No Association of RNF213 Polymorphism with Reversible Cerebral Vasoconstriction Syndrome.

Dear Editor,

Asian cohorts of reversible cerebral vasoconstriction syndrome (RCVS) have unique characteristics such as large proportions with idiopathic RCVS and pure cephalalgic presentation, and a lower prevalence of hemorrhagic strokes.123 It can be hypothesized that genetic factors contribute to the risk of developing idiopathic RCVS such that the clinical manifestations will differ between ethnic groups. However, genetics studies have rarely addressed this issue.

The Ring Finger Protein 213 gene (RNF213) is a susceptibility gene of moyamoya disease, whose polymorphism is highly prevalent in East Asians.4 Moreover, RNF213 variants are also related to intracranial artery stenosis and dissection, which are more common in Asians than in Caucasians.56 Based on these findings, we hypothesized that RNF213 is a susceptibility gene for intracranial arteriopathy that predisposes Asians to idiopathic RCVS.

We prospectively screened patients who presented with thunderclap headache from November 2016 to January 2018. The required number of included patients was calculated to detect an RNF213 mutation in 30% of RCVS patients assuming a RCVS prevalence of 57% in the patients who have thunderclap headache7 with 80% power, with an overall significance criterion of 5%. Patients with subarachnoid hemorrhage due to aneurysmal rupture were excluded. Causes of thunderclap headache were classified using our previously described protocol.3 RCVS was diagnosed based on the third edition beta version of the International Classification of Headache Disorders (ICHD-3 beta).8 RCVS was categorized into definite (angiogram-proven) and probable (angiogram-negative). This study was approved by Samsung Medical Center Institutional Review Board (2016-09-122).

Fifty eligible patients who gave informed consents were included in this study. The mean age of the 50 subjects was 47.8 years (range 20–62 years) and they were predominantly female (n=33, 66.0%). The 50 patients included 34 (68.0%) with RCVS and 6 (12.0%) with other secondary causes: 4 with intracranial arterial dissection, 1 with meningitis, and 1 with cervicogenic headache. The remaining 10 (20.0%) patients were classified as having primary thunderclap headache. The demographics and characteristics of patients with RCVS vs. those with non-RCVS etiology are summarized in Table 1. Most (94.1%) of the RCVS patients were idiopathic. The demographics and vascular risk factors did not differ between patients with RCVS and those with non-RCVS etiology. Two (5.9%) patients with RCVS had accompanying neurological complications.

Table 1

Demographics and characteristics of the study patients

	RCVS (n=34)	Non-RCVS (n=16)	p
Age, years	49.9 [27–62]	43.1 [20–59]	0.06
Sex, male	10 (29.4)	7 (43.7)	0.31
Hyperlipidemia	5 (14.7)	2 (12.5)	1.00
Diabetes mellitus	2 (5.9)	1 (6.2)	1.00
Hypertension	2 (5.9)	1 (6.2)	1.00
Ischemic stroke	1 (2.9)	0 (0)	1.00
Intracerebral hemorrhage	1 (2.9)	0 (0)	1.00
Ischemic heart disease	0 (0)	0 (0)	-
Arrhythmia	1 (2.9)	0 (0)	1.00
Diagnosis
RCVS	34 (100.0)
Intracranial arterial dissection		4 (25.0)
Primary thunderclap headache		10 (62.5)
Other*		2 (12.5)
Associated neurological symptoms	3 (8.8)	6 (37.4)
Neurological complications
Cerebral infarction	0 (0)	0 (0)
Cortical SAH	1 (2.9)	0 (0)
PRES	0 (0)	0 (0)
Seizure	1 (2.9)	0 (0)
RCVS etiology
Idiopathic	32 (94.1)
Postpartum	0 (0)
Medication	2 (5.9)

Data are median [interquartile range] or n (%) values.

*Other includes meningitis and cervicogenic headache.

PRES: posterior reversible encephalopathy syndrome, RCVS: reversible cerebral vasoconstriction syndrome, SAH: subarachnoid hemorrhage.

The patients underwent blood sampling for the genome analysis. The c.14429G>A mutation of RNF213 (GenBank accession number NM_001256071.1) was tested,4 which revealed that neither the patients with RCVS nor those with other causes of thunderclap headache carried the c.14429G>A (p.Arg4810Lys) mutation of RNF213.

Our data suggest that RNF213 is unrelated to the development of RCVS, and hence that RCVS and moyamoya disease have different genetic backgrounds despite overlap in their pathophysiology such as in endothelial dysfunction.49

The different complication rates between Asian and Western cohorts may be attributable to differences in study settings and social factors, such as the headache-clinic-based (Korea and Taiwan) vs. stroke-center-based (United States) recruitment of patients.123 The easy accessibility to university hospitals under the Korean National Health Insurance program might lead to a larger proportion of patients consulting headache specialists and being diagnosed with RCVS before they develop neurological deficits. In addition, illicit drug use is relatively rare in Korea, while it is reported as a major cause of RCVS in Western patients.1310 Genetic factors other than RNF213 may additionally contribute the development of idiopathic RCVS.