Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients
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Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients Rayssa Leal Borges-Medeiros 1 & João Ricardo Mendes de Oliveira 1,2 Received: 3 September 2019 / Accepted: 3 November 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract 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. https://doi.org/10.3389/fncel. 2019.00250, 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. Keywords PFBC . Phenocopy . Digenic disease . MEA6 . SLC20A2
Dear Editor, Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by ectopic brain calcification with symmetrical and bilateral patterns affecting the basal ganglia and cerebellum (Quintáns et al. 2018). The pathophysiology of PFBC has been linked to pathogenic variants in one of the five genes described until now (SLC20A2, PDGFB, PDGFRB, XPR1, and MYORG) (Wang et al. 2012; Keller et al. 2013; Nicolas et al. 2013; Legati et al. 2015; Yao et al. 2018). This disorder results in a complex clinical heterogeneity that might include motor and neuropsychiatric symptoms (Quintáns et al. 2018). However, the genetic basis of this
* João Ricardo Mendes de Oliveira [email protected] 1
Keizo Asami Laboratory, Universidade Federal de Pernambuco, Recife, Brazil
2
Neuropsychiatric Department, Universidade Federal de Pernambuco, Av. Professor Moraes Rego, 1235, Cidade Universitária, Recife, Pernambuco 50670-901, Brazil
phenotypic PFBC heterogeneity is not understood and even not fully explained by a single variant. Recently, Wang et al. (2019) presented their findings on the MEA6 gene (MGEA6/CTAGE5) and its contribution to cerebellar de
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