Objective: In this study, patients with Fahr syndrome were analyzed for etiology, and genetic testing was performed for patients with Fahr disease from Northeast China and South Korea.

Background: Ambiguous definition of Fahr syndrome is a neurological disorder characterized by calcification of bilateral symmetrical basal ganglia and other regions of the brain. However, in general, Fahr syndrome indicates BGC with secondary causes, while Fahr disease refers to primary or idiopathic calcification. The most common cause of Fahr syndrome is parathyroid disease, but other causes can be also observed. Fahr syndrome with specific CT findings makes radiological diagnosis easy, but it is challenging to find out causative factors. Fahr disease has some familial genetic predisposition and is often referred to as IBGC or PFBC. To date, there are four pathogenic genes reported – SLC20A2, PDGFRB, PDGFB and XPR1. To our knowledge, IBGC-related genes in Asia are mostly SLC20A2, but mutations in PDGFRB and PDGFB have been rarely reported in China.

Methods: We collected 115 patients with pathological bilateral BGC from 6 hospitals. We identified 56 patients with secondary causes which would be further classified, 23 patients with Fahr disease (21 sporadic and 2 familial cases), and uncertained remaining patients without sufficient clinical data. Genetic testing was performed on the patients with Fahr disease by WES.

Results: Of the 56 patients with secondary causes, 44 with parathyroid disease, 3 with systemic lupus erythematosus, 3 with carbon monoxide poisoning, 3 with mitochondrial disease, 1 with trauma, and 2 with congenital diseases were identified. For 23 patients with Fahr disease, we found 3 sporadic cases with de novo heterozygous pathogenic c.730+1G>T, c.1821G>A (p.W607X) and c.971C>A (p.S324X) variants in SLC20A2, and 2 sporadic cases with reported SLC20A2 heterozygous likely pathogenic c.82G>A (p.D28N) and c.1703C> T (p.P568L) variants in SLC20A2 from South Korea. In addition, we identified four heterozygous VUS, c.301T>G (p.W101G) in SLC20A2, c.211G>C (p.G71R) and c.610C>A(p.P204T) in PDGFB and c.2053C>T (p.R685C) in PDGFRB.

Conclusions: The etiologies of Fahr syndrome are diverse and make clinicians challenging to identify，the most common of wich is hypoparathyroidism. We report three de novo mutations, c.730+1G>T, c.1821G>A, and c.971C>A, in SLC20A2 gene in South Korea. These findings expand the mutation spectrum of SLC20A2 was and provides an opportunity to further study the mechanism of calcification in Fahr disease.

References: 1. Nicolas G et al. French IBGC Study Group. Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain 2013;136(Pt 11):3395-407. 2. Batla et al. Deconstructing Fahr’s disease/syndrome of brain calcification in the era of new genes. Parkinsonism Relat Disord 2017;37:1-10. 3. Wang C et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 2012;44(3):254-6. 4. Legato A et al. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 2015;47(6):579-81. 5. Nicolas G et al. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 2013;80(2): 181-87. 6. Keller A et al. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 2013;45(9): 1077-82.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analysis-of-secondary-causes-in-fahrs-syndrome-and-whole-exome-sequencing-in-fahr-disease-from-northeast-china-and-south-korean/