Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.
Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.
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DOI：
10.1186/s13023-015-0335-5
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发表时间：
2015-09-26
影响因子：
3.7
通讯作者：
International AHC Consortium
中科院分区：
文献类型：
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作者：
Panagiotakaki E;De Grandis E;Stagnaro M;Heinzen EL;Fons C;Sisodiya S;de Vries B;Goubau C;Weckhuysen S;Kemlink D;Scheffer I;Lesca G;Rabilloud M;Klich A;Ramirez-Camacho A;Ulate-Campos A;Campistol J;Giannotta M;Moutard ML;Doummar D;Hubsch-Bonneaud C;Jaffer F;Cross H;Gurrieri F;Tiziano D;Nevsimalova S;Nicole S;Neville B;van den Maagdenberg AM;Mikati M;Goldstein DB;Vavassori R;Arzimanoglou A;Italian IBAHC Consortium;French AHC Consortium;International AHC Consortium
最近发现，ATP 1A 3基因突变在儿童交替性偏瘫（AHC 2）患者中普遍存在。基于大量的AHC患者，我们着手确定ATP 1A 3基因内不同突变的谱，并进一步建立与表型的任何相关性。使用专门制定的调查问卷收集了来自155名AHC患者（84名女性，71名男性;年龄在3个月至52岁之间）的国际队列的临床数据，并相对于每名患者的突变ATP 1A 3基因数据进行了分析。总体而言，在85%（132/155）的患者中检测到34种不同的ATP 1A 3突变，其中7种是新的。一般来说，发现突变聚集成五个不同的区域。最常见的突变包括：p.Asp801Asn（43%; 57/132）、p.Glu815Lys（16%; 22/132）和p.Gly947Arg（11%; 15/132）。其中，p.Glu815Lys与严重表型相关，具有更严重的智力和运动残疾。与其他两种常见突变相比，p.Asp801Asn表现出较温和的表型表达，p.Gly947Arg表现出与最有利的预后相关。总体而言，临床特征的比较表明三种主要突变之间的严重程度梯度，智力（p = 0.029）和运动（p = 0.039）残疾的差异具有统计学意义。对于癫痫患者，与p.Asp801Asn突变患者相比，p.Glu815Lys或p.Gly947Arg突变患者癫痫发作的年龄更早（p < 0.001）。关于五个突变簇，一些簇似乎与某些临床表型相关。在有和没有ATP 1A 3突变的患者之间没有发现统计学显著的临床相关性。我们的研究结果表明，AHC 2患者的临床表型高度可变，与某些突变相关，可能与ATP 1A 3基因簇相关。我们对最常见突变患者的临床特征和不常见突变患者的临床表现的描述证实了先前研究的结果，并进一步扩展了基因型-表型相关性的范围。我们的研究结果可能有助于确诊，并可能影响决策，以确保适当的早期医疗干预患者AHC。它们为临床试验中纳入更同质的组提供了更有力的基础。本文的在线版本（doi：10.1186/s13023-015-0335-5）包含补充材料，可供授权用户使用。
Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials. The online version of this article (doi:10.1186/s13023-015-0335-5) contains supplementary material, which is available to authorized users.