A Cohort Study Of Primary Familial Brain Calcification From China

Background:Primary familial brain calcification(PFBC),also known as Fahr's disease or idiopathic basal ganglia calcification,is a rare neurodegenerative disease with bilateral brain calcification mainly affecting the basal ganglia.The clinical manifestations include movement disorders,neuropsychiatric symptoms,and other associated symptoms with diverse severity,while up to 36%–42% of patients remain asymptomatic.Typically,PFBC is inherited as an autosomal dominant trait with four causative genes(SLC20A2,PDGFRB,PDGFB,and XPR1)identified so far.Nicolas et al.estimated that the minimal prevalence of PFBC caused by a variant in one of the four causative genes for autosomal dominant PFBC(AD-PFBC)was 4.5 per 10,000 and further extrapolated an overall minimal prevalence of PFBC of 2.1 per 1,000,which is much higher than previously thought.However,the high proportion(36%–42%)of asymptomatic PFBC patients and clinical selection bias(compared with symptomatic PFBC patients,asymptomatic ones are less likely to undergo a brain CT scan and be diagnosed genetically)might still undermine our ability to accurately estimate the disease prevalence.Objectives:We attempted to minimize clinical selection bias and elucidate the clinical features of genetically confirmed patients and estimate the minimal disease prevalence of PFBC.Methods:A total of 273 PFBC probands were enrolled in a multicenter retrospective cohort study by two different approaches.In Group I(nonsystematic approach),37 probands diagnosed at our clinic were enrolled.In Group II(systematic approach),236 probands were enrolled by searching the medical imaging databases of 50 other hospitals using specific keywords.Genetic testing of four genes known to be causative of autosomal dominant PFBC was performed in all probands using c DNA.All identified variants were further confirmed using genomic DNA and classified according to ACMGAMP recommendations.Results:Thirty-two variants including 22 novel variants were detected in 37 probands.Among these probands,83.8%(31/37)were asymptomatic.Two probands with homozygous pathogenic SLC20A2 variants presented more severe brain calcification and symptoms.Based on the variant detection rate of probands in Group II,we extrapolated an overall minimal prevalence of PFBC of 6.6 per 1,000,much higher than previously reported(2.1 per 1,000).Conclusions:We identified a higher proportion of genetically confirmed PFBC probands who were asymptomatic.These patients would be overlooked due to clinical selection bias,leading to underestimation of the disease prevalence.Considering that PFBC patients with biallelic variants had more severe phenotypes,this specific condition should be focused on genetic counseling.