Primary familial brain calcification: update on molecular genetics.

Area of Science:

• Neurogenetics
• Neuropsychiatry
• Calcium Metabolism

Background:

• Primary familial brain calcification (PFBC) is a rare neurological disorder characterized by abnormal calcium deposits in the brain, particularly in the basal ganglia, cerebellum, and subcortical white matter.
• PFBC presents with clinical heterogeneity, including movement disorders, psychiatric disturbances, and sometimes asymptomatic cases.
• Current research has identified three causative genes: SLC20A2, PDGFRB, and PDGFB.

Purpose of the Study:

• To summarize the genetic basis of primary familial brain calcification.
• To elucidate the roles of SLC20A2, PDGFRB, and PDGFB genes in the pathogenesis of PFBC.
• To highlight the remaining genetic mysteries in PFBC.

Main Methods:

• Literature review of genetic studies on PFBC.
• Analysis of gene functions related to phosphate transport and growth factor signaling.
• Review of reported pathogenic variants and their associated phenotypes.

Main Results:

• Mutations in SLC20A2, encoding the sodium-dependent phosphate transporter 2 (PiT-2), are a significant cause of PFBC, often acting via haploinsufficiency.
• Loss-of-function mutations in PDGFRB and PDGFB may impair pericyte function and blood-brain barrier integrity, leading to calcium accumulation.
• SLC20A2 variants account for approximately 40% of familial and 14% of sporadic PFBC cases, while PDGFRB and PDGFB mutations are less common.

Conclusions:

• Genetic factors, primarily SLC20A2, PDGFRB, and PDGFB mutations, underlie primary familial brain calcification.
• A significant proportion of PFBC cases (~50%) remain genetically unexplained, suggesting the existence of additional causative genes.
• Further research is needed to identify novel genes and understand the complete genetic architecture of PFBC.