable. We aimed at developing the CADASIL scale, a screening tool to be applied in the clinical setting. Methods-A preliminary scale was created assigning weighted scores to common disease features based on their frequencies obtained in a pooled analysis of selected international CADASIL series. The accuracy of the scale versus the genetic diagnosis was tested with receiver operating characteristic analysis after the application of this scale to 61 CADASIL and 54 NOTCH3-negative patients (no pathogenic mutation on exons 2-23 of the NOTCH3 gene). To improve the scale accuracy, we then developed an ad hoc optimization algorithm to detect the definitive scale. A third group of 39 patients affected by sporadic small-vessel disease was finally included in the algorithm to evaluate the stability of the scale. Results-The cutoff score of the definitive CADASIL scale had a sensitivity of 96.7% and a specificity of 74.2%. This scale was robust to contamination of patients with sporadic small-vessel disease. Conclusions-The CADASIL scale is a simple and sufficiently accurate screening tool to select patients with a high probability to be affected by the disease and therefore to be subjected to the genetic testing.