Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification
Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification
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DOI：
10.1093/brain/awt255
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发表时间：
2013-11-01
期刊：
影响因子：
14.5
通讯作者：
Hannequin, Didier
中科院分区：
文献类型：
--
作者：
Nicolas, Gael;Pottier, Cyril;Hannequin, Didier
特发性基底节钙化的特点是大脑中的矿物质沉积，大多数病例为常染色体显性遗传模式和遗传异质性。最近报道了第一个致病基因SLC20A2和PDGFRb。诊断特发性基底节钙化需要排除其他原因，包括与正常衰老有关的钙化，目前尚无标准数据。我们的目标是准确诊断并描述特发性基底节钙化的临床和放射学特征。首先，在600名连续住院的非选定对照中，使用计算机断层扫描的视觉分级标准对钙化进行评估。我们在这些对照的计算机断层扫描中确定了一个年龄特定的阈值，作为三个年龄段内总钙化评分的第99个百分位数的值：60岁。为了研究这种疾病的表型，从几个医学中心招募了基底节钙化的患者。在广泛的病因学评估后，排除了使用相同评分标准低于特定年龄阈值的钙化，以及鉴别诊断为特发性基底节钙化的患者。对SLC20A2和PDGFRb进行Sanger测序。共有72例患者被诊断为特发性基底节钙化，其中25例携带SLC20A2(两个家系，四个散发性病例)或PDGFRb(一个家系，两个散发性病例)突变。有5个突变是新的。71%的特发性基底节钙化患者有症状(临床平均发病年龄：39+/-20岁；上次评估的平均年龄：55+/-19岁)。其中，最常见的体征是：认知障碍(58.8%)、精神症状(56.9%)和运动障碍(54.9%)。SLC20A2突变携带者与PDGFRb突变携带者的临床差异无统计学意义。放射学分析显示，对照组和患者的总钙化评分与年龄呈正相关，但患者的总钙化评分随着年龄的增加而增加更快。SLC20A2的预期总钙化分数高于PDGFRb突变携带者，超出了年龄的单独影响。PDGFRb突变的患者没有表现出皮质钙化或疣状钙化。总的钙化评分在有症状的个体比无症状的个体更严重。自发现第一个致病基因以来，我们首次对一系列特发性基底节钙化患者进行了表型描述。无论遗传状态如何，临床和放射学多样性都得到了证实。钙化的定量与症状状态有关，但钙化的部位和严重程度不能反映整个临床的多样性。其他生物标志物可能有助于更好地预测临床表现。
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: 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.