1 Inserm U1079, Rouen, France.
Brain. 2013 Nov;136(Pt 11):3395-407. doi: 10.1093/brain/awt255. Epub 2013 Sep 24.
Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.
特发性基底节钙化的特征是脑内矿物质沉积，大多数情况下呈常染色体显性遗传模式和遗传异质性。最近报道了第一个因果基因 SLC20A2 和 PDGFRB。诊断特发性基底节钙化需要排除其他原因，包括与正常衰老相关的钙化，但目前尚无正常数据。我们的目标是准确诊断，然后描述特发性基底节钙化的临床和放射学特征。首先，我们使用计算机断层扫描（CT）扫描的视觉评分量表评估 600 名连续住院的未经选择的对照者的钙化情况。我们在这 600 名对照者的 CT 扫描中确定了一个年龄特异性阈值，该值是三个年龄组（<40、40-60 和>60 岁）内总钙化评分的第 99 个百分位数。为了研究疾病的表型，我们从多个医疗中心招募了基底节钙化患者。使用相同的量表，评分低于年龄特异性阈值的钙化以及经过广泛病因评估后被诊断为特发性基底节钙化的患者均被排除在外。对 SLC20A2 和 PDGFRB 进行了 Sanger 测序。共有 72 名患者被诊断为特发性基底节钙化，其中 25 名患者在 SLC20A2（两个家族，四个散发性病例）或 PDGFRB（一个家族，两个散发性病例）中存在突变。其中 5 个突变为新发现。71%的特发性基底节钙化患者有症状（临床发病年龄的平均值：39±20 岁；最后一次评估的年龄平均值：55±19 岁）。其中，最常见的症状是：认知障碍（58.8%）、精神症状（56.9%）和运动障碍（54.9%）。SLC20A2 和 PDGFRB 突变携带者之间似乎没有明显的临床差异。放射学分析显示，在对照组和患者中，总钙化评分与年龄呈正相关，但在患者中，随着年龄的增长，钙化评分的增长速度更快。在考虑年龄因素的情况下，SLC20A2 突变携带者的预期总钙化评分高于 PDGFRB 突变携带者。没有 PDGFRB 突变的患者出现皮质或蚓部钙化。与无症状患者相比，有症状患者的总钙化评分更严重。这是自发现第一个致病基因以来，对特发性基底节钙化患者的病例系列进行的首次表型描述。无论遗传状态如何，临床和放射学多样性都得到了证实。钙化的量化与症状状态相关，但钙化的位置和严重程度并不能反映整个临床多样性。其他生物标志物可能有助于更好地预测临床表达。
