Primary familial brain calcification with known gene mutations: a systematic review and challenges of phenotypic
Vera Tadic1, Ana Westenberger1, Aloysius Domingo2
1Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Importance:
In the past 2 years, 3 genes (SLC20A2, PDGFRB, and PDGFB) were identified as causative of primary familial brain calcification (PFBC), enabling genotype-specific phenotyping.
Objectives:
To provide a systematic literature review on the neuroimaging and clinical phenotype of genetically confirmed PFBC and summarize known pathophysiological mechanisms, to improve and harmonize future phenotype description and reporting by addressing data gaps, and to develop uniform definitions for clinical characterization.
Evidence Review:
We systematically searched the MEDLINE database among articles published from January 1, 2012, through May 31, 2014, for the 3 genes and selected 25 articles from all records (n=75) and from sources cited in the reference lists. Only genetically confirmed cases with individual clinical information were included, leaving 15 reports. Predefined categories for data extraction were different neurologic and psychiatric symptoms, imaging results, and age at onset (AAO). We also assessed availability of information to estimate possible bias.
Findings:
We included a total of 179 cases, 162 of which belong to 25 families. Availability of information ranged from 96.6% for ethnicity to 24.4% for AAO. All cases had calcifications on comprehensive cranial computed tomography, most frequently located in the basal ganglia (70.6%), subcortical white matter (40.8%), cerebellum (34.1%), or thalamus (28.5%). Mean (SD) AAO was 27.9 (22.3) years, and the AAO was comparable across genes (P=.77). The most frequently described signs were movement disorders, such as parkinsonism (12%) and dystonia (19%). Penetrance of the imaging phenotype was 100% compared with only 61% of the clinical phenotype. We propose a novel definition of disease status by specifying PFBC into genetic, clinical, and imaging phenotypes. Pathophysiological pathways converge on impaired phosphorus homeostasis and integrity of the blood-brain barrier.
Conclusions And Relevance:
Especially in rare conditions, meta-analyses are the most suitable tool to extract reliable information on the natural course of a disease. For future analyses, we provide a minimal data set that can be used for systematic clinical and imaging data collection in PFBC and that will also improve informed counseling of patients.
Insights
Primary familial brain calcification (PFBC) is linked to three genes, with imaging findings present in all patients but clinical symptoms in only 61%. This review aids in standardizing PFBC characterization and counseling.
Area of Science:
- Genetics and Neurology
- Neuroimaging
- Rare Diseases
Background:
- Primary familial brain calcification (PFBC) is a rare genetic disorder characterized by intracranial calcifications.
- Recent identification of three causative genes (SLC20A2, PDGFRB, PDGFB) allows for genotype-specific phenotyping.
Purpose of the Study:
- To systematically review the neuroimaging and clinical phenotype of genetically confirmed PFBC.
- To summarize known pathophysiological mechanisms.
- To improve and harmonize future phenotype description and reporting, addressing data gaps and developing uniform definitions for clinical characterization.
Main Methods:
- Systematic literature search of MEDLINE (Jan 2012 - May 2014) for articles on the three causative genes.
- Selection of 25 articles from 75 records, including those from reference lists.
- Inclusion of 15 reports with genetically confirmed PFBC and individual clinical data, extracting neurologic/psychiatric symptoms, imaging results, and age at onset (AAO).
Main Results:
- A total of 179 cases (162 in 25 families) were included.
- Calcifications were universally present on CT scans, predominantly in basal ganglia (70.6%).
- Mean AAO was 27.9 years, comparable across genes. Movement disorders (parkinsonism, dystonia) were most common. Imaging phenotype penetrance was 100%, while clinical phenotype penetrance was 61%.
Conclusions:
- Meta-analyses are crucial for understanding rare disease progression.
- A proposed novel definition categorizes PFBC into genetic, clinical, and imaging phenotypes.
- A minimal data set is provided to guide systematic data collection for improved PFBC research and patient counseling.
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