Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus
Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus
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DOI：
10.1212/01.wnl.0000266594.16202.c1
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发表时间：
2007-07-31
期刊：
影响因子：
9.9
通讯作者：
Dobyns, W. B.
中科院分区：
文献类型：
--
作者：
Guerrini, R.;Moro, F.;Dobyns, W. B.
背景资料：ARX是位于X染色体上的一个配对型同源异型盒基因，包含5个外显子，4个多聚丙氨酸（PolyA）区，一个同源结构域和一个保守的C-末端无芒结构域。对人类的研究已经证明了显着的多效性：畸形表型与同源框中的蛋白质截短突变和错义突变相关;非畸形表型，包括X连锁婴儿痉挛症（ISS），与同源框之外的错义突变和PolyA束的扩展相关。目的：对115例不明原因的儿童ISS进行基因突变分析，探讨ARX基因在儿童ISS中的作用。其中包括两对兄弟。结果如下：我们发现，编码第一个PolyA片段的三核苷酸重复序列从10个扩展到17个GCG重复序列（c.333_334ins[GCG]7），来自四个家庭的6个男孩（5.2%）年龄在2到14岁之间，包括两对兄弟。除ISS外，所有6名男孩均在6个月左右出现重度精神发育迟滞和全身性肌张力障碍，并恶化，最终在2岁内导致稳定的重度四肢瘫痪性运动障碍。3名儿童出现复发性、危及生命的肌张力障碍状态。在4名儿童脑MRI显示多个小病灶的异常空洞T1和信号强度增加T2的壳，可能反映了进行性多灶性组织损失。结论：婴儿痉挛症伴严重运动障碍性四肢轻瘫的表型增加了由单个丙氨酸重复序列的病理性扩增引起的人类疾病的数量。在缺乏一致的围产期病史的情况下，婴儿痉挛和运动障碍性脑瘫的男孩应考虑进行ARX基因检测。
Background: ARX is a paired-type homeobox gene located on the X chromosome that contains five exons with four polyalanine (PolyA) tracts, a homeodomain, and a conserved C-terminal aristaless domain. Studies in humans have demonstrated remarkable pleiotropy: malformation phenotypes are associated with protein truncation mutations and missense mutations in the homeobox; nonmalformation phenotypes, including X-linked infantile spasms (ISS), are associated with missense mutations outside of the homeobox and expansion of the PolyA tracts. Objective: To investigate the role of ARX, we performed mutation analysis in 115 boys with cryptogenic ISS. This included two pairs of brothers. Results: We found an expansion of the trinucleotide repeat that codes for the first PolyA tract from 10 to 17 GCG repeats (c.333_334ins[GCG]7) in six boys (5.2%) ages 2 to 14, from four families, including the two pairs of brothers. In addition to ISS, all six boys had severe mental retardation and generalized dystonia that appeared around the age of 6 months and worsened, eventually leading to stable severe quadriplegic dyskinesia within age 2 years. Three children experienced recurrent, life-threatening status dystonicus. In four children brain MRI showed multiple small foci of abnormal cavitation on T1 and increased signal intensity on T2 in the putamina, possibly reflecting progressive multifocal loss of tissue. Conclusion: The phenotype of infantile spasms with severe dyskinetic quadriparesis increases the number of human disorders that result from the pathologic expansion of single alanine repeats. ARX gene testing should be considered in boys with infantile spasms and dyskinetic cerebral palsy in the absence of a consistent perinatal history.