In the last 7 years, changes in five genes [SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG] have been implicated in the pathogenesis of primary familial brain calcification (PFBC), allowing for genetic delineation of this phenotypically complex neurodegenerative disorder. This review explores how the ensuing plethora of reported PFBC patients and their disease-causing variants improved our understanding of disease, pathogenesis, clinical manifestation, and penetrance.
In PFBC patients, pathogenic changes have been most frequently described in SLC20A2, accounting for approximately the same number of patients as the variants in the other four PFBC genes combined. There is no appreciable relationship between any combination of the following three variables: the type of disease-causing change, the pattern or extent of calcifications, and the presence or nature of clinical manifestation in PFBC patients. Nevertheless, elucidation of underlying genetic factors provided important recent insights into the pathogenic mechanisms of PFBC, which collectively point toward a compromised neurovascular unit.
The ongoing clinical and molecular research increases our understanding of PFBC facilitating diagnosis and identifying potential therapeutic targets for this multifaceted and likely underdiagnosed condition.
aInstitute of Neurogenetics
bDepartment of Neurology, University of Lübeck, Lübeck, Germany
Correspondence to Christine Klein, MD, Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany. Tel: +49 4513101 8200; e-mail: firstname.lastname@example.org