The expanding clinical and genetic spectrum of ATP1A3-related disorders
The expanding clinical and genetic spectrum of ATP1A3-related disorders
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DOI：
10.1212/wnl.0000000000000212
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发表时间：
2014-03-18
期刊：
影响因子：
9.9
通讯作者：
Brockmann, Knut
中科院分区：
文献类型：
--
作者：
Rosewich, Hendrik;Ohlenbusch, Andreas;Brockmann, Knut
目的：我们的目的是描绘的临床和遗传谱的ATP 1A 3相关疾病和识别的一个潜在的基因型-表型correlation.Methods：我们确定了16个新的患者交替偏瘫的儿童（AHC）和3个新的患者与快速发作的肌张力障碍-帕金森综合征（RDP），并包括这些以及所有先前报道的164例突变阳性的AHC和RDP在我们的analysis.Results：主要的临床特征共享的共同AHC和RDP包括一个惊人的不对称，主要是肌张力障碍性运动障碍与rostrocaudal梯度的参与和物理，情感，或化学应激作为触发器。临床过程包括AHC的早发性多相，RDP的迟发性单相或双相，以及中间形式。对8个新的和38个已发表的ATP 1A 3突变的荟萃分析表明，影响跨膜和功能结构域的突变往往与AHC相关，是更严重的表型。结论：AHC和RDP构成了ATP 1A 3相关疾病的连续表型谱的临床原型。中间表型结合标准的两种条件越来越多地认识到。ATP 1A 3基因的有效逐步突变分析可以优先考虑那些外显子，其中目前的知识状态表明突变簇。
Objective:We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation.Methods:We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses.Results:Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18.Conclusion:AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.