Livingston John H, Lin Jean-Pierre, Dale Russell C, Gill Deepak, Brogan Paul, Munnich Arnold, Kurian Manju A, Gonzalez-Martinez Victoria, De Goede Christian G E L, Falconer Alastair, Forte Gabriella, Jenkinson Emma M, Kasher Paul R, Szynkiewicz Marcin, Rice Gillian I, Crow Yanick J
Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.
J Med Genet. 2014 Feb;51(2):76-82. doi: 10.1136/jmedgenet-2013-102038. Epub 2013 Nov 21.
We recently observed mutations in ADAR1 to cause a phenotype of bilateral striatal necrosis (BSN) in a child with the type I interferonopathy Aicardi-Goutières syndrome (AGS). We therefore decided to screen patients with apparently non-syndromic BSN for ADAR1 mutations, and for an upregulation of interferon-stimulated genes (ISGs).
We performed Sanger sequencing of ADAR1 in a series of patients with BSN presenting to us during our routine clinical practice. We then undertook detailed clinical and neuroradiological phenotyping in nine mutation-positive children. We also measured the expression of ISGs in peripheral blood from these patients, and in children with BSN who did not have ADAR1 mutations.
Nine ADAR1 mutation-positive patients from seven families demonstrated an acute (five cases) or subacute (four cases) onset of refractory, four-limb dystonia starting between 8 months and 5 years of age. Eight patients were developmentally normal at initial presentation. In seven cases, the disease was inherited as an autosomal recessive trait, while two related patients were found to have a heterozygous (dominant) ADAR1 mutation. All seven mutation-positive patients assayed showed an upregulation of ISGs (median: 12.50, IQR: 6.43-36.36) compared to controls (median: 0.93, IQR: 0.57-1.30), a so-called interferon signature, present many years after disease onset. No interferon signature was present in four children with BSN negative for mutations in ADAR1 (median: 0.63, IQR: 0.47-1.10).
ADAR1-related disease should be considered in the differential diagnosis of apparently non-syndromic BSN with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR1 mutations in this context, and may suggest novel treatment approaches.
我们最近观察到，患有I型干扰素病Aicardi-Goutières综合征（AGS）的一名儿童中，ADAR1基因突变导致了双侧纹状体坏死（BSN）的表型。因此，我们决定对明显非综合征性BSN患者进行ADAR1基因突变筛查，以及干扰素刺激基因（ISG）上调情况的检测。
我们对在常规临床实践中前来就诊的一系列BSN患者进行了ADAR1基因的桑格测序。然后，我们对9名突变阳性儿童进行了详细的临床和神经放射学表型分析。我们还测量了这些患者外周血以及未携带ADAR1基因突变的BSN儿童外周血中ISG的表达。
来自7个家庭的9名ADAR1突变阳性患者表现出难治性四肢肌张力障碍的急性（5例）或亚急性（4例）发作，起病时间在8个月至5岁之间。8例患者初诊时发育正常。7例患者的疾病为常染色体隐性遗传，而另外2例相关患者被发现存在杂合（显性）ADAR1突变。与对照组（中位数：0.93，四分位间距：0.57 - 1.30）相比，所有7例接受检测的突变阳性患者均表现出ISG上调（中位数：12.50，四分位间距：6.43 - 36.36），即所谓的干扰素特征，在疾病发作多年后仍存在。4例ADAR1基因无突变的BSN儿童未出现干扰素特征（中位数：0.63，四分位间距：0.47 - 1.10）。
在对具有不同病程的严重肌张力障碍的明显非综合征性BSN进行鉴别诊断时，应考虑ADAR1相关疾病。在这种情况下，干扰素特征的发现为ADAR1基因突变的存在提供了一种有用的筛查检测方法，并可能提示新的治疗方法。
