Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation
Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation
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DOI：
10.1093/brain/awt095
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发表时间：
2013-06-01
期刊：
影响因子：
14.5
通讯作者：
Hogarth, Penelope
中科院分区：
文献类型：
--
作者：
Hayflick, Susan J.;Kruer, Michael C.;Hogarth, Penelope
基底神经节高铁神经退行性疾病包括一系列单基因疾病，统称为脑铁蓄积性神经退行性疾病。这些疾病在很大程度上可以通过其相关的临床和神经影像学特征相互区分。本研究的目的是确定与WDR 45突变相关的表型，WDR 45是一种新的神经退行性疾病的致病基因，位于X染色体上，伴有脑铁积累。研究受试者包括在筛选具有脑铁积聚的特发性神经变性患者的大型国际队列后鉴定的WDR 45突变阳性个体。他们的记录进行了审查，包括纵向的临床，实验室和影像学数据。确定了23例突变阳性受试者（20例女性）。他们疾病的自然史是非常一致的：儿童期的整体发育迟缓和成年早期的进一步退化，伴有进行性肌张力障碍、帕金森综合征和痴呆。常见的早期合并症包括癫痫发作、痉挛状态和睡眠障碍。左旋多巴改善了帕金森综合征的症状;然而，几乎所有患者都经历了早期运动波动，并迅速发展为致残性运动障碍，从而导致停用左旋多巴。脑磁共振成像显示铁在黑质和苍白球，与'晕'的T-1高信号在黑质。所有患者都在WDR 45中具有从头突变，编码假定在自噬中发挥作用的β螺旋桨蛋白。β-螺旋桨蛋白相关神经变性是唯一一种伴有脑铁蓄积的X连锁神经变性疾病，与WDR 45的从头突变相关，可通过临床、自然病史和神经影像学特征的独特组合识别。
Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T-1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.