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Primary Familial Brain Calcification With Known Gene Mutations A Systematic Review and Challenges of Phenotypic Characterization

Vera Tadic, MD1; Ana Westenberger, PhD1; Aloysius Domingo, MD1,2; Daniel Alvarez-Fischer, MD1,3; Christine Klein, MD1; Meike Kasten, MD1,3
[+] Author Affiliations
1Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
2Graduate School for Computing in Medicine and Life Science, University of Lübeck, Lübeck, Germany
3Department of Psychiatry, University of Lübeck, Lübeck, Germany
JAMA Neurol. 2015;72(4):460-467. doi:10.1001/jamaneurol.2014.3889.
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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.

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Figure 1.
Proposed Disease Mechanism of Brain Calcification

A, Under physiological conditions, endothelial cells secrete platelet-derived growth factor B (PDGFB) that binds to PDGF receptor β (PDGFRB) on pericytes. This process is necessary for the recruitment of pericytes and correct proliferation and migration along the blood vessels. Inorganic phosphate (Pi) in the brain parenchyma is taken up by Pi transporter 2 (PiT-2). From the brain cell, Pi is secreted through XPR1. B, Under pathologic conditions, the PDGF ligand or receptor loses its normal function, leading to pericyte dysfunction and an altered blood-brain barrier. Pi accumulates in the brain parenchyma owing to its reduced uptake by PiT-2. The proposed disease mechanism of mutated XPR1 has not yet been published in detail. However, the mechanism was found to reduce efflux of phosphate from cells.13 Whether glial and/or neuronal cells participate in the diseased state of primary familial brain calcification remains unknown.

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Figure 2.
Flowchart of the Literature Review

We identified 179 cases of primary familial brain calcification (PFBC), 162 of whom belonged to 25 families. IBGC indicates idiopathic basal ganglia calcification; PFBC, primary familial brain calcification.

aInformation was unavailable for the remaining 5.0% of cases.

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Figure 3.
Mutations in the 3 Genes Linked to Primary Familial Brain Calcification (PFBC)

The diagrams depict the mutations reported in the articles taken for review and by Nicolas et al,26 which are analyzed in the Discussion section. We also included c.1101C>G (discussed by Hsu et al15) in the review, although it is a synonymous change, thus depicted in this figure. The deletion of the entire SLC20A2 gene is not depicted (discussed by Baker et al21) but is included in the review. Numbers in boxes represent exons.

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Figure 4.
Several Issues of Known Gene Mutation in Primary Familial Brain Calcification (PFBC)

A, Availability of information for ages at examination, onset, and diagnosis. B, Affected regions in cranial computed tomography (CCT). C, Clinical status according to gene mutation in PFBC. D, Frequency of clinical symptoms in PFBC.

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