Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid
Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid
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DOI：
10.1002/ajmg.b.32020
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发表时间：
2012-03-01
影响因子：
2.8
通讯作者：
Stankiewicz, Pawel
中科院分区：
文献类型：
--
作者：
Derwinska, Katarzyna;Mierzewska, Hanna;Stankiewicz, Pawel
中脑多巴胺（DA）神经元的发育受几种转录因子的调控，包括Nurr 1，Wnt 1，Lmx 1a/1b，En 1，En 2，Foxa 1，Foxa 2和Pitx 3。PITX 3是TH（酪氨酸羟化酶）启动子的上游共激活剂。Pitx 3-/-小鼠黑质和腹侧被盖区多巴胺能神经元选择性丢失，导致黑质纹状体通路和背侧纹状体中DA水平显著降低，并表现出异常的纹状体依赖性认知障碍和神经行为活动。用左旋多巴、多巴胺或多巴胺受体激动剂治疗这些小鼠，逆转了它们的几种感觉运动障碍。在常染色体显性遗传性先天性白内障和眼前节（眼）间充质发育不良（ASMD）患者中已报告了PITX 3的杂合错义突变，而在小眼球和神经功能缺损患者中已发现纯合错义突变。使用临床寡核苷酸阵列比较基因组杂交（aCGH），我们已经确定了一个类似的317 kb半合子缺失10q24.32，涉及PITX 3在一个17岁的男性与SmithMagenis综合征样表型，包括轻度智力障碍，睡眠障碍，多动，和侵略性和自我毁灭的行为。有趣的是，在我们的患者中没有发现眼睛异常。对他的脑脊液中神经递质的分析显示没有左旋多巴，并且儿茶酚胺代谢物的水平显著降低。重要的是，左旋多巴治疗我们的病人，导致他的攻击性行为和轻微改善他的注意力广度，延长时间的集中，更好的睡眠温和缓解。(C)2012 Wiley Periodicals，Inc.
The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3-/- mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an similar to 317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a SmithMagenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep. (C) 2012 Wiley Periodicals, Inc.