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Table of Contents    
Year : 2014  |  Volume : 62  |  Issue : 3  |  Page : 257-261

Characteristics of CADASIL in Chinese mainland patients

Department of Neurology, The Chinese Peoples' Liberation Army General Hospital, Beijing, China

Date of Submission03-Mar-2014
Date of Decision06-Mar-2014
Date of Acceptance08-Jun-2014
Date of Web Publication18-Jul-2014

Correspondence Address:
Jia-Tang Zhang
Department of Neurology, The Chinese Peoples' Liberation Army General Hospital, 28 Fu Xing Road, Hai Dian District, Beijing 100853
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.136900

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 » Abstract 

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been reported in many geographical regions. However, relatively few reports about CADASIL in Chinese were reported. Materials and Methods: We retrospectively collected and analyzed clinical characteristics, magnetic resonance (MRI) features and genetic data of 52 Chinese mainland CADASIL patients. Results: Mean age of onset was 42.43 years. The primary clinical manifestations included: Ischemic stroke/transient ischemic attack (62.5%), primary intracerebral hemorrhage (25%), vertigo (25%), migraine (39.58%), dementia (18.75%) and emotional disturbance (20.83%). The most frequently observed MRI abnormalities were hyperintensity in the cerebral white matter on T2-weighted images and multiple infarcts, high-signal lesions on T2 images in anterior temporal lobes and external capsule were uncommon. The highest mutation frequency was in exon regions, 4 and 3, followed by exon 11. Granular osmiophilic material (GOM) was identified in 66.67% of the cases examined with biopsy. Conclusions: Most characteristics of Chinese mainland CADASIL patients are similar to those of CADASIL patients living in other regions. However, the prevalence of primary intracerebral hemorrhage and vertigo is much higher in Chinese mainland CADASIL patients. Significant leukoaraiosis in anterior temporal poles on T2-weighted image are uncommon. Exons 3 and 4 are the mutation hotspots.

Keywords: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral hemorrhage, Chinese mainland, clinical manifestation, genetics, ischemic stroke

How to cite this article:
Tan QC, Zhang JT, Cui RT, Xu QG, Huang XS, Yu SY. Characteristics of CADASIL in Chinese mainland patients. Neurol India 2014;62:257-61

How to cite this URL:
Tan QC, Zhang JT, Cui RT, Xu QG, Huang XS, Yu SY. Characteristics of CADASIL in Chinese mainland patients. Neurol India [serial online] 2014 [cited 2022 Aug 15];62:257-61. Available from: https://www.neurologyindia.com/text.asp?2014/62/3/257/136900

 » Introduction Top

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease that occurs worldwide, which is caused by mutations in the NOTCH3 gene. [1] The pathological hallmarks is the presence of granular osmiophilic material (GOM) in smooth muscle cells of small blood vessels. [2] The primary clinical manifestations include recurrent cerebral infarction (CI) or transient ischemic attack (TIA), migraine, emotional disturbances, and dementia, the main image features include multiple infarcts and extensive white matter hyperintensities. [3] The clinical course and genetic mutations of CADASIL are highly variable among different regions, but there are still limited information available in China.

 » Materials and Methods Top

Between January 1, 2002, and March 31, 2013, 14 index cases and their affected family members (men, 28; women, 24) were diagnosed with CADASIL in the Department of Neurology of the General Hospital of the People's Liberation Army. These patients were from 14 unrelated families who lived in 9 provinces located within the Chinese mainland. Diagnosis of CADASIL was confirmed by direct sequencing of the NOTCH3 gene. Patient data and follow-up information were recorded in a registration form. Use of human clinical materials was approved by the Ethical Committee of the General Hospital of the Chinese People's Liberation Army. All patients gave written informed consent.

NOTCH3 genetic analysis was done using DNA extracted from patient blood samples. Screening for NOTCH3 mutations initially included exons 3 and 4, which are the known locations for CADASIL-related mutations. [4] When no mutations were found, all 23 NOTCH3 exons were sequenced. For skin biopsy, a 6-8 mm full-thickness biopsy was performed on the upper arm, fixed, and examined for GOM using electron microscopy.

