Research Summary

Understanding phenotypes in Moya moya disease by re-sequencing 17q25'ter region: An imaging genomics approach


Dr P N Sylaja  MD, DM                                                                                                  Dr Moinak Banerjee MSc, PhD, PDF

Host Instituition                                                                                                            Host Instituition

Comprehensive stroke care center,                                                                                Human Molecular Genetics Laboratory,

Sree Chitra Tirunal Institute for Medical Sciences and Technology,                             Rajiv Gandhi Centre for Biotechnology, 

Trivandrum, Kerala.                                                                                                       Trivandrum, Kerala.


Moyamoya disease (MMD) is a rare chronic cerebrovascular disorder characterized by progressive bilateral occlusion of the supra-clinoid internal carotid artery (ICA) and its main branches. This is associated with the development of fine collateral networks, adjacent to the site of occlusion in the deep areas of the brain. Epidemiological data have shown strong regional differences with a high occurrence in Asian countries primarily Japan, China and Korea. An incidence of approximately 1 per 100 000 has been reported in Japan. The incidence in non-Asian countries, frequently cited in the literature is 0.1 per 100 000. Recently genome-wide linkage analysis and exome analysis studies identified the ring finger protein 213 gene (RNF213) on 17q25.3 as the strongest susceptibility gene for MMD in East Asian population. Mutational analysis studies revealed a single missense mutation in RNF213 (p.R4810K). This mutation was detected in 90% of Japanese, 79% of Korean and 23% of Chinese MMD cases. It strongly increased the risk to develop MMD with an OR of 338.9 (p =10-100) in Japanese, 135.6 (p = 10-25) in Korean and 14 in Chinese populations respectively. The mutated allele occurs in 95.1% of familial MMD cases and 79.2% of sporadic MMD cases. The homozygous mutation, was associated with an earlier onset and a more severe disease course suggesting it a potential biomarker for predicting prognosis. In addition, MMD presents with a characteristic angiographic picture which involves the bilateral stenosis or occlusion at the terminal portion of the ICA and at the proximal portion of the anterior and middle cerebral arteries, abnormal vascular network seen in the vicinity of the arterial occlusion. Moyamoya like angiographic picture occurs in intracranial atherosclerotic disease, sickle cell disease and intracranial arterial dissection which may confuse the diagnosis and management. Vessel wall imaging (VW-MR) is a novel imaging technique which helps to differentiate the various aetiologies of distal intracranial arterial occlusion which demonstrates eccentric arterial wall thickening in intracranial atherosclerotic disease while smooth, homogeneous, concentric arterial wall thickening and enhancement in vasculitic disorders. However, VW-MR imaging studies with MMD found a lack of arterial wall thickening and enhancement. Interestingly, clustering of patients with MMD has been observed particularly from the south eastern region of Indian subcontinent which points towards geographical differences in the distribution of the disease in the Indian subcontinent itself which indirectly gives a clue to the possibility of a genetic association. We planned to conduct an imaging genomics study to explore the genetics of MMD in south Indian population


Figure Legend: Figure 1: Axial flair sequence showing chronic infarcts in the left MCA territory with volume loss and gliosis, in addition “Ivy sign” noted (arrow) in the left temporo-parietal region. Figure 2: Digital subtraction angiography showing significantly attenuated bilateral supraclinoid internal carotid artery, MCA-M1, ACA-A1 with basal collaterals simulating puff of smoke typical of Moya moya disease.