**5. Pathogenesis**

The mechanisms leading to the above-mentioned pathology are not entirely known. It is not clear what leads to migration and proliferation of smooth muscle cells in the intima and leads to its thickening. Moreover, why this thickening happens only in the circle of Willis is unknown. Many features of the disease point towards a hereditary predisposition- high incidence in Japanese people, familial occurrence, association with other congenital disorders like sickle cell anemia,

neurofibromatosis, Down syndrome, etc. A multifactorial mode of inheritance has been suggested. A possible linkage of the disease with markers located on chromosome 6, chromosome 17, chromosome 8q23 has been suggested [18–20]. Recently, a genetic locus in the Ring Finger Protein [RNF] 213 gene was also associated with MMD [7]. A higher carrier rate in Eastern Asia probably explains the higher prevalence of the disorder in Japan and other eastern Asian countries as compared to the Western world [21].

Moyamoya angiopathy has been identified with many genetic disorders like Neurofibromatosis 1, Noonan syndrome, Costello syndrome, Sickle cell disease, GUCY1A3 mutations, BRCC3/MTCP1 gene mutation, Down syndrome, Turner syndrome, etc. [19] Moyamoya disease associated with other familial or acquired conditions has also been termed as 'quasi-MMD'. It was noted that unilateral presentation was more common than bilateral and hemorrhagic manifestations were less common in quasi- MMD [21].

Although genetic predisposition to the disease exists, the majority of cases are sporadic. Certain acquired factors have been suggested for disease progression. These include vasculitis [3], infections [20], cranial trauma [22], post-irradiation state [23] to name a few.
