Imagine keeping a journal of “firsts” for your newborn child; the first time she smiles back at you, the first time she grabs a toy, the first time she says a word. Slowly, you notice you are writing less in your journal. Those ‘firsts’ quietly become ‘lasts.’ These milestones don’t happen often, if at all. New milestones slow down and then stop altogether. Now, you are writing down firsts that you never could have planned for. For parents who have a child with Rett syndrome, this is what they describe when this rare neurodevelopmental disorder enters their lives.
Children with Rett syndrome develop normally for the first six to eighteen months of life. Then, loss of speech, purposeful hand movements replaced with repetitive motions such as wringing, loss of motor coordination and balance, and slowed physical development are tell-tale symptoms that appear. As time progresses, some children may develop seizures varying in frequency as well as irregular breathing, scoliosis, sleep disturbances, and gait problems. It is not that the child never learned; it is that these skills appeared and then slowly faded away. This neurodevelopmental disorder affects approximately 1 in 10,000 female births and there are roughly 9,000 individuals in the United States living with this syndrome. A loss-of-function mutation in the MECP2 gene, located on the X chromosome, causes Rett syndrome. This is why Rett syndrome almost exclusively affects girls.
The methyl CpG binding protein 2 (MECP2) gene, implicated in Rett syndrome, acts like a tuner, adjusting other neuronal genes up or down so that neuronal activity stays in balance. MECP2 is located on the X chromosome. Typically, MECP2 is mutated on one X chromosome leading to a “bad X.” Since females have two X chromosomes in each cell, one of these copies is randomly inactivated early in development. This process is known as X-inactivation and ensures that there is equal gene expression and protein production between males and females. Because of this, a mosaic brain is created in which some neurons produce healthy MECP2, while others produce a faulty version of MECP2 or none at all. While this mosaicism provides some benefit as girls are able to survive MECP2 mutations because not every cell carries the “bad X”, this also leads to Rett syndrome with a range of severity. When the mutated MECP2 gene is present, it acts as a broken tuner and is no longer able to appropriately control the volume of gene expression. The neurons are still there, but nothing is in tune.
Boys only have one X chromosome. If that single X chromosome carries the MECP2 loss-of-function mutation, almost all of their neurons will lack a functional MECP2 and there is no backup. This degree of loss is usually not compatible with survival beyond birth or the first year of life. Boys who do survive often have different MECP2 variants or mosaicism that spare some function, and they tend to have earlier and more severe symptoms.
What if there was a way to reset, or at least carefully adjust, the tuner that MECP2 provides for gene activity in neurons? In Rett syndrome, the neurons are still present, but their connections are off. Today, treatment focuses on physical and occupational therapy as well as medications for associated seizures. However, there is still no cure. Directly fixing the MECP2 gene is challenging and the only FDA-approved drug specifically for Rett is trofinetide. Trofinetide is an analog of the GPE fragment cleaved from IGF-1, a growth factor that crosses the blood brain barrier and modulates synaptic maturation and neuroinflammation. In clinical trials, trofinetide reduced neuroinflammation and led to modest but meaningful improvements in overall symptoms. Additionally, there are several early-phase trials that are testing AAV-based gene therapies that can be delivered into the cerebrospinal fluid (CSF) or ventricles of the brain. These viral vectors contain a “mini-gene” version of the MECP2 gene designed to add a working copy while limiting the risk of too much protein. There is also another AAV that delivers a full length MECP2 gene that regulates the amount of protein made by the gene to avoid high levels of MECP2.
MECP2 and Rett show how a single gene can shape the entire course of a person’s life, but they also shed light on something more hopeful. The neurons are still present, they are just improperly tuned. As research moves from supporting these neural circuits with drugs like trofinetide to trying to correct the root of the problem itself, the goal is not only to prevent future ‘lasts’, but also to make space for new firsts that once seemed impossible.
King Lab at Creighton University 