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

BACKGROUND: Cerebral 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. METHODS: Clinical 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. RESULTS: Genetic 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. CONCLUSIONS: Our 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.

Novel Characteristics of Race-Specific Genetic Functions in Korean CADASIL.

Background and Objectives: Previous studies found differences in the characteristics of NOTCH3 mutations in Caucasians and Asians with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, we sought to investigate the correlations between genetic and clinical/radiological findings in Korean CADASIL patients including some variants of unknown significance (VUS). Materials and Methods: We screened 198 patients with a suspected diagnosis of CADASIL between 2005 and 2015 via Sanger sequencing. Results: A total of 34 subjects (52.5 ± 9.5 years) were included. The majority of the mutations were in exon 3 and exon 11. R75P mutations (n = 5), followed by Y465C and R544C mutations (n = 4) were the most prevalent. Patients with those mutations exhibited less frequent anterior temporal (AT) or external capsular (EC) hyperintensities compared to patients with other locus mutations. Hemorrhagic stroke (HS) was found to be associated with mutations in exon 3 (R75P), exon 9 (Y465C), exon 11 (R587C), and exon 22 (R1175W variants), which were common locations in our study. Although it is unclear that genetic differences might affect the phenotypes in ethnicities, Asian population shows less migraine or seizure, but more intracerebral hemorrhage. Unlike in westernized countries, typical AT or EC hyperintensities may not be significant MRI markers, at least in Korean CADASIL patients. Furthermore, similar to R75P phenotypes, it is a novel finding that patients with Y465C and R1175W VUS have less frequent AT involvement than Caucasians. Conclusion: The associations between HS and common genetic locations account for the increased development of intracerebral hemorrhage in Koreans rather than Caucasians. We suggest that some CADASIL mutations appear to impart novel region-specific characteristics.

The CADASIL Scale-J, A Modified Scale to Prioritize Access to Genetic Testing for Japanese CADASIL-Suspected Patients.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is definitely diagnosed by genetic testing. Such testing involves the analysis of exons 2-24 of NOTCH3, which encode the epidermal growth factor-like repeat domain, where CADASIL mutations are localized. We previously reported clinical diagnostic criteria for screening CADASIL-suspected Japanese patients prior to genetic testing. Because of its high sensitivity but low specificity, most patients need to undergo genetic testing. In this study, we aimed to develop the CADASIL scale-J, a modified scale to prioritize access to genetic testing for CADASIL-suspected Japanese patients. METHODS: We modified the CADASIL scale reported by Pescini et al based on clinical features of 126 CADASIL patients and 53 NOTCH3-negative CADASIL-like patients diagnosed up until March 2016 (Phase 1). For validation, we recruited 69 consecutive patients for genetic testing of NOTCH3 from April 2016 to March 2017 (Phase 2). RESULTS: We developed the CADASIL scale-J with a score ranging from 0 to 25 and the cut-off value of 16, using 8 items: hypertension, diabetes, young onset (≤50 years old), pseudobulbar palsy, stroke/TIA, family history, subcortical infarction, and temporal pole lesion. The sensitivity and specificity of the CADASIL scale-J were 78.9% and 85.7%, respectively. In Phase 2, we obtained a positive predictive value of 70.0% and a negative predictive value of 89.2%. In this study, we identified 54 mutations, 7 of which were novel. CONCLUSIONS: The CADASIL scale-J is helpful to prioritize access to genetic testing for CADASIL-suspected Japanese patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Argentina.

CADASIL is the most common cause of hereditary stroke and vascular dementia. Published information about this disease in South America is scant. We describe clinical and demographic characteristics of 13 patients (10 families) with CADASIL from Argentina.Methods Medical records, diagnostic tests and family history of patients with CADASIL were reviewed.Results Thirteen patients with CADASIL (10 families) were included. All patients had European ancestry. Initial presentation was stroke in most patients (n = 11). Stroke patients later developed cognitive complaints (n = 9), migraine with aura (n = 1), apathy (n = 4) and depression (n = 6). External capsule and temporal lobe involvement on MRI were characteristic imaging findings. Two patients died after intracerebral hemorrhage.Conclusion This is the first report of non-related patients with CADASIL in South America addressing ancestry. Since European ancestry is not highly prevalent in all South American countries, there may be variable incidence of CADASIL within this region.

R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.

The first Indian-origin family with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

We report the first family of Indian origin known to be affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Seventeen members of the family spanning 3 generations had neurologic syndromes compatible with CADASIL, of whom 5 were genetically confirmed carriers of the Notch3 gene R141C mutation in exon 4 (421(C→T) and 141(Cys→Arg)). Our report highlights that CADASIL not only occurs sporadically in South Asians, but also may account for stroke in South Asians with a strong family history. Furthermore, the similarity of clinical presentations described here to those typical for Caucasian case series suggests that the CADASIL phenotype is preserved across racial groups.

