Current Treatments & Emerging Treatments for Rett Syndrome

Rett Syndrome

Etiology: RTT is genetic but not inherited

Rett syndrome (RTT) is a rare lifelong neurodevelopmental disorder that affects gross motor, fine motor, and communication skills with comorbid conditions that include epilepsy, gastrointestinal (GI) dysfunction, nutritional deficits, movement disorders, autonomic dysfunction, orthopedic issues, cardiovascular complications, and mood regulation difficulties. Classic RTT, as well as several variants (atypical RTT), occur based on several specific genetic changes (mutations) in the methyl-CpG-binding protein 2 (MECP2) gene. The genetic changes are hypothesized to result in problems with protein production critical for brain development, but the exact cause is still being investigated. Very few cases of this genetic disorder are inherited; it is extremely unlikely that a child with RTT will have a sibling with the disorder.

Current options to treat RTT-related symptoms

Although severe, children with RTT (which are almost always females) can live into adulthood with appropriate care – over 70% of affected individuals will live 50 years or longer. The current options for RTT treatment depend on the severity of the disease and the presence of many possible symptoms; however, there are currently no treatments approved by the U.S. Food and Drug Administration (FDA) to treat the core symptoms of RTT, which include ambulation, hand function and communication.

Most individuals with RTT require substantial assistance with every aspect of daily living. The medical management of RTT symptoms, comorbid conditions, and the psychosocial impacts of the disease requires a multidisciplinary approach and a comprehensive therapeutic toolkit. Below, find some of the most common RTT-associated symptoms and the therapies endorsed by RTT experts:

Seizures. Most patients diagnosed with RTT have abnormal electroencephalogram (EEG) findings by age two, and up to 90% of all patients with RTT will have at least one seizure in their life. Although no particular anti-epileptic medication has shown better effectiveness in treating seizures in RTT, divalproex sodium (Depakote), oxcarbazepine (Trileptal), zonisamide (Zonegran), and levetiracetam (Keppra) are recommended.

GI issues. Roughly 92% of children and adults with RTT experience some degree of GI dysmotility, such as complications with chewing and swallowing, gastroesophageal reflux, constipation and delayed gastric emptying. Recommended therapies to treat common GI disorders in RTT are omeprazole, Miralax, Senna, Milk of Magnesia, or the insertion of a gastrostomy tube.

Growth and nutrition. Poor growth and trouble gaining weight are common problems in RTT. A body mass index in the 25th percentile is considered a reasonable target in clinical practice. Use of a gastrostomy tube is indicated in about a third of patients with RTT for extremely poor growth, to augment fluid intake, if there is a risk of aspiration, or if feeding times are prolonged. Duo-Cal, Natural Harvest, or Nutren 2.0 can also be used to increase caloric and nutrient intake.

Movement disorders. Movement disorders such as dystonia, chorea, and tremor are common in patients with RTT. Standard physical therapy recommends the use of a gait trainer, occupational therapy considerations are using an elbow brace, and speech therapy can employ augmentative and alternative communication strategies. Eye-gaze-based devices such as Tobii DynaVox and PRC Accent devices can help with unusual eye movements, and the antiparkinson agents trihexyphenidyl (Artane) and carbidopa and levodopa combination (Sinemet) can help with uncontrolled muscle movements.

Autonomic dysfunction. Breath-holding and hyperventilation are more common during wakefulness, while disturbances such as shallow breathing or short periods of stopping breathing (apnea) can occur during sleep. Anti-anxiety medications such as sertraline (Zoloft), escitalopram (Lexapro), citalopram (Celexa), or fluoxetine (Prozac) may be prescribed. Interestingly, findings from a 2008 study found that Prozac increased the number of MECP2-producing cells in mice, probably because the drug suppresses the production of serotonin, a chemical messenger between nerve endings in the brain.

Bone health. People with RTT experience frequent fractures due to low bone density. Vitamin D3, calcium carbonate, and zoledronic acid are recommended supplements to strengthen bones and prevent fractures.

Cardiovascular issues. Because about 40% of patients with RTT have a prolonged QTc (a form of irregular heartbeat), yearly electrocardiograms are recommended in all patients to identify the presence of long QTc syndrome. Medications that might cause QTc prolongation, such as some antipsychotics, and tricyclic antidepressants, should be avoided in patients with a history of QTc abnormality. Prolonged QT syndrome is a serious disorder that can increase the risk of a potentially fatal ventricular arrhythmia (Torsades de Pointes) that may contribute to the increased risk of sudden death in patients with RTT. The beta blockers propranolol (Inderal) and betaxolol (Kerlone) are recommended for use in patients with long QTc.

