From the Department of Pediatrics and Adolescent Medicine (H.R., A.O., P.H., L.S., R.S., J.G., K.B.), Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University; Department of Pediatrics (M.B.), Hospital Dritter Orden, Munich, Germany; Departments of Pediatric Neurology (I.C.), Hospital Maria Pia do Centro Hospitalar do Porto, Portugal; 4IRCCS Stella Maris (S.F.), Calambrone, Pisa; Department of Clinical and Experimental Medicine (S.F.), University of Pisa, Italy; Neurogenetics Unit (C.M.L.), Department of Neurology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil; and Children's Hospital of Eastern Ontario (S.S.), Ottawa, Canada.
Neurology. 2014 Mar 18;82(11):945-55. doi: 10.1212/WNL.0000000000000212. Epub 2014 Feb 12.
We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation.
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.
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.
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.
我们旨在描绘 ATP1A3 相关疾病的临床和遗传谱，并认识到潜在的基因型-表型相关性。
我们鉴定了 16 例新的儿童交替性偏瘫（AHC）患者和 3 例新的快速进展性肌张力障碍-帕金森病（RDP）患者，并将这些患者以及之前报道的 164 例 ATP1A3 突变阳性 AHC 和 RDP 患者的临床和分子发现纳入我们的分析中。
AHC 和 RDP 的主要共同临床特征包括明显不对称、主要为肌张力障碍的运动障碍，受累呈头足梯度，并受躯体、情绪或化学应激源触发。临床过程包括 AHC 的早发型多相性、RDP 的晚发型单相或双相性以及中间型。对 8 个新的和 38 个已发表的 ATP1A3 突变的荟萃分析表明，影响跨膜和功能域的突变倾向于与更严重的 AHC 表型相关。大多数突变位于外显子 8、14、17 和 18。
AHC 和 RDP 构成了 ATP1A3 相关疾病连续表型谱中的临床原型。越来越多的是同时符合两种疾病标准的中间表型。ATP1A3 基因的高效逐步突变分析可能会优先考虑那些当前知识状态表明存在突变簇的外显子。
