DEXTROMETHORPHAN IN RETT SYNDROME

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。Rett综合征（RTT）是一种神经发育障碍，发生在1：10，000 - 22，000的女孩中，对大脑和全身神经元造成破坏性后果。在70%具有规定的临床特征的个体中，已鉴定出位于染色体Xq 28上的编码甲基-CpG结合蛋白-2（MeCP 2）的基因突变。MeCP 2与核DNA结合，并与甲基化的CpG核苷酸结合，在转录沉默中起重要作用。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，导致严重的智力迟钝。死后脑放射自显影研究表明，前额叶皮层中谷氨酸/NMDA（N-甲基-D-天冬氨酸）受体亚型的数量显著且不成比例地增加，特别是在年轻女孩中。在10岁之后，NMDA受体数量的这种急剧增加降低到低于对照值。此外，在RTT患者的脑脊液（CSF）和脑灰质中通过1H光谱（MRS）研究记录了谷氨酸增加，但没有任何其他氨基酸。年轻RS患者中兴奋性氨基酸（EAA）受体的异常增加与行为和癫痫特征以及RTT 2和3期（18个月-15岁）中观察到的GI紊乱一致。此外，15岁以下RTT患者的不明原因猝死与癫痫发作频率无关，与神经兴奋性毒性的这一时期一致。RTT（18个月）中的特异性临床特征的评论，以及2年时报告的EAA谷氨酸/甘氨酸和NMDA受体增加，表明自闭症样特征、癫痫发作、手绞、易怒和神经递质改变之间存在因果关系。15岁后症状的逐渐改善与谷氨酸/NMDA受体降低至低于对照值相一致。此外，成骨细胞中存在的NMDA受体可能在RS中观察到的骨质减少中发挥作用。重要的是要注意，如果通过使用NMDA受体的竞争性阻断剂美沙芬来阻断脑和成骨细胞中过量的NMDA受体，可以改善脑中的尖峰活动和骨密度。类似的效果也可以改善食管自主神经功能障碍，通过改善运动和减少反流来衡量。该研究将纳入90例突变阳性患者。将<5岁、5-10岁和11-14.99岁的每个年龄组中的30名受试者分配至3个治疗组中的每一个，所述3个治疗组由0.25 mg/Kg/天、2.5 mg/Kg/天、5 mg/Kg/天以2个分开的剂量组成。根据FDA指南，我们只能纳入5-14.99岁的患者。一旦在该年龄组中确定了安全性，我们将在他们的批准下将研究扩展到< 5岁的人群。

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 RS 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 mutation positive patients. 30 subjects in each age group ranging from <5 years, 5-10 years, and 11-14.99 year 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 their approval.