Disordered sleep. Sleep difficulties associated with RTT involve issues with initiating sleep (30% have trouble falling asleep at least once per week) and maintaining sleep (50% awaken at night more than once per week). Poor sleep contributes to daytime somnolence, increased seizure frequency, behavior dysregulation, and decreased sleep duration of family and caregivers. Consider the contribution of seizures, GI reflux, pain related to constipation, or muscle spasms to nighttime awakenings Providers should counsel patients and caregivers on good sleep hygiene and consider melatonin, clonidine, trazodone, mirtazapine, or gabapentin to promote restful sleep. Exercise caution when using trazodone and mirtazapine, as they can cause QTc prolongation (see the above section on cardiovascular issues).

Abnormal spine curvature. Scoliosis and kyphosis are both common in RTT, typically presenting between 8 and 11 years of age and progressing with age. Surgery may be required if the curvature is severe, causes impaired gait, or has an impact on respiration. Thoracolumbosacral or ankle-foot orthosis braces may also be considered to support the spinal column and improve gait.

Emotional issues. Children with RTT may become increasingly agitated and irritable as they get older, possibly due to frustration with communication. Periods of crying or screaming may begin suddenly, for no apparent reason, and last for hours. Some children may experience fears and anxiety. Anti-anxiety medications such as sertraline (Zoloft), Lexapro, Celexa, and Prozac may be prescribed to lessen these bouts and the underlying anxiety.

Emerging treatments for core RTT symptoms

Although individuals with RTT can live well into adulthood with the existing options for managing the physical symptoms, clinicians are interested in better solutions for the core symptoms of RTT, as well as in reducing the number of medications and interventions needed to manage the complications of the disease successfully. Medications that improve general neuronal function, as well as gene therapy, are in trial to measure the impact on global function in RTT:

Trofinetide. The agent trofinetide contains a modified version of glypromate, a protein fragment thought to reduce inflammation and improve the health of connections between nerve cells, restoring synaptic function. It showed promise in the Phase 3 LAVENDER trial, which enrolled 187 female patients with RTT and randomized them 1:1 to receive either placebo or 200 mg of trofinetide twice daily for 12 weeks. The coprimary endpoints in this study were the results of two validated rating scales: Rett Syndrome Behavior Questionnaire (RSBQ) and Clinical Global Impression Scale-Improvement (CGI-I). In July 2022, trofinetide’s maker Acadia Pharmaceuticals submitted a new drug application to the FDA for the treatment of RTT in patients two years of age and older, and a decision is expected from the agency on March 12, 2023. If approved, this twice-daily therapy would be the first-ever treatment for RTT core symptoms of communication and behavior. Acadia also is running an open-label Phase 2/3 trial called DAFFODIL to investigate trofinetide use in 15 girls with RTT ages 2 to 5. The results of that trial are expected by July 2023.

Blacarmesine. This drug activates sigma-1 receptors in the endoplasmic reticulum and modulates the activity of ion channels and signaling molecules, including inositol phosphates, protein kinases, and calcium channels, to modulate calcium homeostasis and mitochondrial function. The activation of sigma-1 receptors can attenuate oxidative stress linked to inflammation and increase the release of brain-derived neurotrophic factor (BDNF), which is decreased in MECP2 deficiency. This agent is in several trials, including the AVATAR Phase 3 study of adults with RTT and the EXCELLENCE Phase 2/3 study in pediatric patients with RTT. Findings from AVATAR indicate a clinically significant improvement in the RSBQ scores of participants who received the study drug for seven weeks. Participants on blacarmesine also had improvements in a secondary endpoint, their scores on the Anxiety, Depression, and Mood Scale (ADAMS), which has been clinically validated for use in RTT.

Gene therapy. The goal of gene therapy in RTT treatment is to introduce a fully functional copy of the MECP2 gene into the brains of individuals with RTT. The MECP2 gene is dosage-sensitive, suggesting that therapy levels need to be kept within a narrow range to achieve efficacy while avoiding overexpression-related toxicity. Two current Phase 1/2 open-label trials are currently underway to evaluate the safety, tolerability, and efficacy of using an adeno-associated virus (AAV9) to introduce MECP2 into neurons deficient in a functional copy of this gene.


Despite the burden and severity of RTT, the current treatment landscape relies heavily on managing secondary and tertiary symptoms of the disease but doesn’t address the primary or core symptoms. The most frequently reported causes of death in patients with RTT are sudden, unexplained death with no apparent underlying cause, likely due to uncontrolled seizures, fatal arrhythmia, aspiration, and pneumonia associated with lack of mobility – core symptoms of the disease. Although managing the disease through multiple drugs and therapies is currently the standard in RTT treatment, promising targeted therapies in the pipeline include pharmacologic and gene therapy; these avenues provide the potential for meaningful improvements in the lives of patients with RTT and their families.



  • Neul, J, Percy, A, et al. Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemp Clin Trials. 2022 Mar;114:106704. doi: 10.1016/j.cct.2022.106704. Epub 2022 Feb 8. PMID: 35149233.