Rett Syndrome: The Search for the Cure

Rett Syndrome: The Search for the Cure

“The halt marks the start of developmental regression or the devastating decline of a child who once seemed perfectly healthy.”

It's every parent's desire for their child to grow into a happy and healthy young person. Every milestone is an exhilarating rush of pride: watching your daughter take her first wobbly steps, hearing her say “mama” for the first time. Now, imagine the chilling fear that slowly sets in as you realize that time seems to be moving in reverse. Your daughter's movements start to become slower and weaker instead of stronger. You can't remember the last time she spoke. This is the reality for Miriam and Daniel of Staunton, Virginia, whose daughter Cordelia was recently diagnosed with Rett syndrome.1

Rett syndrome (RTT) is a neurodevelopmental disorder that appears in girls between 6 and 18 months of age. Early in life, RTT patients pass normal developmental milestones such as learning to talk and walk. However, their developmental progress eventually halts. Warning signs at this stage include disproportionately small head size, overall delay in growth, and poor muscle tone.2 The halt marks the start of developmental regression or the devastating decline of a child who once seemed perfectly healthy. "Regression is so slow and you kind of have these little hopes," says Miriam.1 For patients like Cordelia, regression entails the loss of abilities such as speech, motor skills, and social interaction.2 Patients lose the capability to make purposeful movements with their hands and acquire involuntary, repetitive hand-wringing motions. They develop features similar to autism such as an expressionless face, hypersensitivity to sound, lack of eye contact, and indifference to their surroundings. Breathing difficulties, scoliosis, and seizures top off the list of debilitating symptoms of RTT.2 Although deterioration plateaus over time, most patients with RTT will sadly become wheelchair users due to limited mobility. They can live to be 70 years old, but much of those decades is spent in pain and frustration.2

The genetic cause of RTT is not yet fully understood. More than 99% of RTT cases are sporadic, meaning that the mutation was not inherited from a parent.2 This has caused difficulty studying the genetic basis of RTT in the past because one of the best ways to search for disease-related genes is to examine the genetic profiles of families with a history of that disease. However, research has shown that the gene involved in RTT is MECP2. RTT results from a mutation in MECP2 that causes it to lose its function and produce less MECP2 protein.2 MECP2 is located on the X chromosome. Females have 2 X chromosomes; this means that their other, non-mutated X chromosome will still produce some MECP2. Conversely, males have only one X chromosome; if they have a mutation in MECP2, they lose the MECP2 protein entirely.2 This is why RTT is only observed in females – in males, it is fatal, while in females it is debilitating but survivable.

“Development is a complex process that requires many genes to be turned on or off in a carefully timed manner.”

The role of MECP2 has not yet been fully characterized. However, MECP2 is known to be involved in regulating expression of other genes. This means that it can act as a switch, turning some genes on and other genes off.3 Development is a complex process that requires many genes to be turned on or off in a carefully timed manner. If there is not enough functional MECP2, such as in a girl with RTT, it will lead to developmental abnormalities.

MECP2 has been studied in rat models. MECP2 was found to be expressed in the developing rat brain and is thought to play a role in helping brain cells mature.4 There are a few proposed mechanisms for how MECP2 does this. MECP2 may affect the levels of norepinephrine and dopamine in the brain.5 These are two important chemicals that send signals to regulate neural pathways. Norepinephrine is important in respiratory and cognitive function. Lack of MECP2 can harm the functioning of cells in the brain that produce norepinephrine, thus disturbing certain respiratory and cognitive pathways and resulting in the respiratory and cognitive symptoms of RTT.6 Dopamine is produced in an area of the brain called the substantia nigra pars compacta (SNpc). This area is fundamental to normal motor behaviour. Lack of MECP2 may affect SNpc cells, causing a decrease in dopamine levels. This could be responsible for motor dysfunction in RTT patients.6 However, further research is necessary to determine the exact pathways through which loss of function in MECP2 affects the brain.

A wide variety of treatments for RTT are used. Physical therapy and occupational therapy are useful in maintaining or improving motor skills. Speech-language therapy can be used to teach nonverbal communication and improve social interaction. Various medications can be prescribed that will target symptoms such as breathing problems and seizures.7 Although several treatments are successful in improving symptom severity8, none tackle the underlying cause of the disease.

