DEXTROMETHORPHAN IN RETT SYNDROME

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Rett综合征(RTT)是一种神经发育障碍，发生在1：10,000-22,000女孩中，对大脑和系统神经元造成毁灭性后果。在70%具有指定临床特征的个体中，已发现位于染色体Xq28上的甲基CpG结合蛋白-2(MeCP2)基因突变。MeCP2与核DNA结合，并与甲基化的CpG核苷酸结合，在转录沉默中发挥重要作用。到目前为止，RTT还没有有效的治疗方法，治疗仍然是姑息性的。不幸的是，大脑在其最旺盛的生长阶段首当其冲，导致严重的精神发育迟滞。 死后脑放射自显影研究表明，前额叶皮质中谷氨酸/NMDA(N-甲基-D-天冬氨酸)受体亚型的数量显著和不成比例地增加，特别是在年轻女孩中。在10岁以后，NMDA受体数量的急剧增加减少到低于控制值。此外，在RTT患者的脑脊液(CSF)和脑灰质中，通过1H波谱(MRS)研究发现谷氨酸增加，但没有任何其他氨基酸。较年轻的RTT患者兴奋性氨基酸(EAA)受体的异常增加与行为和癫痫特征以及RTT第二和第三阶段(18个月-15岁)出现的胃肠功能障碍相一致。此外，15岁以下RTT患者的原因不明猝死与癫痫发作频率无关，与这一神经兴奋毒性时期不谋而合。RTT(18个月)的病因学临床特征开始出现，据报道在2年后EAA谷氨酸/甘氨酸和NMDA受体增加，这表明自闭症样特征的出现、癫痫发作、手部绞痛、易怒和神经递质改变之间存在因果关系。15岁以后症状的逐渐改善与谷氨酸/NMDA受体减少到低于对照组的值相一致。此外，成骨细胞中存在的NMDA受体可能在RS的骨量减少中起作用。 值得注意的是，通过使用NMDA受体的竞争性阻滞剂右美沙芬来阻断大脑和成骨细胞中过多的NMDA受体是否可以改善大脑中的棘波活动和骨密度。类似的效果也可以改善食道自主神经功能障碍，这可以通过改善动力和减少反流来衡量。这项研究将包括90名MeCP2突变阳性患者。将5岁、5-10岁和11-14.99岁的30名受试者分配到3个治疗组，分别为0.25 mg/kg/d、2.5 mg/kg/d、5 mg/kg/d，分两次剂量。根据FDA的指导方针，我们只能包括5-14.99岁的患者；一旦在这个年龄段确定了安全性，我们将在FDA批准的情况下将研究扩大到5岁以上的患者。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rett syndrome (RTT) is a neurodevelopmental disorder that occurs in 1:10,000-22,000 girls with devastating consequences to brain and systemic neurons. In 70% of individuals having the prescribed clinical features, mutations in the gene encoding for methyl-CpG-binding protein-2 (MeCP2) located on chromosome Xq28 have been identified. MeCP2 is associated with nuclear DNA, and binds to methylated CpG nucleotides, playing a vital role in transcriptional silencing. To date, there is no effective therapy for RTT, and treatment remains palliative. Unfortunately, the brain bears the brunt of the disease during its most vigorous phase of growth, resulting in severe mental retardation. Postmortem brain autoradiographic studies demonstrate a striking and disproportionate increase in the number of glutamate/NMDA (N-methyl-D-aspartate) subtype of receptors in the prefrontal cortex, particularly in younger girls. After the age of 10 years, this dramatic increase in the number of NMDA receptors is reduced to below control values. Furthermore, increased glutamate, but not any other amino acid, has been documented in cerebrospinal fluid (CSF), as well as in brain gray matter by 1H spectroscopic (MRS) studies in RTT patients. The aberrant increase in the excitatory amino acid (EAA) receptors in younger RTT patients coincides with the behavioral and epileptic profile, and GI disturbances seen in RTT stages 2 and 3 (18 months-15yrs). Moreover, sudden unexplained death in RTT patients below the age of 15 years is unrelated to seizure frequency and coincides with this period of neuroexcitotoxicity. Commencement of the pathognomonic clinical features in RTT (18 months), with reported increases in EAA glutamate/glycine and NMDA receptors at 2 years, suggests a causal relationship between the onset of autistic-like features, seizures, hand wringing, irritability, and neurotransmitter alterations. The gradual amelioration of symptoms after 15 years of age coincides with a reduction of glutamate/NMDA receptors to below that of control values. Additionally, NMDA receptors that are present in osteoblasts may play a role in the osteopenia seen in RS. It would be important to note if blocking excessive numbers of NMDA receptors in brain and osteoblasts by use of dextromethorphan, a competitive blocker of the NMDA receptors, could improve spike activity in brain, and bone density. Similar effects could also improve esophageal autonomic dysfunction, measurable by improved motility and reduced reflux. The study will include 90 MeCP2 mutation positive patients. 30 subjects in each age group ranging from <5 years, 5-10 years, and 11-14.99 years will be assigned to each of the 3 treatment arms consisting of 0.25 mg/Kg/day, 2.5 mg/Kg/day, 5 mg/Kg/day in 2 divided doses. As per the FDA guidelines we can only include those patients between 5-14.99 years; once safety has been established in this age group we will extend the study to those < 5 years, with FDA's approval.