 » Results Top

Clinical findings of these 52 patients are summarized in [Table 1]. The mean age at onset of neurological symptoms among the 48 symptomatic patients was 42.43 + 8.92 years (range 22-59 years). The age range of 4 asymptomatic mutation carriers was 19 to 32 years. Transient ischemic attack (TIA)/ischemic stroke (IS) was the most common presenting symptom in 30 (62.53%) patients; 14 patients had recurrent strokes. Primary intracerebral hemorrhage (PICH) was the presenting feature in 12 (25%) patients from 4 families; of these 7 had history of hypertension. Of the 6 deaths in patients with PICH, 4 patients died due to recurrent hemorrhages and 3 patients who were bedridden died due to pulmonary infections. Other presenting symptoms included: Vertigo (25%), migraine (39.58%), and dementia (18.75%) and 12 patients complained loss of memory, but did not meet the diagnostic criteria for dementia. Emotional disturbances were found in 20.83% patients. Some symptoms that are considered rare in CADASIL included epilepsy in 1 patient and tinnitus in 3 patients.

Of 41 mutation carriers who had MRI, 36 patients (87.8%; 33 symptomatic, 3 asymptomatic) had abnormal findings. Mean age of patients with normal MRI scan was 31.4 years (range, 20-42 years). The most frequently observed MRI abnormality multifocal white matter hyperintensities on T2-weighted images [Figure 1] was seen in 80.56% patients and multiple infarcts [Figure 2] in 69.44% (25/36) patients, no abnormal contrast enhancement was observed [Figure 3]. Widespread leukoaraiosis involving the periventricular white matter was detected in 2 asymptomatic patients (aged 19, 32 years, respectively). Twelve patients had 19 PICHs [Figure 4]. Involvement of anterior temporal lobes and external capsule was uncommon, present in 11.11% and 8.33% patients, respectively [Figure 5] and [Figure 6].
Figure 1: T2-FLAIR image shows leukoaraiosis involving extensive white matter

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Figure 2: T2-FLAIR image shows multiple ischemic lesions in bilateral basal ganglia

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Figure 3: Contrast enhancement image shows no enhancement

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Figure 4: T1-weighted images show a cerebral hemorrhagic lesion in the right frontal lobe, and cerebromalacia of an old hemorrhage in the left basal ganglia

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Figure 5: T2-weighted image shows hyperintensity lesions in the anterior temporal pole

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Figure 6: T2-weighted image shows widespread leukoaraiosis involving both external capsules

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Table 1: Clinical, genetic and MRI features of CADASIL patients in Chinese mainland

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Eleven different NOTCH3 mutations and a polymorphism were identified in those patients [Table 1]. Individuals within the same family carried the same mutation. Exon 4 and exon 3 were the most common mutation sites, responsible for 35.71% (5/14) and 28.57% (4/14) of the families with CADASIL in Chinese mainland, respectively, followed by exon 11, which was detected in 21.43% (3/14) families.

Many patients refused pathological examination because of the invasiveness of surgical biopsy and so just 9 patients consented. Out of these, in 6 patients, GOM was observed in the basal layer of smooth muscle cells of small blood vessels.

 » Discussion Top

CADASIL is an inherited disease with onset in early adulthood and considerably affects the quality of life thereby increases the family and social economic burden. Although, there is no specific treatment, the diagnosis increases awareness in adult patients of risk factors for ischemic events and aids in the identification of high-risk fetuses. Thus, the ability of clinicians to recognize the characteristics of CADASIL is important. The incidences of CADASIL is high in North America, [5] Europe, [6],[7] and Asia [8],[9],[10],[11],[12] and there is substantial variability in the clinical manifestation of the disease. The present study has revealed some differences and some similarities in the clinical characteristics of CADASIL between Chinese mainland and other countries. Average age of onset in Chinese patients was 42.43 years (range: 22-59 years) with equal gender distribution. Clinical features of CADASIL include: Recurrent TIA/IS, migraines with aura, dementia, vertigo, emotional disturbances, and white matter abnormalities and multiple infarcts on MRI. Chinese mainland patients exhibited these features in common with patients from other regions, with TIA/CI being the most common symptom. Though PICH is relatively uncommon in Caucasian CADASIL patients, [11],[13],[14] it was seen presenting in 25% patients, in this study. Korean and Chinese patients have higher rates of PICH, 12.3%-25%. [12],[15],[16] Of the 12 patients with PICH, 7 patients had hypertension only 3 patients had hypertension among 36 patients with no PICH. In an earlier study in China, of the 6 patients with hypertension, 5 patients had PICH and none of the 15 patients without hypertension had PICH. [12] A Korean study revealed no significant differences between the PICH and no-PICH groups in regard to hypertension. [17] In the subsequent expanded study, the same authors showed significant association between PICH and hypertension. [16] The small number of patients in our study and infrequent reports of PICH in CADASIL patients from other parts of world makes it rather difficult to conclude a firm relationship between hypertension and PICH in CADASIL patients. Nevertheless, hypertension is a potential risk factor for PICH in CADASIL patients. As PICH is associated with high mortality and morbidity, strict control of blood pressure is recommended for CADASIL patients. [18]

