Moyamoya disease in Southeast Asians: genetic and autopsy data, new cases, systematic review, and meta-analysis of all patients from the literature

Abstract

Background: Moyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans.

Methods: By retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination.

Results: The study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years (n = 24), 43.4 ± 8.7 years in patients admitted to our center (n = 11), and 23.4 ± 22.4 years in patients from the international literature (n = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case.

Conclusion: Clinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.

Keywords: RNF213 p.R4810K variant; East Asian; European Caucasian; Histopathology; Moyamoya disease; Southeast Asian.

Fig. 1

Flowchart of the literature search

Fig. 2

Histopathological staining of the internal carotid artery of a deceased female Thai Moyamoya patient: A high-grade Moyamoya pathology in the form of thickening and undulation and partly Duplication or triplication of the internal elastic membrane (white arrow) (Elastica van Gieson staining); B fibrocellular thickening and smooth muscle cell proliferation of the tunica intima (actin staining) (black star)