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.
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References
Baker M, Strongosky AJ, Sanchez-Contreras MY et al (2014) SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia. Neurogenetics. https://doi.org/10.1007/s10048-013-0378-5
DeMeo NN, Burgess JD, Blackburn PR et al (2018) Co-occurrence of a novel PDGFRB variant and likely pathogenic variant in CASR in an individual with extensive intracranial calcifications and hypocalcaemia. Clin Case Rep. https://doi.org/10.1002/ccr3.1265
Fjaer R, Brodtkorb E, Øye AM et al (2015) Generalized epilepsy in a family with basal ganglia calcifications and mutations in SLC20A2 and CHRNB2. Eur J Med Genet. https://doi.org/10.1016/j.ejmg.2015.10.005
Fujioka S, Strongosky AJ, Hassan A et al (2015) Clinical presentation of a patient with SLC20A2 and THAP1 deletions: differential diagnosis of oromandibular dystonia. Parkinsonism Relat Disord 21:329–331.https://doi.org/10.1016/j.parkreldis.2014.12.024
Gazzo AM, Daneels D, Cilia E et al (2016) DIDA: a curated and annotated digenic diseases database. Nucleic Acids Res. https://doi.org/10.1093/nar/gkv1068
Geschwind DH, Loginov M, Stern JM (1999) Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease). Am J Hum Genet. https://doi.org/10.1086/302558
Hsu SC, Sears RL, Lemos RR, Quintáns B, Huang A, Spiteri E, Nevarez L, Mamah C, Zatz M, Pierce KD, Fullerton JM, Adair JC, Berner JE, Bower M, Brodaty H, Carmona O, Dobricić V, Fogel BL, García-Estevez D, Goldman J, Goudreau JL, Hopfer S, Janković M, Jaumà S, Jen JC, Kirdlarp S, Klepper J, Kostić V, Lang AE, Linglart A, Maisenbacher MK, Manyam BV, Mazzoni P, Miedzybrodzka Z, Mitarnun W, Mitchell PB, Mueller J, Novaković I, Paucar M, Paulson H, Simpson SA, Svenningsson P, Tuite P, Vitek J, Wetchaphanphesat S, Williams C, Yang M, Schofield PR, de Oliveira JR, Sobrido MJ, Geschwind DH, Coppola G (2013) Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 14:11–22. https://doi.org/10.1007/s10048-012-0349-2
Keller A, Westenberger A, Sobrido MJ, García-Murias M, Domingo A, Sears RL, Lemos RR, Ordoñez-Ugalde A, Nicolas G, da Cunha JE, Rushing EJ, Hugelshofer M, Wurnig MC, Kaech A, Reimann R, Lohmann K, Dobričić V, Carracedo A, Petrović I, Miyasaki JM, Abakumova I, Mäe MA, Raschperger E, Zatz M, Zschiedrich K, Klepper J, Spiteri E, Prieto JM, Navas I, Preuss M, Dering C, Janković M, Paucar M, Svenningsson P, Saliminejad K, Khorshid HR, Novaković I, Aguzzi A, Boss A, le Ber I, Defer G, Hannequin D, Kostić VS, Campion D, Geschwind DH, Coppola G, Betsholtz C, Klein C, Oliveira JR (2013) Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 45:1077–1082. https://doi.org/10.1038/ng.2723
Knowles JK, Santoro JD, Porter BE, Baumer FM (2018) Refractory focal epilepsy in a paediatric patient with primary familial brain calcification. Seizure. https://doi.org/10.1016/j.seizure.2018.02.001
Legati A, Giovannini D, Nicolas G, López-Sánchez U, Quintáns B, Oliveira JR, Sears RL, Ramos EM, Spiteri E, Sobrido MJ, Carracedo Á, Castro-Fernández C, Cubizolle S, Fogel BL, Goizet C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnun W, Paucar M, Paulson H, Pariente J, Richard AC, Salins NS, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini JL, Coppola G (2015) Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 47:579–581. https://doi.org/10.1038/ng.3289
Lescai F, Franceschi C (2010) The impact of phenocopy on the genetic analysis of complex traits. PLoS One. https://doi.org/10.1371/journal.pone.0011876
Nicolas G, Pottier C, Maltête D et al (2013) Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology. https://doi.org/10.1212/WNL.0b013e31827ccf34
Oliveira JRM, Sobrido MJ, Spiteri E, Hopfer S, Meroni G, Petek E, Baquero M, Geschwind DH (2007) Analysis of candidate genes at the IBGC1 locus associated with idiopathic basal ganglia calcification (“Fahr’s disease”). J Mol Neurosci 33:151–154. https://doi.org/10.1007/s12031-007-0030-7
Quintáns B, Oliveira J, Sobrido MJ (2018) Primary familial brain calcifications. في: Handbook of Clinical Neurology
Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quintáns B, Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S, Liu M, Wang QK, Forster IC, Zhang X, Liu JY (2012) Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44:254–256. https://doi.org/10.1038/ng.1077
Wang XT, Cai XY, Xu FX et al (2019) MEA6 deficiency impairs cerebellar development and motor performance by tethering protein trafficking. Front Cell Neurosci. https://doi.org/10.3389/fncel.2019.00250
Yao XP, Cheng X, Wang C et al (2018) Biallelic mutations in MYORG cause autosomal recessive primary familial brain calcification. Neuron. https://doi.org/10.1016/j.neuron.2018.05.037
Zhang F, Wang Y, Wang T et al (2018) cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.1804083115
Acknowledgments
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
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Borges-Medeiros, R.L., de Oliveira, J.R.M. Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients. J Mol Neurosci 70, 142–144 (2020). https://doi.org/10.1007/s12031-019-01430-9
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DOI: https://doi.org/10.1007/s12031-019-01430-9