Primary familial brain calcification (PFBC) – SLC20A2 and PDGFRB genes


Primary familial brain calcification (PFBC) is a disorder of varying severity, characterized by the presence of calcifications in the blood vessels inside the brain. It mainly affects the basal ganglia, although other regions of the brain may also be affected. This disease is also known as familial idiopathic basal ganglia calcification (FIBGC) or bilateral striopallidodentale calcinosis (BSPDC).

The main signs and symptoms of this process include movement alterations such as dystonia, bradykinesia, tremor, choreoathetosis and unstable passage; psychiatric and behavioral difficulties in about 20 to 30% of individuals, including difficulty concentrating, memory loss, personality changes, psychosis and dementia. In addition, some individuals may have dysphagia, difficulty in language, headaches, vertigo, seizures or urinary problems.

Primary familial cerebral calcification is due to mutations in one of several genes: mainly SLC20A2 or PDFRB, and to a lesser extent, MYORG, PDGFB or XPR1. However, in approximately half of the affected individuals the genetic cause is unknown. Approximately 40 percent of cases are due to mutations in the SLC20A2 gene (solute carrier family 20 member 2). It is followed by mutations in the PDGFRB gene (platelet derived growth beta receptor factor), responsible for approximately 10 percent of cases. A small percentage of affected individuals have changes in other genes, such as MYORG (myogenesis regulating glycosidase (putative)), PDGFB (platelet derived growth factor subunit B) and XPR1 (xenotropic and polytropic retrovirus receptor 1).

The SLC20A2 gene, located on the short arm of chromosome 8 (8p11.21), encodes the sodium-dependent phosphate transporter 2 (PiT-2). This protein is highly active in neurons, where it plays an important role in phosphate homeostasis. Phosphate is necessary for many cellular functions, including metabolic processes, signaling between cells and the production of nucleic acids and fats. More than 60 mutations of the SLC20A2 gene responsible for the development of primary family cerebral calcification have been identified. Most of the mutations described consist of amino acid changes in the PiT-2 protein that seriously affect its ability to transport phosphate in cells. As a result, blood phosphate levels increase. Excess phosphate combines with calcium and forms deposits inside the blood vessels of the brain.

The PDGFRB gene, located on the long arm of chromosome 5 (5q32), encodes the platelet derived growth factor beta receptor (PDGFRB). The PDGFB protein will bind to this receptor, which is found in the cell membrane of certain cell types. This binding results in the activation of a series of proteins in multiple signaling pathways. The signaling pathways stimulated by the PDGFB protein control many important processes in the cell, such as cell growth, proliferation and survival. Therefore, cellular signaling mediated by PDGFB protein is important for the development of many cell types throughout the body. At least six mutations in the PDGFRB gene have been identified in individuals with primary familial brain calcification, consisting of certain amino acids in the PDGFB protein beta receptor (PDGFRB). These changes impair the signaling capacity of this protein.

Although it is unknown how mutations of the PDGFRB gene result in the development of this condition, an altered signaling of the pathway mediated by the PDGFB protein can disrupt the processes that regulate the concentration of calcium and phosphate in brain cells. Consequently, the accumulation of a considerable amount of calcium in the cells that line the blood vessels in the brain leads to the calcification of these vessels.

In most cases, primary familial brain calcification is inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the disease. Thus, usually an affected person has a parent with the condition. Less frequently it is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with primary familial brain calcification (PFBC), by means of the complete PCR amplification of the exons of the SLC20A2 and PDGFRB genes, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).