Abstract
Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123I-ioflupane and 123I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2-related PFBC patients with parkinsonism.
Highlights
Primary familial brain calcification (PFBC), known as Fahr’s disease or idiopathic basal ganglia calcification, is a rare neuropsychiatric disorder[1]
In addition to dopamine transporter single photon emission computed tomography (SPECT) using 123I-ioflupane, we examined 123I-metaiodobenzylguanidine (MIBG) scintigraphy that is useful to differentiate Lewy body-related disorders from other neurodegenerative disorders in genetically confirmed PFBC patients with parkinsonism[20,21,22,23]
Mutagenesis analysis in Xenopus laevis oocytes showed that disease-causing mutants decreased Pi uptake activity without an obvious effect on the wild-type PiT-2 function, indicating that the underlying mechanism is due to haploinsufficiency rather than a dominant-negative effect[6]
Summary
Primary familial brain calcification (PFBC), known as Fahr’s disease or idiopathic basal ganglia calcification, is a rare neuropsychiatric disorder[1]. Individuals with brain calcification can be clinically asymptomatic[2,3,4] This condition is typically transmitted in an autosomal dominant fashion and is genetically heterogeneous[5]. Mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to be responsible for PFBC and have been detected in both familial and sporadic cases[6,7,8,9]. These four disease-causing genes do not account for all cases of PFBC, indicating additional genetic heterogeneity. Sorting Intolerant from Tolerant; CADD: Combined Annotation Dependent Depletion; ACMG-AMP: the American College of Medical Genetics and Genomics and the Association for Molecular Pathology; ExAC: The
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