“If it were possible to restore MECP2 function in [brain] cells, could RTT symptoms be cured?”

It is important to note that RTT does not actually kill brain cells.9 With this in mind, if it were possible to restore MECP2 function in these cells, could RTT symptoms be cured? A group of scientists used a mouse model to study this exciting proposal. They genetically modified mice so that their MECP2 gene could be turned on and off when they wanted. When the researchers slowly turned the gene back on, they found that the mice became healthy again.10 This exciting result implies that if we found a way to restore MECP2 levels in RTT patients’ cells, we might be able to cure RTT.

A recent study has brought to light a possible mechanism for restoration of MECP2 in RTT patients. The researchers identified two important segments of the MECP2 protein. They developed a shortened version of the human MECP2 gene that produced just the most important domains of the protein and inserted it into mice with RTT symptoms in which the MECP2 gene had been removed. They found that this “gene therapy” was able to decrease the mice’s RTT symptoms and extend their survival.11 Normal mice that had the shortened gene inserted did not show any obvious effects, despite having an extra copy of MECP2; the authors hypothesized that the shortened protein is unstable enough to minimize the negative effects of overexpression.11 This implies that the therapy is safe for use and will not lead to too much MECP2 production, which can be just as dangerous to the delicate balance in the brain as not enough MECP2.11 More research will be required before approval of this gene therapy for use in patients with RTT. However, the knowledge that one day we may be able to reverse the devastating symptoms of RTT, even in those who have suffered for decades, is comforting for patients with RTT and their loved ones. The power of a single gene to cause such severe deterioration is alarming. However, the power of a fragment of that same gene to reverse symptoms opens up an exciting world of possibilities – and gives us a glimpse of a possible future where terrible diseases like RTT are scarce.

Works Cited:

1. Calello M. For Staunton child with Rett syndrome, NY clinical trial offers hope against rare disorder. News Leader. October 20, 2017. Available at:

2. Chahrour M, Zoghbi HY. The story of Rett syndrome: From clinic to neurobiology. Neuron, 2007;56(3):422-437.

3. Chahrour M, Jung SY, Shaw C, et al. MeCP2, key contributor to neurological disease, activates and represses transcription. Science, 2008;320:1224-1229. doi:10.1126/science.1153252.

4. Jung BP, Jugloff DGM, Zhang G, Logan R, Brown S, Eubanks JH. The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells. J Neurobiol, 2003;55(1):86-96. doi:10.1002/neu.10201.

5. Zoghbi HY, Milstien S, Butler IJ, et al. Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome. Ann Neurol, 1989;25(1):56-60. doi:10.1002/ana.410250109.

6. Taneja P, Ogier M, Brooks-Harris G, Schmid DA, Katz DM, Nelson SB. Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome. J Neurosci, 2009;29(39):12187-12195. doi:10.1523/jneurosci.3156-09.2009.

7. What are the treatments for Rett syndrome? National Institute of Child Health and Human Development web site.

8. Lotan M, Isakov E, Merrick J. Improving functional skills and physical fitness in children with Rett syndrome. J Intellect Disabil Res, 2004;48(8):730-735. doi:10.1111/j.1365-2788.2003.00589.x.

9. Guy J, Gan J, Selfridge J, Cobb S, Bird A. Reversal of neurological defects in a mouse model of Rett syndrome. Science, 2007;315:1143-1147. doi:10.1126/science.1138389.

10. Panayotis N, Pratte M, Borges-Correia A, Ghata A, Villard L, Roux JC. Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse. Neurobiol Dis, 2011;41(2):385-397. https://doi-org/10.1016/j.nbd.2010.10.006.

11. Tillotson R, Selfridge J, Koerner MV, et al. Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature, 2017;550:398-401. doi:10.1038/nature24058.

Cite This Article:

Hunter R., Chan G., Palczewski K., Lewis K., Ho J. Rett Syndrome: The Search for the Cure. Illustrated by K. Lee. Rare Disease Review. March 2018. DOI:10.13140/RG.2.2.17813.01762.

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