Hypertension alone may not explain the high rate of PICH in Chinese and Korean CADASIL patients. R544C mutation is relatively common in CADASIL patients with PICH [12],[15] and the present study supports this association. PICH is closely associated with the frequency of cortical microbleeds; [15],[19],[20] however, microbleeds were not observed in our study. In our cohort, only one CADASIL patient with PICH was on anti-platelet agent. Of the 12 PICH patients, in 6 patients, the death was related to PICH. PICH has been reported independently associated with poor clinical outcomes. [16]

Vertigo was reported rarely in CADASIL patients from other parts of the world; [12] however, 25% of patients in our study presented with vertigo and most of patients with IS had infarctions in the posterior circulation. Brain stem lacunar infarctions are more common among the Asian CADASIL patients [8] than the Caucasian CADASIL patients. [19] The reported frequency of migraine in other studies in CADASIL patients varied between 5% and 13.5%. [8],[9] However, it was 39.58% of patients in our study. This rate is similar to patients in Germany (35%), [10] Japan (25-40%), [21] and Arabic countries (38%). [22]

Subjects with normal MRI findings were more often younger as compared to patients with abnormal MRI. [23] In our study, few subjects had normal MRI. Multifocal leukoaraiosis and infarcts were the most common MRI features. High-signal lesions in the anterior temporal pole on T2-images are regarded as a useful diagnostic marker for CADASIL in Caucasians, as 89-95% of patients exhibit this indicator. [3],[24] However, in the studies in China only 42.9-46% of patients display this marker, [8],[12] and even fewer (11.11%) in our study. It appears that anterior temporal hyperintensities may not be a sensitive marker for CADASIL in Chinese patients.

In agreement with previous findings, [4],[8],[25] most NOTCH3 mutations in the present study were identified in exons 4 and 3, with the most common being exon 4, followed by exon 3, and then exon 11. In contrast, exon 11 was the most common mutation site in Chinese Taiwan population. [12] Similar geographic variations have been described in Italy [7] suggesting that the spectrum of NOTCH3 mutations varies among races as well as geographic regions. Even if a study directly sequences all NOTCH3 exons, false-negative results may still be obtained. [25] Thus, skin biopsies, which are relatively easy to perform and have an accuracy between 45-100%, [3],[26],[27] are crucial for the accurate diagnosis of CADASIL. The low rate of accuracy in the present study may be a result of the samples, a laboratory reagent, or technical factors.

The present study suggests that the clinical features with the exception of PICH and vertigo in Chinese patients are similar to those reported from other parts of world. In Chinese mainland, patients suspected to have CADASIL should first be screened for the NOTCH3 mutation on exons 4 and 3, and then exon 11.

