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.

Keywords: Fahr’s disease; idiopathic basal ganglia calcification; primary familial brain calcification.

Figure 1

Reported variants in seven genes linked to PFBC along the protein sequence and their topologic protein models. (a) The reported variants in the SLC20A2 gene and topology protein model of PiT2. (b) PDGFRB gene and PDGF-Rβ. (c) PDGFB gene. (d) XPR1 gene and XPR1. (e) MYORG gene and MYORG. (f) JAM2 gene and JAM2. (g) CMPK2 gene. There is no obvious hotspot for SLC20A2, MYORG, and JAM2 genes. The variants tend to cluster in the tyrosine kinase domain of the PDGFRB gene, the mature protein product between positions 82 and 190 of the PDGFB gene, and in the SPX domain of the XPR1 gene. Meaning of symbols: *, stop codon; ?, unknown (a variant affecting the initiation codon cannot be predicted).

Figure 1

Reported variants in seven genes linked to PFBC along the protein sequence and their topologic protein models. (a) The reported variants in the SLC20A2 gene and topology protein model of PiT2. (b) PDGFRB gene and PDGF-Rβ. (c) PDGFB gene. (d) XPR1 gene and XPR1. (e) MYORG gene and MYORG. (f) JAM2 gene and JAM2. (g) CMPK2 gene. There is no obvious hotspot for SLC20A2, MYORG, and JAM2 genes. The variants tend to cluster in the tyrosine kinase domain of the PDGFRB gene, the mature protein product between positions 82 and 190 of the PDGFB gene, and in the SPX domain of the XPR1 gene. Meaning of symbols: *, stop codon; ?, unknown (a variant affecting the initiation codon cannot be predicted).

Figure 2

The structure of the neurovascular unit (NVU) and protein model of seven PFBC-causative genes. The NVU is composed of neurons, astrocytes, vascular SMCs, pericytes, and endothelial cells. Each element of the NVU interacts tightly with the other, which leads to an effective system used to regulate cerebral blood flow and maintain BBB integrity. PDGFRB, PDGFB, MYORG, and JAM2 are highly expressed in the composite cells of the NVU. The neurons and endothelial cells secrete PDGF-B, which binds to PDGF-Rβ. The PDGF-Rβ is mainly encoded on the surface of neurons, vascular SCMs, and pericytes. MYORG is specifically encoded in the endoplasmic reticulum of the astrocytes. JAM2 is mainly encoded in endovascular cells and astrocytes. CMPK2 is highly encoded in neurons and endothelial cells. PiT2 and XPR1, which are highly encoded in the brain, mediate Pi uptake into cells and efflux from cells, respectively.