The Genetics of Primary Familial Brain Calcification: A Literature Review

Abstract

Primary familial brain calcification (PFBC), also known as Fahr’s disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

XPR1: a regulator of cellular phosphate homeostasis rather than a Pi exporter

“…cRNA of other potential XPR1 modulators such as Kirrel, Myorg, IP6K1/2, PPIP5K1/2 and KIDINS220 were also co-expressed and again, failed to enhance Pi export in the presence of XPR1. Mutations in Kirrel and Myorg are, as XPR1, associated with familial brain calcification whereas IP6K1/2 and PPIP5K1/2 are additional kinases that phosphorylate IP5 and IP7, respectively [ 8 ]. KIDINS220 has recently been identified as an essential co-factor for XPR1 localization and function [ 6 ].…”

“…The impact is well documented in the context of familial brain calcification where mutations in XPR1 as well as in SLC20A2, MYORG, PDGFB (platelet-derived growth factor subunit B) and a few other genes lead to mineralization in the basal ganglia and potentially other brain regions (cerebellum, subcortical white matter and thalamus). The presence of bone matrix proteins in affected areas indicates an osteogenic environment [ 31 ] where disturbance of the local Pi balance may exacerbate pathological calcification, rather than mutations in SLC20A2 or XPR1, respectively, causing toxic Ca/Pi precipitates [ 8 ]. Accordingly, mutations in SLC20A2 or XPR1 have a lower penetrance and a later onset than other mutations associated with familial brain calcification (MYORG, PDGFB and PDGFRB) [ 2 ].…”

“…XPR1 is phylogenetically well conserved, and homologues are found in metazoans. XPR1 is broadly expressed in cell lines and various organs, also in tissues that are not primarily associated with Pi homeostasis [ 8 , 10 ]. Mutations in XPR1 have been found in a cohort of patients with familial brain calcification, a condition that is also associated with mutations in phosphate transporters of the SLC20 family [ 8 , 18 ].…”

“…XPR1 is broadly expressed in cell lines and various organs, also in tissues that are not primarily associated with Pi homeostasis [ 8 , 10 ]. Mutations in XPR1 have been found in a cohort of patients with familial brain calcification, a condition that is also associated with mutations in phosphate transporters of the SLC20 family [ 8 , 18 ]. Moreover, the kidney-specific conditional knock-out of XPR1 caused an increased urinary excretion of Pi.…”

Basal Ganglia Calcification: A Case Report of Two Siblings With Fahr's Disease

“…FD is predominantly autosomal dominantly inherited, and mutations have been identified in four causative genes (SLC20A2, XPR1, PDGFB, and PDGFRB) [ 1 ]. Nevertheless, around 50% of FD patients have yet to receive a genetic diagnosis [ 6 ]. The physiopathological mechanism of FD is not completely understood.…”