“I am often asked to describe the experience of raising a child with a disability – to try to help people who have not shared that unique experience to understand it, to imagine how it would feel. It’s like this……
When you’re going to have a baby, it’s like planning a fabulous vacation trip – to Italy. You buy a bunch of guidebooks and make your wonderful plans. The Coliseum. The Michelangelo David. The gondolas in Venice. You may learn some handy phrases in Italian. It’s all very exciting.
After months of eager anticipation, the day finally arrives. You pack your bags and off you go. Several hours later, the plane lands. The stewardess comes in and says, “Welcome to Holland.”
“Holland?!?” you say. “What do you mean Holland?? I signed up for Italy! I’m supposed to be in Italy. All my life I’ve dreamed of going to Italy.”
But there’s been a change in the flight plan. They’ve landed in Holland and there you must stay.
The important thing is that they haven’t taken you to a horrible, disgusting, filthy place, full of pestilence, famine, and disease. It’s just a different place.”
-Excerpt from “Welcome to Holland” by Emily Perl Kingsley
Rett Syndrome is a neurodevelopmental disorder that surprises many parents since children often have normal development during the first 6 to 18 months of life, which is then followed by a period of neurological regression where they show problems like loss of language and coordination, repetitive hand movements, delayed growth, and occasionally seizures.
In the past, Rett Syndrome fell under the classification of autism-related conditions, among Asperger syndrome and childhood disintegrative disorder. Despite sharing many behavioral characteristics with autism, including repetitive behaviors, difficulties in social communication, and susceptibility to seizures, Rett Syndrome was redefined as a distinct syndrome due to its genetic origin. Rett Syndrome is caused by a single mutation in a gene known as MECP2 which produces the MeCP2 protein that then regulates many other genes. Because of MeCP2’s regulatory role, a single mutation in the MECP2 gene can cause widespread changes in many functions throughout the body.
Rett Syndrome is a rare condition that affects every 1 in 10,000 live female births. In contrast, males with the mutation experience problems so severe, resulting in early-life death. The gender difference exists because Rett Syndrome is X-linked, meaning the gene involved (MECP2) is located on the X chromosome, which females have 2 of, giving them a sort of safety net if the gene on only one of the X chromosomes is mutated. Mutations in MECP2 are some of the most common genetic risk factors associated with intellectual disabilities in females. Despite knowing which gene causes Rett Syndrome, the full scope of how Rett Syndrome affects the brain is unclear, partly due to the limited access of human brain tissue for research.
Much of our current understanding of Rett Syndrome has come from rodent studies, but translating treatment strategies from animal models to patients has proven to be difficult, with many previous treatment options failing to show effectiveness in humans. Furthermore, studies that have looked at human brain tissue often use data from patients that differ widely from one another, making it incredibly hard to understand exactly what is happening in the brain. Reconciling findings in animal models and reducing the variability seen in human studies is critical if successful therapeutic interventions are to be produced.
In a recent research article, Dr. Lee Cyn Ang and Dr. Victoria Siu at Western University, in collaboration with Dr. Mojgan Rastegar from the University of Manitoba, showed how mutations of MECP2 in patients with Rett Syndrome affected protein breakdown throughout the brain. They used imaging and genetic tools to study post-mortem brain tissue that was donated from four patients with Rett Syndrome (3 females, 1 male) and compared it with post-mortem brain tissue donated from six control individuals without a known neurological disorder.
The researchers found that the MeCP2 protein was seen in Rett Syndrome neurons (brain cells responsible for processing information) and not significantly different in terms of where in the neurons it existed compared to controls, and even between females and males. However, the real differences were seen in the supportive glial cells, which are important for supporting neuronal communication and regulating the brain’s immune response. In glial cells, there was a significant reduction in MeCP2 protein relative to the control group. These glial cell MeCP2 changes were found in the white matter tracts, which connect distant regions of the brain. This was an important discovery because most of the previous research on Rett Syndrome focused on studying neurons rather than the other cells in the brain like glial cells. This work reveals new avenues for research into understanding how Rett syndrome affects the brain – an important step toward developing treatments.
The researchers also found that the time between the surgical removal of the brain tissue and its chemical preservation process, known as ‘post-mortem delay’, had a significant impact on how much MeCP2 protein was detected. When energy-dependent processes in the brain begin to shut down after death, cells and molecules begin to break down. Chemically preserving brain tissue allows researchers to “freeze” the brain in its current state to prevent any changes that occur after death. In essence, the longer it takes after death to preserve brain tissue, the more time there is for cells to die which makes research results less accurate.
Originally, variability in the levels of protein from previous Rett Syndrome research was thought to be due to differences in brain cell activity between individuals. However, this research suggests that post-mortem delay may be the main cause of variability. This is a positive finding since the time delay can be accounted for and controlled in future studies. This has implications not just for Rett Syndrome research, but for research into many other neurodegenerative disorders which investigate proteins that are sensitive to post-mortem delay.
This study was the first to show that detection of MeCP2 protein is heavily influenced by post-mortem delay and that brain tissue from patients with Rett syndrome showed significantly reduced levels of MeCP2 protein in the supportive glial cells – a finding only previously shown in animal models but never in human tissue. While the specifics of how MECP2 mutations lead to the symptoms of Rett Syndrome are still unclear, understanding the effects of post-mortem delay will help future studies control for variability, and expedite the process in developing therapeutics for disorders alike. But until then…
“So you must go out and buy new guide books. And you must learn a whole new language. And you will meet a whole new group of people you would never have met.
It’s just a different place. It’s slower-paced than Italy, less flashy than Italy. But after you’ve been there for a while and you catch your breath, you look around…. and you begin to notice that Holland has windmills….and Holland has tulips. Holland even has Rembrandts.
But everyone you know is busy coming and going from Italy… and they’re all bragging about what a wonderful time they had there. And for the rest of your life, you will say “Yes, that’s where I was supposed to go. That’s what I had planned.”
And the pain of that will never, ever, ever, ever go away… because the loss of that dream is a very very significant loss.
But… if you spend your life mourning the fact that you didn’t get to Italy, you may never be free to enjoy the very special, the very lovely things … about Holland.”
-Continuation of above excerpt from “Welcome to Holland” by Emily Perl Kingsley
Photo by Jonathan Borba on Unsplash
Pejhan S, Siu VM, Ang LC, Del bigio MR, Rastegar M. Differential brain region-specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey-white matter variation. Neuropathol Appl Neurobiol. 2020;
Kingsley, E. P. (2001). Welcome to Holland. CONTACT-[FALKIRK] THEN OXFORD-, 14-14.