Genotypic and phenotypic variation of CADASIL among Chinese, Indians and Rungus in Malaysia
Keywords:CADASIL, Malaysia, R544C
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of small cerebral arteries. This case series aims to describe the mutations in NOTCH3 and their phenotypes in Malaysia. We included patients who were genetically confirmed to have CADASIL, diagnosed at the University of Malaya Medical Centre, Malaysia. Family members who fulfilled clinical or imaging criteria, and patients from two previous published Malaysian families were also included. Six families (eleven cases) were included in this series. Genetic testing revealed NOTCH3 mutations in c.328C>T (p.Arg110Cys, R110C), c.553T>G (p.Cys185Gly, C185G), c.1630C>T (p.Arg544Cys, R544C) and c.160C>T (p.Arg54Cys, R54C). Two out of four Chinese families had R544C mutation in exon 11, with a later age of onset, absence of migraine and lack of anterior temporal pole involvement on MRI. One family with mixed Indian and Chinese ancestry had a mutation in exon 3 with R110C and another Indian family exon 4 with C185G mutation. This case series highlights the genotypic and phenotypic variability of CADASIL in a multi-ethnic country. The finding of p.Arg544Cys mutation among the older Chinese families, similar to those reported in Jeju Island and Taiwan, suggest the need to screen the older Chinese stroke patients with typical MRI changes.
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(4):630-634. https://doi.org/10.1161/STROKEAHA.109.568402
Chen S, Ni W, Yin X-Z, Liu H-Q, Lu C, Zheng Q-J, et al. Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study. CNS Neurosci Ther. 2017;23(9):707-716. https://doi.org/10.1111/cns.12719
Choi JC, Kang S-Y, Kang J-H, Park J-K. Intracerebral hemorrhages in CADASIL. Neurology. 2006;67(11):2042-2044. https://doi.org/10.1212/01.wnl.0000246601.70918.06
Choi JC, Song S-K, Lee JS, Kang S-Y, Kang J-H. Diversity of stroke presentation in CADASIL: study from patients harboring the predominant NOTCH3 mutation R544C. J Stroke Cerebrovasc Dis. 2011;22(2):126-131. https://doi.org/10.1016/j.jstrokecerebrovasdis.2011.07.002
De Silva KRD, Gamage R, Dunuwille J, Gunarathna D, Sirisena D, Weerasinghe A, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a patient from Sri Lanka. J Neurol Sci. 2009;16(11):1492-1493. https://doi.org/10.1016/j.jocn.2009.01.019
Dichgans M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: phenotypic and mutational spectrum. J Neurol Sci. 2002;203-204(Special_Issue):77-80. https://doi.org/10.1016/s0022-510x(02)00270-8
Eswaradass VP, Ramasamy B, Kalidoss R, Gnanagurusamy G. Cadasil coma: Unusual cause for acute encephalopathy. Ann Indian Acad Neurol. 2015;18(4):483-484. https://doi.org/10.4103/0972-2327.160072
Gurumukhani JK, Ursekar M, Singhal BS. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL): a case report with review of literature. Neurol India. 2004;52(1):99-101. https://www.ncbi.nlm.nih.gov/pubmed/15069251
Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2002;358(9298):2049-2051. https://doi.org/10.1016/S0140-6736(01)07142-2
Kim Y-E, Yoon CW, Seo SW, Ki C-S, Kim YB, Kim J-W, et al. Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neurol Sci. 2013;35(3):726.e1-6. https://doi.org/10.1016/j.neurobiolaging.2013.09.004
Lee Y-C, Liu C-S, Chang M-H, Lin K-P, Fuh J-L, Lu Y-C, et al. Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese. J Neurol. 2009;256(2):249-255. https://doi.org/10.1007/s00415-009-0091-3
Liao Y-C, Hsiao C-T, Fuh J-L, Chern C-M, Lee W-J, Guo Y-C, et al. Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles. PLoS ONE. 2015;10(8):e0136501. https://doi.org/10.1371/journal.pone.0136501
Lim K-S, Tan A-H, Lim C-S, Chua K-H, Lee P-C, Ramli N, et al. R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL. PLoS ONE. 2015;10(8):e0135470. https://doi.org/10.1371/journal.pone.0135470
Liu X, Zuo Y, Sun W, Zhang W, Lv H, Huang Y, et al. The genetic spectrum and the evaluation of CADASIL screening scale in Chinese patients with NOTCH3 mutations. J Neurol Sci. 2015;354(1-2):63-69. https://doi.org/10.1016/j.jns.2015.04.047
Nandhagopal R. CADASIL - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Sultan Qaboos Univ Med J. 2011;11(2):284-285.
Oberstein SAL, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, et al. Cerebral microbleeds in CADASIL. Phys Ther. 2001;57(6):1066-1070. https://doi.org/10.1212/wnl.57.6.1066
Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004;127(Pt 11):2533-2539. https://doi.org/10.1093/brain/awh282
Panagariya A, Sharma B, Shubhakaran. CADASIL in a family from north-west India. J Assoc Physicians India. 2004;52:580-581. https://www.ncbi.nlm.nih.gov/pubmed/15645988
Rutten JW, Dauwerse HG, Gravesteijn G, van Belzen MJ, van der Grond J, Polke JM, et al. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol. 2016;3(11):844-853. https://doi.org/10.1002/acn3.344
Rutten JW, Haan J, Terwindt GM, van Duinen SG, Boon EMJ, Oberstein SAJL. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014;14(5):593-603. https://doi.org/10.1586/14737159.2014.922880
Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci. 1993;114(1):7-12. https://doi.org/10.1016/0022-510x(93)90041-v
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(Pt 9):2031-2038. https://doi.org/10.1093/brain/awh223
Stojanov D, Vojinovic S, Aracki-Trenkic A, Tasic A, Benedeto-Stojanov D, Ljubisavljevic S, et al. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Bosn J Basic Med Sci. 2015;15(1):1-8. https://doi.org/10.17305/bjbms.2015.247
Tan Q-C, Zhang J-T, Cui R-T, Xu Q-G, Huang X-S, Yu S-Y. Characteristics of CADASIL in Chinese mainland patients. Neurol India. 2014;62(3):257-261. https://doi.org/10.4103/0028-3886.136900
Wilder-Smith E, Shen Y, Ng YK, Yu GX, Chew NK, Tan CT, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Chinese family: clinical, radiological and skin biopsy features. J Clin Neurosci. 2004;11(3):304-307. https://doi.org/10.1016/j.jocn.2003.05.007
Yadav S, Bentley P, Srivastava P, Prasad K, Sharma P. The first Indian-origin family with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Neurol Sci. 2011;22(1):28-31. https://doi.org/10.1016/j.jstrokecerebrovasdis.2011.05.023
How to Cite
Copyright (c) 2019 Tsun Haw Toh, Kheng Seang Lim, Ching Ching Ng, Imran Idris, Sherrini Bazir Ahmad, Thien Thien Lim, Irene Looi, Ai Huey Tan, Chung Kin Chan, Chun Shen Lim, Chong Tin Tan
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The observations and associated materials published or posted by NeurosciRN are licensed by the authors for use and distribution in accord with the Creative Commons Attribution license CC BY-NC 4.0 international, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.