Diversity of stroke presentation in CADASIL: study from patients harboring the predominant NOTCH3 mutation R544C.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the NOTCH3 gene. Several characteristic population-specific clinical phenotypes and neuroimaging features have been reported in CADASIL. This study investigated the clinical stroke presentation and cranial magnetic resonance imaging (MRI) findings in a group of patients with CADASIL. We reviewed the clinical stroke presentation and brain MRI findings in 73 consecutive Korean patients aged >18 years diagnosed with CADASIL between May 2004 and April 2009. Brain MRI images were also scored for lacunar infarction and cerebral microbleeds. Intracranial atherosclerosis (ICAS) was assessed by magnetic resonance angiography. Disability was measured with the modified Rankin scale (mRS) and classified as good (mRS score 0-2) or poor (mRS score 3-5). In this study, 65 of the 73 patients (90.3%) had the same R544C genotype. A total of 40 episodes of cerebral infarction were confirmed in 31 patients, with a mean age at onset of 58.8 ± 11.4 years (range, 38-76 years). Twelve patients (16.9%) had ICAS, and 5 of these patients had symptomatic stenoses. Intracerebral hemorrhage occurred in 9 patients (12.3%). Both intracerebral hemorrhage and ICAS were associated with poor clinical outcome. Our data demonstrate the diversity of clinical stroke presentation according to ethnicity and vascular risk factors.

Screening for NOTCH3 gene mutations among 151 consecutive Korean patients with acute ischemic stroke.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of cerebral small blood vessels caused by mutations in the NOTCH3 gene. The initial detection of CADASIL may be more difficult among Asian populations because common clinical phenotypes and neuroimaging findings are not frequently found in these populations. The purpose of this study was to screen the NOTCH3 gene for mutations among consecutive patients with acute ischemic stroke from our region in Korea. METHODS: Between April 2008 and March 2009, 151 consecutive patients with acute ischemic stroke were screened for NOTCH3 mutations. All patients underwent a detailed clinical examination and structured interview for clinical symptoms and family history. We reviewed brain magnetic resonance imaging data from stroke patients to assess the severity of white-matter hyperintensity lesions, the number of cerebral microbleeds, and the number of lacunar infarctions. Polymerase chain reaction was used to screen exons 3, 4, 6, 11, and 18 of the NOTCH3 gene. RESULTS: Among 151 consecutive patients with acute ischemic stroke, 6 patients (4.0%; 95% confidence interval [CI] 0.9-7.1) possessed a NOTCH3 gene mutation. All patients exhibited the same R544C mutation in exon 11. Four of these 6 patients presented with large artery atherosclerosis. The prevalence of CADASIL in patients with neuroimaging features consistent with advanced small-vessel disease was 36.0% (95% CI 8.0-64.8). CONCLUSIONS: In this region, NOTCH3 gene mutations are frequently found in acute stroke patients who present with neuroimaging features consistent with advanced small-vessel disease.

A Chinese pedigree of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): clinical and radiological features.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebral vascular disease thought to be confined to Japan. This paper reports a Chinese pedigree of CARASIL in which two patients exhibited all of the typical clinical features of the disease. The radiological features are also discussed and compared with those of CADASIL. These cases illustrate the unique clinical and radiological features of CARASIL and challenge the idea that CARASIL is limited to the Japanese population.

Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, most clinical, molecular and neuroimaging information has come from Caucasians. Therefore, we investigated the spectrum of NOTCH3 mutations and MRI features in CADASIL patients of Chinese origin on Taiwan. METHODS: Mutational analysis of NOTCH3 exons 2 to 23 by direct nucleotide sequencing was performed in patients with clinically suspected CADASIL. MRI findings were retrospectively evaluated and scored using a modified Schelten's scale. RESULTS: Nine different point mutations of NOTCH3 were identified in 21 unrelated patients. Intriguingly, 47.6 % were in exon 11, and 19 % in each of exon 4 and 18. R544C was very common and present in all patients with a mutation in exon 11. Many patients with NOTCH3 R544C share the same haplotype linked to the mutation using markers D19S929 and D19S411, which flank the NOTCH3. The sensitivity of T2-weighted MRI detecting anterior temporal abnormality was only 42.9 %. Furthermore, the neuroimaging evidence of intracerebral hemorrhage (ICH) was present in 23.8 % of the 21 patients. CONCLUSIONS: A population-specific mutational spectrum of CADASIL was found in the Chinese patients on Taiwan. The Chinese patients carrying NOTCH3 R544C may descend from a common ancestor. Anterior temporal hyperintensity on T2-weighted MRI may not be a sensitive marker for CADASIL. ICH is a relatively common manifestation of CADASIL in East Asians, especially in the presence of hypertension.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Arabs.

