Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients

  • Rayssa Leal Borges-Medeiros
  • João Ricardo Mendes de OliveiraEmail author


Primary familial brain calcification (PFBC), widely known as Fahr’s disease, is a rare disorder caused by pathogenic variants in SLC20A2, PDGFB, PDGFRB, XPR1, or MYORG genes. It is characterized by ectopic brain calcification, mostly affecting basal ganglia, thalamus, and cerebellum. PFBC patients can present a wide spectrum of symptoms including cognitive, neuropsychiatric, and motor alterations. However, it is well established that PFBC individuals also present high clinical heterogeneity, though the genetic cause of this phenotypic is not understood. Recently, Wang et al. (Front Cell Neurosci., 2019) reported on the role of MEA6 gene in cerebellar development and motor performance, also citing that MEA6 might be linked to PFBC. A MEA6 variant was described in 2007 as a PFBC candidate gene in an American family. However, this family was later linked to the SLC20A2 gene discarding the MEA6 as a PFBC-gene and also some members were confirmed as phenocopy. Additionally, five independent studies have been shown that variants in a second gene, not related to PFBC, were identified in PFBC patients, promoting a complex and heterogeneous phenotype. Thus, further investigation is required to explain whether and how MEA6 contributes to the clinical presentation in this American family. Finally, this letter highlights the possible digenic influence on clinical heterogeneity of PFBC patients, and such a possibility might advance our understanding of PFBC phenotypes.


PFBC Phenocopy Digenic disease MEA6 SLC20A2 



The authors would like to thank Dr. Matt P. Keasey for editing. The contributions of the authors were financially supported by CNPq and FACEPE, Brazil

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Keizo Asami LaboratoryUniversidade Federal de PernambucoRecifeBrazil
  2. 2.Neuropsychiatric DepartmentUniversidade Federal de PernambucoRecifeBrazil

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