The Genetics of Primary Familial Brain Calcifications

Bilateral accumulation of calcium in the brain, most commonly in the basal ganglia, but also in the cerebellum, thalamus, and brainstem can be inherited in an autosomal dominant fashion and is then referred to as primary familial brain calcifications (PFBC). Clinical manifestations include a spectrum of movement disorders and neuropsychiatric abnormalities. In the past 2 years, 3 genes have been identified to cause PFBC, (ie, SLC20A2, PDGFRB, and PDGFB). SCL20A2 encodes the Type III sodium-dependent inorganic phosphate (Pi) transporter 2 (PiT2) and, when mutated, uptake of Pi is severely impaired likely causing buildup of calcium phosphate. The second identified cause of PFBC is mutations in PDGFRB, which codes for platelet-derived growth factor receptor beta (PDGF-R beta). Interestingly, the third PFBC gene is PDGFB that encodes the ligand of PDGF-R beta, which is secreted during angiogenesis to recruit pericytes, thereby implying impairment of the blood-brain barrier as a disease mechanism of PFBC.