Childhood Cerebral Arteriopathy in Glycogen Storage Disease Type 1.

Introduction: Glycogen storage disease type 1 (GSD1) is a rare genetic metabolic disorder caused by defects of glucose-6-phosphatase complex, resulting in a wide array of manifestations such as hepatomegaly, hypoglycemia and hyperlipidemia. Previously, cerebrovascular complications had been described in 7 pediatric or young patients. However, the mechanism remains unknown. This study aims to describe the phenotypes of 6 cases and explore the possible mechanisms of cerebral arteriopathy in GSD1. Methods: All patients with GSD1 and cerebral arteriopathy were included. Cerebral arteriopathy was demonstrated by MRA/DSA and classified according to anatomic and temporal features. Possible mechanisms were explored using vessel wall imaging and targeted or whole-exome sequencing. Results: In this single center study, 6 unrelated patients with GSD1 and cerebral arteriopathy were identified (4 females). Mutational analysis confirmed the diagnosis of GSD1a and 1b in 3 patients, respectively. The median age at neurologic onset was 9 years (range, 5-11 years). Unilateral and bilateral cerebral arteriopathies were observed in 3 patients (figure), respectively, resulting in ischemic stroke in 1, TIA in 2 and non-ischemic symptoms in 3 patients. Arterial lesions typically involved the bifurcation of internal carotid artery, with or without lenticulostriate collaterals. Follow-up MRA performed at 12-24 months’ interval in 3 patients showed progression of arteriopathy (arrows). Vessel wall imaging performed in 5 patients displayed shrinkaged lumen of affected segments without plaque. Carotid ultrasound ruled out subclinical atherosclerosis. Genetic analysis in 4 patients revealed no pathologic variants known to be associated with cerebrovascular disorder such as moyamoya disease/syndrome. Conclusions: Pediatric GSD1 patients might be predisposed to progressive steno-occlusive cerebral arteriopathy, probably through non-atherosclerotic mechanisms.