 » References Top

1.Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol 2009;8:643-53.  Back to cited text no. 1
2.Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, et al. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest 2000;105:597-605.  Back to cited text no. 2
3.Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, et al. Diagnostic strategies in CADASIL. Neurology 2002;59:1134-8.  Back to cited text no. 3
4.Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssière C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997;350:1511-5.  Back to cited text no. 4
5.Gorelick PB. CADASIL: Do the clinical and MRI profiles differ for women and men? Stroke 2012;43:8-10.  Back to cited text no. 5
6.Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: Study in 200 consecutively recruited individuals. Stroke 2010;41:630-4.  Back to cited text no. 6
7.Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain 2004;127:2031-8.  Back to cited text no. 7
8.Wang Z, Yuan Y, Zhang W, Lv H, Hong D, Chen B, et al. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. J Neurol Neurosurg Psychiatry 2011;82:534-9.  Back to cited text no. 8
9.Yin XZ, Ding MP, Zhang BR, Liu JR, Zhang L, Wang PZ, et al. Report of two Chinese families and a review of Mainland Chinese CADASIL patients. J Neurol Sci 2009;279:88-92.  Back to cited text no. 9
10.Peters N, Herzog J, Opherk C, Dichgans M. A two-year clinical follow-up study in 80 CADASIL subjects: Progression patterns and implications for clinical trials. Stroke 2004;35:1603-8.  Back to cited text no. 10
11.Pradotto L, Orsi L, Daniele D, Caroppo P, Lauro D, Milesi A, et al. A new NOTCH3 mutation presenting as primary intracerebral haemorrhage. J Neurol Sci 2012;315:143-5.  Back to cited text no. 11
12.Lee YC, Liu CS, Chang MH, Lin KP, Fuh JL, Lu YC, et al. Population- specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese. J Neurol 2009;256:249-55.  Back to cited text no. 12
13.Oh JH, Lee JS, Kang SY, Kang JH, Choi JC. Aspirin-associated intracerebral hemorrhage in a patient with CADASIL. Clin Neurol Neurosurg 2008;110:384-6.  Back to cited text no. 13
14.Rinnoci V, Nannucci S, Valenti R, Donnini I, Bianchi S, Pescini F, et al. Cerebral hemorrhages in CADASIL: Report of four cases and a brief review. J Neurol Sci 2013;330:45-51.  Back to cited text no. 14
15.Choi JC, Kang SY, Kang JH, Park JK. Intracerebral hemorrhages in CADASIL. Neurology 2006;67:2042-4.  Back to cited text no. 15
16.Choi JC, Song SK, Lee JS, Kang SY, Kang JH. Diversity of stroke presentation in CADASIL: Study from patients harboring the predominant NOTCH3 mutation R544C. J Stroke Cerebrovasc Dis 2013;22:126-31.  Back to cited text no. 16
17.Kim Y, Choi EJ, Choi CG, Kim G, Choi JH, Yoo HW, et al. Characteristics of CADASIL in Korea: A novel cysteine-sparing Notch3 mutation. Neurology 2006;66:1511-6.  Back to cited text no. 17
18.Viswanathan A, Guichard JP, Gschwendtner A, Buffon F, Cumurcuic R, Boutron C, et al. Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: A two-centre cohort study. Brain 2006;129:2375-83.  Back to cited text no. 18
19.Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke 2004;35:1415-20.  Back to cited text no. 19
20.Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry TA. Cerebral microbleeds in CADASIL: A gradient-echo magnetic resonance imaging and autopsy study. Stroke 2002;33:67-71.  Back to cited text no. 20
21.Ishiko A, Shimizu A, Nagata E, Ohta K, Tanaka M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephaloapthy (CADASIL): A hereditary cerebrovascular disease, which can be diagnosed by skin biopsy electron microscopy. Am J Dermatopathol 2005;27:131-4.  Back to cited text no. 21
22.Bohlega S, Al Shubili A, Edris A, Alreshaid A, Alkhairallah T, AlSous MW, et al. CADASIL in Arabs: Clinical and genetic findings. BMC Med Genet 2007;8:67.  Back to cited text no. 22
23.van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages-3 rd -6 th decades. Radiology 2003;229:683-90.  Back to cited text no. 23
24.Singhal S, Rich P, Markus HS. The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features. AJNR Am J Neuroradiol 2005;26:2481-7.  Back to cited text no. 24
25.Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: Implications for diagnostic strategies. Arch Neurol 2005;62:1091-4.  Back to cited text no. 25
26.Malandrini A, Gaudiano C, Gambelli S, Berti G, Serni G, Bianchi S, et al. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology 2007;68:1430-2.  Back to cited text no. 26
27.Tikka S, Mykkanen K, Ruchoux MM, Bergholm R, Junna M, Pöyhönen M, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 2009;132:933-9.  Back to cited text no. 27


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1]

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