Last month, Caroline received the clinical diagnosis for Rett Syndrome based on meeting full essential (and most of the supportive) criteria for the disorder.
Caroline's first blood test involving the full gene sequencing did not detect the MECP2 gene
mutations associated with about 85% of Rett Syndrome cases. In 15% of the cases, the disorder is caused by deletions in the MECP2 gene. Today, Caroline's geneticist called to inform us that Caroline's second blood test revealed a heterozygous deletion of exon 3 and a partial deletion of exon 4 in the MECP2 gene.
The MECP2 gene, which is located in the X chromosome, regulates the protein in our bodies that helps us talk, walk, and do everyday things we sometimes take for granted. Mutations or deletions in the MECP2 gene disturb the function of those skills (though mutations in a couple of other genes including CDKL5 and FOXG1 have also been implicated in variant Rett cases). The "glitch" in the gene results in Rett Syndrome.
I already knew Caroline had Rett Syndrome, but hearing the exact molecular reason was still sad. I started thinking about how we went through our entire pregnancy and Caroline's first year not knowing what was happening to her body. We never thought that the various symptoms--gross and fine motor delays, teeth grinding, sleeping issues, reflux, etc.--were all pieces of the same puzzle. Nobody did. It wasn't until Caroline started to lose her words and ability to use her hands that it became clear that we were dealing with something much more serious than we ever imagined.
The disorder, however, doesn't affect Caroline's intelligence or her ability to love. She is an affectionate and sweet baby. She understands and will always understand what is said to her because the brain remains intact. In fact, there are a number of ways to communicate involving eye gaze, which we are already starting to figure it out. If we ask Caroline to point to her mommy, daddy, grandmom, dog, etc., she looks in the right direction. There is also technology that enables the use of eye gaze to act as a "mouse" to point to words or images on a computer screen. I am excited about the possibilities around communication!
(Further explanation from the International Rett Syndrome Foundation website)The link between Rett Syndrome and the MECP2 gene :
Rett syndrome is primarily caused by a sporadic mutation in the MECP2 gene on the X chromosome. The MECP2 gene makes a protein, also called MeCP2, believed to play a pivotal role in silencing, turning off or regulating the activity of other genes. The MECP2 mutation (change in the gene) causes the turn-off/regulatory mechanism to fail, allowing other genes to function abnormally. So, RTT is a genetic disorder of developmental arrest or failure of brain maturation. This is thought to occur when subsets of neurons and their connections (synapses) are disrupted during a very dynamic phase of brain development. This deviation occurs at the end of pregnancy or in the first few months of life during the critical phases of synapse development. How mutations in MeCP2 lead to RTT is not well understood but is the focus of intense research.
Why development is normal in the first few months:
RTT results from a chain of events beginning with the MECP2 genetic mutation. Mutations occur naturally in everyone all the time and most do not cause problems. The MECP2 mutation results in a shortage or absence of normal MeCP2 protein needed to regulate or direct other genes. These other genes affect or control the normal development of selected regions of the brain responsible for sensory, emotional, motor and autonomic function during the critical period of infancy when important milestones are expected to be achieved. Development appears to be normal in early infancy until the MeCP2-related regulation or control is needed. Without these controllers, selected regions of the brain do not develop properly. This explains why the child appears to be developing normally in the first months of life.
