The clinical and genetic spectrum of primary familial brain calcification

Area of Science:

• Neurodegenerative diseases
• Neurogenetics
• Vascular biology

Background:

• Primary familial brain calcification (PFBC), or Fahr's disease, is a rare neurodegenerative disorder.
• Characterized by progressive, bilateral calcification in brain microvessels, particularly basal ganglia, cerebral, and cerebellar structures.
• Associated with altered Neurovascular Unit (NVU) function, impacting calcium-phosphorus metabolism, blood-brain barrier integrity, and leading to neurodegeneration.

Purpose of the Study:

• To summarize the current understanding of Primary Familial Brain Calcification (PFBC).
• To outline the genetic basis, clinical manifestations, and radiological findings of PFBC.
• To highlight the lack of specific disease-modifying treatments for PFBC.

Main Methods:

• Review of existing literature on Primary Familial Brain Calcification.
• Analysis of genetic studies identifying causative genes.
• Compilation of clinical and radiological data associated with different genetic forms.

Main Results:

• Seven causative genes identified: four with dominant (SLC20A2, PDGFB, PDGFRB, XPR1) and three with recessive (MYORG, JAM2, CMPK2) inheritance.
• Clinical symptoms vary widely, from asymptomatic cases to movement disorders, cognitive decline, and psychiatric issues.
• Specific radiological patterns, such as central pontine calcification (MYORG) and cortical calcification (JAM2), can suggest particular genetic mutations.

Conclusions:

• PFBC pathogenesis involves NVU dysfunction, leading to calcification and neurodegeneration.
• Genetic heterogeneity exists, with distinct genes linked to specific inheritance patterns and radiological features.
• Current therapeutic options are limited to symptomatic management, with no disease-modifying drugs available.