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.