A Case of Multiple Intracranial Major Artery Stenoses With Coexisting PCSK9 p.E32K and RNF213 p.R4810K Variants

Kotaro Noda; Yorito Hattori; Mika Hori; Mariko Harada-Shiba; Masafumi Ihara

doi:10.1212/NXG.0000000000200099

A Case of Multiple Intracranial Major Artery Stenoses With Coexisting PCSK9 p.E32K and RNF213 p.R4810K Variants

Neurol Genet. 2023 Sep 5;9(5):e200099. doi: 10.1212/NXG.0000000000200099. eCollection 2023 Oct.

Authors

Kotaro Noda¹, Yorito Hattori¹, Mika Hori¹, Mariko Harada-Shiba¹, Masafumi Ihara¹

Affiliation

¹ From the Department of Neurology (K.N., Y.H., M.I.), National Cerebral and Cardiovascular Center, Suita; Department of Neurology and Neurological Science (K.N.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University; Department of Endocrinology (M.H.), Research Institute of Environmental Medicine, Nagoya University; and Cardiovascular Center (M.H.-S.), Osaka Medical and Pharmaceutical University, Takatsuki, Japan.

Abstract

Objectives: Familial hypercholesterolemia (FH), caused by PCSK9 p.E32K, is characterized by early-onset coronary artery disease. However, the relationship between PCSK9 p.E32K and cerebrovascular disease is unclear. One of our patients with the PCSK9 p.E32K had several intracranial artery stenoses (ICAS). The objective of this case series was to identify factors that may be associated with ICAS in the variant carriers.

Methods: A 75-year-old Japanese woman with FH carrying PCSK9 p.E32K was found to have 5 asymptomatic ICAS when brain magnetic resonance angiography (MRA) was performed. We retrospectively investigated additional patients with FH who underwent brain MRA at our institution to explore the unknown factors accelerating ICAS.

Results: We investigated an additional 5 patients with FH who underwent brain MRA. Of them, only one had mild ICAS. The RNF213 p.R4810K that is an established genetic risk for ICAS, particularly in East Asians, was identified only in the patient with 5 ICAS.

Discussion: PCSK9 and RNF213 play an important role in lipid metabolism and endothelial integrity. Therefore, together, these variants could be involved in the development of multiple ICAS. Our case series indicated that PCSK9 p.E32K carriers should undergo early brain screening to obtain appropriate stroke prevention measures in the asymptomatic stage.