Cooley Coleman Jessica A, Moffitt Bridgette A, Bridges William C, Jones Kelly, May Melanie, Skinner Cindy, Friez Michael J, Skinner Steven A, Schwartz Charles E, Boccuto Luigi
Greenwood Genetic Center, Greenwood, SC, 29646, USA.
School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC, 29634, USA.
Metab Brain Dis. 2025 Feb 13;40(2):124. doi: 10.1007/s11011-025-01546-5.
Genetic abnormalities of the MECP2 gene cause several conditions grouped under the umbrella term of MECP2-related disorders and characterized by a variety of phenotypes. We applied a functional approach to identify metabolic profiles in two patients with Rett syndrome (RTT) and one patient with MECP2 duplication syndrome (MRXSL). Such an approach is based on the Phenotype Mammalian Microarray (PM-M) technology, which is designed to assess the cellular production of energy in the presence of different compounds generating distinct metabolic environments. The findings in the three case models were compared versus 50 controls. Although the small number of samples prevented most results from reaching significant p-values when adjusted with the Benjamini-Hochberg correction, some interesting trends emerged. Some compounds indicated metabolic trends shared by the two conditions, like increased energy production in the presence of energy sources such as pectin, adenosine, and pyruvic acid, or decreased metabolic response to certain hormones. Other compounds showed opposite trends for the two disorders, like interleukin-1 beta (IL-1 beta), which caused decreased energy production in the RTT group but increased energy production in the patient with MRXSL. The response to IL-1 beta also offers valuable insights into the pathogenic mechanism and potential therapeutic approaches. The metabolic profiling of MECP2-related disorders bears a remarkable translational potential since it may be helpful to investigate the molecular abnormalities underlying the phenotypical variety in this spectrum of conditions, develop biomarkers for the identification of ideal candidates for treatments like the recently approved trofenatide, and identify potential targets for the development of novel therapeutic approaches.
MECP2基因的遗传异常会导致几种被归类在MECP2相关疾病这一统称之下的病症，并具有多种表型特征。我们采用了一种功能方法来确定两名雷特综合征（RTT）患者和一名MECP2重复综合征（MRXSL）患者的代谢谱。这种方法基于表型哺乳动物微阵列（PM-M）技术，该技术旨在评估在存在产生不同代谢环境的不同化合物的情况下细胞的能量产生。将这三个病例模型的研究结果与50名对照进行了比较。尽管样本数量较少，在使用Benjamini-Hochberg校正进行调整后，大多数结果未能达到显著的p值，但仍出现了一些有趣的趋势。一些化合物显示出两种病症共有的代谢趋势，例如在存在果胶、腺苷和丙酮酸等能量来源时能量产生增加，或者对某些激素的代谢反应降低。其他化合物在两种病症中呈现相反的趋势，比如白细胞介素-1β（IL-1β），它在RTT组中导致能量产生减少，但在MRXSL患者中导致能量产生增加。对IL-1β的反应也为致病机制和潜在治疗方法提供了有价值的见解。MECP2相关疾病的代谢谱分析具有显著的转化潜力，因为它可能有助于研究这一系列病症中表型多样性背后的分子异常，开发生物标志物以识别像最近获批的曲非那肽这样的治疗理想候选者，并确定新治疗方法开发的潜在靶点。