OBJECTIVE: To investigate the Notch 3 mutation spectrum in Arab patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL, which is an inherited cerebrovascular disease characterized by recurrent subcortical ischemic stroke starting in the third or fourth decade. METHODS: Complete neurological evaluation and sequencing of the Notch 3 gene were carried out at King Faisal Specialist Hospital & Research Centre in 2007 on 2 families from Riyadh, Kingdom of Saudi Arabia and Sudan affected by CADASIL. RESULTS: The index cases had adult onset stroke, vascular dementia, behavioral and psychiatric symptoms and accelerated deaths. In both families, abnormal magnetic resonance imaging findings were detected in symptomatic and asymptomatic individuals. All Notch 3 exons were screened for mutations in both families and no known or novel mutation could be found; although, in one family the brain biopsy showed the typical granular osmiophilic material deposition and the vascular smooth muscle cells. CONCLUSION: This is the first 2 cases of CADASIL in Arabs, which occur without an obvious Notch 3 mutation.

CADASIL in Arabs: clinical and genetic findings.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is increasingly recognized as an inherited arterial disease leading to a step-wise decline and eventually to dementia. CADASIL is caused by mutations in NOTCH3 epidermal growth factor-like repeat that maps to chromosome 19. CADASIL cases have been identified in most countries of Western and Central Europe, the Americas, Japan, Australia, the Caribbean, South America, Tanzania, Turkey, South Africa and Southeast Asia, but not in Arabs. METHODS: We studied three families from Saudi Arabia (Family A), Kuwait (Family B) and Yemen (Family C) with 19 individuals affected by CADASIL. RESULTS: The mean age of onset was 31 +/- 6 and the clinical presentation included stroke in 68%, subcortical dementia in 17% and asymptomatic leukoariosis detected by MRI in 15%. Migraine and depression were frequently associated, 38% and 68% respectively. The mean age of death was 56 +/- 11. All NOTCH3 exons were screened for mutations, which revealed the presence of previously reported mutations c.406C>T (p.Arg110>Cys) in two families (family A&B) and c.475C>T (p.Arg133>Cys) mutation in family C. CONCLUSION: CADASIL occurs in Arabs, with clinical phenotype and genotype similar to that in other ethnic groups.

Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation.

OBJECTIVE: To elucidate the phenotype, genotype, and MRI findings of Korean patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mutation carriers. METHODS: The authors studied 40 members of nine unrelated Korean CADASIL families. After genetic analysis of Notch3, clinical and MRI findings were correlated in 27 mutation carriers. RESULT: Notch3 mutation sites were C174R (one family, n = 3), R133C (one family, n = 3), R587C (one family, n = 1), R544C (two families, n = 5), and R75P (four families, n = 15). The clinical features were typical of CADASIL, but the frequency of migraine in the Korean population appears low. MRI abnormalities were found in 54% of the mutant carriers, the most common being white matter hyperintensities. The prevalence of lacunes and microbleeds increased with patient age. Anterior temporal areas were less often involved in subjects with R75P mutations than in those where mutations occurred in other sites (p = 0.02). Gradient echo imaging identified microbleedings in 33% of mutation carriers (64% of those with abnormal MRI), whereas diffusion-weighted MRI showed abnormal findings in only one patient. Neurologic disability was related to the number of lacunar infarcts and the lesion volume of white matter hyperintensities (p < 0.001) whereas MMSE score was related to the number of lacunar infarcts (p < 0.005). CONCLUSIONS: Although Korean cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mutation carriers show similar clinical and MRI findings, these abnormalities appear less frequently than in other populations. Relatively frequent microbleedings on gradient echo imaging suggest that treatment should be individualized according to MRI findings. The novel mutation of R75P, not involving a cysteine residue, is related to less frequent involvement of the anterior temporal area, thus broadening the spectrum of CADASIL.

The spectrum of Notch3 mutations in 28 Italian CADASIL families.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cause of hereditary cerebrovascular disease. It results from mutations in the Notch3 gene, a large gene with 33 exons. A cluster of mutations around exons 3 and 4 was originally reported and limited scanning of these exons was suggested for the diagnosis in most cases. OBJECTIVE: To report Notch3 mutation analysis in 28 unrelated Italian CADASIL families from central and south Italy. RESULTS: The highest rate of mutations was found in exon 11 (21%) and only 18% of mutations were in exon 4. This may be related to the peculiar distribution of Notch3 mutations in the regions of origin of the families. CONCLUSIONS: The results suggest that limited scanning of exons 3 and 4 is inadvisable in CADASIL cases of Italian origin.

Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and depression, but not migraine. A skin biopsy in the proband patient showed characteristic pathological findings of CADASIL on electron microscopy. Afterward, genetic analysis found an Arg332Cys mutation at exon 6 of NOTCH3. Neuropsychological evaluation showed vascular dementia in two of four affected people. Head MRI showed multiple infarcts in bilateral basal ganglia, thalami, periventricular white matter, external capsules, and brainstem, but involvement of the anterior temporal pole was found only in two people with milder symptoms. To our knowledge, the Arg332Cys NOTCH3 mutation at exon 6, which was identified in the studied family, has not been reported in Asian populations. Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL.