Genetic and Proteomic Contributions to the Pathophysiology of Moyamoya Angiopathy and Related Vascular Diseases

Abstract

This literature review describes the pathophysiological mechanisms of the current classes of proteins, cells, genes, and signaling pathways relevant to moyamoya angiopathy (MA), along with future research directions and implementation of current knowledge in clinical practice. Objective: This article is intended for physicians diagnosing, treating, and researching MA. Methods and Results: References were identified using a PubMed/Medline systematic computerized search of the medical literature from January 1, 1957, through August 4, 2020, conducted by the authors, using the key words and various combinations of the key words "moyamoya disease," "moyamoya syndrome," "biomarker," "proteome," "genetics," "stroke," "angiogenesis," "cerebral arteriopathy," "pathophysiology," and "etiology." Relevant articles and supplemental basic science articles published in English were included. Intimal hyperplasia, medial thinning, irregular elastic lamina, and creation of moyamoya vessels are the end pathologies of many distinct molecular and genetic processes. Currently, 8 primary classes of proteins are implicated in the pathophysiology of MA: gene-mutation products, enzymes, growth factors, transcription factors, adhesion molecules, inflammatory/ coagulation peptides, immune-related factors, and novel biomarker candidate proteins. We anticipate that this article will need to be updated in 5 years. Conclusion:It is increasingly apparent that MA encompasses a variety of distinct pathophysiologic conditions. Continued research into biomarkers, genetics, and signaling pathways associated with MA will improve and refine our understanding of moyamoya's complex pathophysiology. Future efforts will benefit from multicenter studies, familybased analyses, comparative trials, and close collaboration between the clinical setting and laboratory research.

Research progress of moyamoya disease combined with renovascular hypertension

“…16 genes are currently involved in moyamoya disease vasculopathy. Renovascular hypertension is also described in the literature with the exception of RNF 213 (38,39). For example, in a case of progressive and symptomatic moyamoya disease vasculopathy caused by hemizygous deletion of BRCC3/MTCP1, he underwent left renal allotransplantation and right nephrectomy for renovascular hypertension in infancy (40).…”

Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort

“…A larger sample might allow separating the effect of these two variables (age at disease onset and stroke before diagnosis). Nevertheless, it is also likely that genetic factors, still partially unknown, could determine both an early-onset and a more severe disease (54,55).…”

Maternal Stroke Associated With Pregnancy

“…91 In addition, patients with trisomy 21, sickle cell disease, a history of brain radiation, neurofibromatosis type 1, or severe intracranial atherosclerotic disease can develop secondary moyamoya syndrome. 91 Moyamoya disease is more common in women and often presents in early adulthood during the childbearing years. In a systematic review of 54 articles, more than 95% of women diagnosed with moyamoya disease before pregnancy had good pregnancy outcomes.…”

“…Pregnant women with moyamoya disease, a progressive stenoocclusive cerebrovascular disorder affecting the terminal internal carotid arteries and their intracranial branches, are at increased risk of both ischemic stroke due to hypoperfusion and hemorrhagic stroke due to rupture of fragile moyamoya collaterals. Idiopathic primary moyamoya disease is most common in East Asian populations, and multiple genetic variants have been identified contributing to its pathogenesis 91 . In addition, patients with trisomy 21, sickle cell disease, a history of brain radiation, neurofibromatosis type 1, or severe intracranial atherosclerotic disease can develop secondary moyamoya syndrome 91 .…”

“…Idiopathic primary moyamoya disease is most common in East Asian populations, and multiple genetic variants have been identified contributing to its pathogenesis 91 . In addition, patients with trisomy 21, sickle cell disease, a history of brain radiation, neurofibromatosis type 1, or severe intracranial atherosclerotic disease can develop secondary moyamoya syndrome 91 . Moyamoya disease is more common in women and often presents in early adulthood during the childbearing years.…”