Supplementary Material for: Fahr's Disease Linked to a Novel <b><i>SLC20A2 </i></b>Gene Mutation Manifesting with Dynamic Aphasia

Background: Idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease, is a rare disorder characterized by widespread cerebral calcifications, an autosomal dominant pattern of inheritance and clinical and genetic heterogeneity. The recently identified IBGC gene, SLC20A2, encodes for type III sodium-dependent phosphate transporter 2 and its loss-of-function mutations may lead to the regional accumulation of inorganic phosphate in the brain, causing calcium phosphate deposition. Objective: To describe the clinical, neuroimaging and genetic findings in an Italian family with IBGC. Methods: The family members underwent clinical and radiological examination in order to diagnose IBGC according to standard criteria and screening for SLC20A2 gene mutations. The affected subjects also underwent neuropsychological longitudinal assessments and functional neuroimaging investigations. Results: The 2 affected family members harbored a novel missense mutation, G1618A, in the SLC20A2 gene, leading to gly540-to-arg (G540R) substitution in a highly conserved residue. This is the first SLC20A2 gene mutation associated with familial IBGC reported in the Italian population and is damaging according to all prediction programs. In the index case we observed a fair correlation between cortical areas with no calcifications but with significant hypometabolism at [18F]FDG-PET (inferior frontal premotor cortex) and the neuropsychological picture dominated by dynamic aphasia and buccofacial apraxia. Conclusion: These findings expand the catalog of SLC20A2 mutations identified to date and add dynamic aphasia to the spectrum of neuropsychological deficits reported in IBGC, supporting the use of functional neuroimaging studies for better investigation of genotype-phenotype correlations.背景：特发性基底节钙化（Idiopathic basal ganglia calcification, IBGC）又称法尔病（Fahr's disease），是一种罕见的神经系统疾病，以广泛的大脑钙化、常染色体显性遗传模式以及临床和遗传异质性为特征。近期鉴定出的IBGC致病基因SLC20A2，编码Ⅲ型钠依赖性磷酸转运蛋白2，其功能丧失性突变可导致脑内无机磷酸盐区域性蓄积，进而引发磷酸钙沉积。 目的：描述一个意大利家族性特发性基底节钙化患者的临床、神经影像学及遗传学表现。 方法：对该家族成员进行临床与影像学检查，依据标准诊断标准确诊特发性基底节钙化，并对SLC20A2基因开展突变筛查。对受累患者同时实施纵向神经心理学评估与功能性神经影像学检测。 结果：2名受累家族成员的SLC20A2基因携带来自1种新型错义突变G1618A，该突变导致编码蛋白第540位甘氨酸替换为精氨酸（G540R），该位点处于高度保守的氨基酸残基区域。这是意大利人群中首次报道的与家族性特发性基底节钙化相关的SLC20A2基因突变，且经所有预测软件验证均判定为致病性突变。在先证者中，我们观察到[18F]FDG-PET扫描显示无钙化但存在显著低代谢的皮层区域（额下回运动前皮层），与以运动性失语和口面失用为核心表现的神经心理学特征具有良好相关性。 结论：本研究拓展了目前已报道的SLC20A2基因突变谱系，并将运动性失语纳入特发性基底节钙化相关的神经心理学缺陷谱，同时支持通过功能性神经影像学研究进一步深入探究基因型-表型关联。