Lack of Major Ophthalmic Findings in Patients with Primary Familial Brain Calcification Linked to SLC20A2 and PDGFB
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by symmetrical and bilateral brain calcification. It is typically inherited as an autosomal dominant disorder, and de novo variants have also been described. Interestingly, just recent studies have reported the first autosomal recessive PFBC-causative gene. PFBC patients exhibit high clinical heterogeneity including Parkinsonism, dystonia, ataxia, depression, and migraine. Mice studies, an important research tool, have been a breakthrough in increasing the understanding of PFBC’s main signs and symptoms, and many findings reported in these mice have been subsequently reported in patients. One phenotype that has been observed in PFBC mice models but not in PFBC patients, however, is the development of ophthalmic abnormalities. This way, this report focused on performing an ophthalmic assessment in six Brazilian patients genetically diagnosed with PFBC. The assessments showed that none of the PFBC individuals included presented any of the ophthalmic abnormalities reported in mice models, such as cataracts, ocular calcification, abnormal iris and lens morphology, and retinal deterioration. Additionally, of the six PFBC patients described, two SLC20A2 mutation carriers showed physiological excavation of the optic nerve head and partial vitreous detachment, while just one individual presented bilateral narrowing of retinal arterioles. In summary, no evidence of similar ophthalmological abnormalities found in mice were found in our patients; nonetheless, further studies in larger sample size are warranted to corroborate with our findings. To our knowledge, this study is the first to focus on investigating, in PFBC patients, the ophthalmological phenotypes described in the PFBC mice models.
KeywordsBrain calcification SLC20A2 PDGFB Eye globe
The contributions of the authors to this letter were financially supported by CNPq, Brazil.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- Anheim M, López-Sánchez U, Giovannini D, Richard AC, Touhami J, N’Guyen L, Rudolf G, Thibault-Stoll A, Frebourg T, Hannequin D, Campion D, Battini JL, Sitbon M, Nicolas G (2016) XPR1 mutations are a rare cause of primary familial brain calcification. J Neurol 263:1559–1564. https://doi.org/10.1007/s00415-016-8166-4 CrossRefGoogle Scholar
- Ferreira JB, Pimentel L, Keasey MP, Lemos RR, Santos LM, Oliveira MF, Santos S, Jensen N, Teixeira K, Pedersen L, Rocha CR, Dias da Silva MR, Oliveira JRM (2014) First report of a De novo mutation at SLC20A2 in a patient with brain calcification. J Mol Neurosci 54:748–751. https://doi.org/10.1007/s12031-014-0357-9 CrossRefGoogle Scholar
- Hozumi I, Kurita H, Ozawa K, Furuta N, Inden M, Sekine SI, Yamada M, Hayashi Y, Kimura A, Inuzuka T, Seishima M (2018) Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1). J Neurol Sci 388:150–154. https://doi.org/10.1016/j.jns.2018.03.014 CrossRefGoogle Scholar
- Jensen N, Schrøder HD, Hejbøl EK, Füchtbauer EM, de Oliveira JRM, Pedersen L (2013) Loss of function of Slc20a2 associated with familial idiopathic basal ganglia calcification in humans causes brain calcifications in mice. J Mol Neurosci 51:994–999. https://doi.org/10.1007/s12031-013-0085-6 CrossRefGoogle Scholar
- Keller A, Westenberger A, Sobrido MJ, García-Murias M, Domingo A, Sears RL, Lemos RR, Ordoñez-Ugalde A, Nicolas G, da Cunha JEG, 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 HRK, 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 JRM (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 CrossRefGoogle Scholar
- Quintáns B, Oliveira J, Sobrido MJ (2018) Primary familial brain calcifications. Handbook of Clinical NeurologyGoogle Scholar
- Wallingford M, Chia J, Leaf E et al (2016) SLC20A2 deficiency in mice leads to elevated phosphate levels in cerbrospinal fluid and glymphatic pathway-associated arteriolar calcification, and recapitulates human idiopathic basal ganglia calcification. Brain Pathol 3:[Epub ahead of print]:64–76. https://doi.org/10.1111/bpa.12362 Google Scholar
- Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JRM, 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 (2012a) Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44:254–256. https://doi.org/10.1038/ng.1077 CrossRefGoogle Scholar
- Wang S, Xu L, Jonas JB, Wang YS, Wang YX, You QS, Yang H, Zhou JQ (2012b) Five-year incidence of retinal microvascular abnormalities and associations with arterial hypertension: the Beijing eye study 2001/2006. Ophthalmology 119:2592–2599. https://doi.org/10.1016/j.ophtha.2012.06.031 CrossRefGoogle Scholar
- Yao XP, Cheng X, Wang C, Zhao M, Guo XX, Su HZ, Lai LL, Zou XH, Chen XJ, Zhao Y, Dong EL, Lu YQ, Wu S, Li X, Fan G, Yu H, Xu J, Wang N, Xiong ZQ, Chen WJ (2018) Biallelic mutations in MYORG cause autosomal recessive primary familial brain calcification. Neuron 98:1116–1123.e5. https://doi.org/10.1016/j.neuron.2018.05.037 CrossRefGoogle Scholar