Study On The Clinical Features And Mechanism Of Cerebrovascular Disease In Patients With Glycogen Storage Disease Type I

Introduction:Glycogen storage disease type Ⅰ(GSD I)is a hereditary metabolic disorder.While the dietary therapy has decreased the mortality rates of patients with GSD I,the current dilemma is how to manage the long-term complications and improve the quality of life.Patients with GSD I have multiple cardiovascular risk factors such as hyperlipidemia,hyperuricemia and renal injury.Previously,a total of 7 cases had been reported to suffer from the cerebrovascular complications.However,the risk and mechanism of cerebrovascular involvement in patients with GSD I remain unknown.As for the surveillance,prevention and treatment of cerebrovascular complications in patients with GSD I,no recommendations had been mentioned in the most updated management guidelines of GSD I.Objectives:To determine the prevalence of cerebrovascular involvement in patients with GSD I in this single center study.To summarize the clinical,radiologic characteristics,treatment and prognosis of patients with GSD I and cerebrovascular involvement.To explore the metabolic and genetic contribution to the cerebrovascular disorders in patients with GSD I.Methods:Between September 2014 and January 2019,patients with GSD I referred to the Peking Union Medical College Hospital were invited to undergo non-invasive cerebrovascular assessments.Written informed consent from all participants(or their legal guardians)was obtained.The clinical,laboratory and imaging data at baseline and follow-up were collected.Cerebrovascular investigations include transcranial Doppler and/or multi-model MRI.Cerebral arteriopathy was diagnosed if MRA showed the appearance of an arterial abnormality(stenosis,irregularity,occlusion,banding,pseudoaneurysm,dissection flap)not attributable to an exogeneous thrombus or normal developmental variant.High-resolution MRI were used to detect the presence of vessel wall thickening or plaque.DNA were extracted from peripheral white blood cells.Targeted gene or whole exome sequencing were used to detect genetic variants related to moyamoya vasculopathy and pediatric stroke.GSD I related parameters were compared between patients with and without cerebrovascular disorders.Significance was set at P<0.05.Results:(1)Patient characteristics.During the 4.5-year study period,there were 175 patients with genetically confirmed GSD I who referred to this hospital.Seventy-seven were female(44.00%),the median age at last follow-up was(13.8±8.3)years,140 subjects were diagnosed of GSD Ia(80.00%).Neurological symptoms were recorded in 17 participants(9.7%),including ischemic stroke in one,transient ischemic attack in one and non-specific symptoms in other patients.Eighty-eight subjects underwent the transcranial Doppler and 34 participants performed MRA.A total of 6 patients with GSD I were identified to have cerebral arteriopathy(minimum detection rate 3.4%).(2)Clinical and imaging features of cerebral arteriopathy in patients with GSD I.The 6 subjects with GSD I and cerebral arteriopathy came from different families,four were female,the subtype of GSD I were GSD Ia and GSD Ib in 3 subjects respectively.The age at onset of neurological manifestations was(9.2±4.2)years(median,IQR),prior to the diagnosis of GSD I in 2 subjects.The age at diagnosis of cerebral arteriopathy was(12.6±6.7)years.Initial neurological presentations included ischemic stroke in one,transient ischemic attack in one and headache/dizziness in 4 subjects.Based on MRA,the cerebrovascular abnormalities could be classified into 2 types:moyamoya vasculopathy and unilateral MCA stenosis(3 subjects respectively).Compared to patients with unilateral MCA stenosis,patients with moyamoya vasculopathy were younger at onset with more severe neurological manifestations.After the diagnosis of cerebral arteriopathy,the dietary therapies were optimized in all patients.Short-term Aspirin was administered in the subjects with moyamoya vasculopathy and ischemic events.The remaining 4 patients received no specific treatments.During the median follow-up of(2.0± 1.7)years,all 3 patients with moyamoya vasculopathy experienced clinical progression,including new onset of transient ischemic attack in one and progressive headache in 3 subjects.All of them underwent unilateral of bilateral encephalo-duro-arterio-synangiosis surgeries(EDAS).resulting in significant clinical improvement.Patients with unilateral MCA stenosis were clinically stable.Follow-up MRA was performed in 3 subjects with an interval of(1.1-5.0)years(range),the arterial stenosis progressed in all.High-resolution MRI was performed in 5 subjects.The affected MCA showed the narrowed lumen without vessel wall thickening or plaque.(3)The association between GSD I related parameters and cerebral arteriopathy.Subjects who had performed MRA were classified as case group(with cerebral arteriopathy,n=6)and control group(without cerebral arteriopathy,n=28).Compared to the control group,there were more patients with GSD Ib in the case group(OR 7.5,95%Cl 2.229-25.239.P=0.012).The sex,age at MRA investigation and GSD I associated parameters at baseline and during follow-up were similar between the 2 groups.(4)Causative genetic variants in patients with GSD I and cerebral arteriopathy.Target gene sequencing and whole exome sequencing were performed in 2 patients with GSD I and cerebral arteriopathy,respectively.A total of 8 rare nonsynonymous variants in five genes were detected from these 4 patients,including one splice and three missense variants in RNF213,and four missense variants in PCNT,SMARCAL1,ABCC6,and MTHFR respectively.Conclusion:The prevalence of cerebrovascular complications in patients with GSD I might be underestimated.In this study,moyamoya vasculopathy and unilateral MCA stenosis are the 2 phenotypes in patients with GSD I and cerebral arteriopathy.The arterial lesion might be progressive with increased risk of stroke in young patients.Both pediatrics and neurologists should be aware of this rare but important eomplication.The pathophysiology of cerebral arteriopathy in patients with GSD I were unclear,probably via a non-atherosclerosis mechanism.The association between the rare RNF213 variants and cerebral steno-occlusive arteriopathy in patients with GSD I was unclear,which needs further research.