Clinical and Molecular Features of 5 European Multigenerational Families With Moyamoya Angiopathy

Abstract

Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.

Livedo racemosa in neurological diseases: an update on the differential diagnoses

“…3) [38]. It has a higher incidence in Japan and Korea, probably due to founder mutations [39][40][41][42]. Histopathological studies have shown that pathophysiological pathways of European and Asian MA seem identical despite different genetic predispositions [43].…”

Paladin is a phosphoinositide phosphatase regulating endosomal VEGFR2 signalling and angiogenesis

“…Importantly, PALD1 has been genetically associated with Moyamoya disease in two families. Moyamoya disease is caused by the occlusion of the carotid artery and its branches, causing characteristic pronounced collateral vessel formation and stroke in the central nervous system (Grangeon et al , 2019). A potential causal link between the hyperactive endothelial signalling observed in the Pald1 −/− mouse and excessive collateral formation in patients with Moyamoya disease need further investigations.…”

Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene

“…18 For instance, variants of RNF213 account for the genetic susceptibility of Asian patients, with approximately 80% with moyamoya harboring the heterozygous p.R4810K founder variant. 19 RNF213 has been shown in vivo and in vitro to play a significant role in controlling angiogenesis through regulating the expression of matrix metalloproteinases in endothelial cells. 20 We now expand the spectrum of genetic arteriopathies to include CBL-mediated arteriopathy.…”