Rett Syndrome

What Causes Rett Syndrome?

A mutation in the MECP2 gene causes RTS. This gene is responsible for producing a protein called methylcytosine binding protein 2, a compound that plays a crucial role in normal brain development and helps control the normal function of other genes. Many different MECP2 mutations can cause the disorder, but fewer than ten different mutations account for most cases. The RTS mutations interfere with the normal production of the methylcytosine binding protein, leading to dysfunction in other genes.

The MECP2 gene is located on the X chromosome. Girls have two copies of the X chromosome, one inherited from each parent. Boys have only one X chromosome inherited from their mother. They inherit a Y chromosome from their father.

When girls have the RTS mutation on one of their X chromosomes and their other MECP2 gene is normal, the normal copy of the gene compensates, to a degree, for the mutated gene. Even if RTS results, the developing fetus is likely to survive.

However, if boys have a mutated MECP2 gene on their only X chromosome, there is no normal copy of the gene to compensate. Scientists believe this leads to severe complications that are usually fatal to the fetus. This explains why RTS almost always affects girls.

Is Rett Syndrome Hereditary?

The mutation that causes RTS usually occurs spontaneously, meaning that the change in the gene is triggered during the development of the fetus. It is rarely passed directly from a parent to a child. However, in some cases, a woman may carry the mutation without showing signs of the disorder herself. In these cases, the mutation may be passed from the woman to her child. These inherited cases are thought to represent fewer than one percent of all RTS cases.

How Is Rett Syndrome Detected?

RTS often goes unnoticed early on because the first signs of the disorder may be subtle. Some babies show indications, such as poor muscle tone or feeding difficulties, in their first few months, but typically the more noticeable symptoms of RTS don’t appear until significantly later.

The earliest signs of RTS can include:

• Delays in motor skills such as crawling or walking
• Lack of eye contact
• Reduced interest in toys
• Slowed head growth
• Unusual hand movements

How Is Rett Syndrome Diagnosed?

If a child shows symptoms that could indicate RTS, a doctor will typically begin the diagnostic process with tests to rule out other potential causes. Diagnostic tests can include blood tests, hearing and vision tests, urine tests, brain activity exams, and imaging exams.

To make a diagnosis of RTS, doctors will look for several distinctive characteristics of the disorder, including:

• Loss of motor skills in the hands
• Repetitive, unusual hand movements
• Loss of language skills
• Loss of motor or coordination skills such as walking

If these diagnostic criteria suggest RTS, doctors may conduct genetic testing to detect the MECP2 mutation.  If the mutation is present, the diagnosis is confirmed

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Rett Syndrome Treated?

There is no cure for RTS. Treatment of the disorder focuses on alleviating symptoms and preventing complications. Standard treatment courses include:

• Medications to control breathing difficulties, sleep issues, muscle tone problems, and other complications
• Anti-seizure medications
• Physical therapy
• Occupational therapy
• Speech therapy
• Regular monitoring for potential complications, such as scoliosis and heart problems

How Does Rett Syndrome Progress?

RTS typically progresses through four distinct stages.

• Stage I. This early onset stage usually begins between 6 and 18 months. Symptoms in this stage may be subtle and often go unnoticed. The stage can last from a few months up to a year.
• Stage II. In this stage, the relatively rapid development of symptoms occurs. Babies lose motor and intellectual skills. Deterioration of skills can happen quickly, sometimes over a few weeks. This stage usually occurs between the ages of 1 and 4.
• Stage III. This stage usually begins between the ages of 2 and 10 and lasts for years. During this stage, deterioration plateaus and some symptoms may improve moderately. Sometimes seizures develop during this stage.
• Stage IV. In this final stage, physical symptoms worsen; mobility decreases, and problems with muscle tone and strength increase. Abnormal spinal development (scoliosis) may occur. Other symptoms, such as hand movements and communication problems, may stabilize or improve. Seizures may also improve during this stage. The fourth stage of the disorder usually begins after the age of 10 and can last for decades.

How Is Rett Syndrome Prevented?

There is no known way to prevent RTS. The MECP2 gene mutation that causes the disorder almost always happens spontaneously, and scientists have not identified any risk factors that appear to increase the risk of the mutation.

RTS is rarely inherited, but if you have a family history of the disorder, a genetic counselor can advise you on your risks if you plan to have children.

Rett Syndrome Caregiver Tips

RTS has a significant impact on families, but with the proper knowledge and support, parents can help their children lead the best life possible while taking care of their own mental and physical health. Keep these tips in mind as you learn to live with RTS.

• Learn as much as you can about the disorder. The effects of RTS are complex and vary significantly from child to child. The more you know about how the condition works, the better you’ll be able to deal with your child’s unique circumstances.
• Get support. RTS requires much of caregivers as they take care of and advocate for their children. The support of people who know what you’re going through is a crucial part of maintaining your own health. The International Rett Syndrome Foundation can guide you to support resources.
• Don’t lose sight of what your child can do. Even as RTS imposes limitations, your child is still capable of living a rewarding life. With the proper support, your child can learn to participate in their own daily care and build their communication skills.

Some people with Rett syndrome also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with RTS:

• Many people with RTS experience epileptic seizures.
• Some people with RTS experience movement-related symptoms similar to those of Parkinson’s disease.
• People with RTS may experience insomnia.
• Anxiety is common in people with RTS.

Rett Syndrome Brain Science

Scientists know that mutations in the MECP2 gene cause RTS, but they don’t know precisely how. The methylcytosine binding protein appears to switch other genes on and off, and proper protein production plays a crucial role in neurological development. Ongoing research is looking at other brain-chemical “switches” that operate similarly. The study aims to better understand how the methylcytosine binding protein works and, potentially, to find alternative “switches” that could play a part in therapies for RTS.

Other research focuses on the RTS mutation itself. Some scientists believe that variations in the mutation contribute to varying severity of the disorder. It is also possible that mutations in other genes may play a role in the disorder’s development.

Rett Syndrome Research

Title: A Study to Evaluate Ketamine for the Treatment of Rett Syndrome

Stage: Recruiting

Principal investigator:  Alan Percy, MD 

University of Alabama Birmingham School of Medicine

Birmingham, AL

This study is designed to assess oral ketamine for the treatment of Rett Syndrome and consists of up to 4 ascending dose cohorts, each assessing a 1-dose level of ketamine vs. placebo. Patients will receive, in either order, a 5-day BID regimen of both placebo and the cohort-specified dose level of oral ketamine. Patients may only participate in 1 cohort. Safety and tolerability will be assessed via patient disposition, vital signs, physical examination, adverse events, and concomitant medication use. Efficacy will be evaluated via physician and caregiver questionnaires and assessments, and continuous, wearable, at-home biosensor data collection. An independent safety committee will review safety data from each cohort to determine if the subsequent ascending dose cohort is warranted. A total of 12 patients per cohort and up to 48 patients are anticipated at approximately 7 sites. The screening period will last between 2 and 4 weeks, the cross-over treatment period will last 4 weeks, and the safety follow-up period will last 2 weeks. Total patient participation is approximately 8-10 weeks.

Title: Treatment of Mitochondrial Dysfunction in Rett Syndrome With Triheptanoin

Stage: Recruiting

Principal Investigator: Daniel Tarquinio, DO 

Center for Rare Neurological Diseases

Norcross, GA

This study aims to evaluate the safety and tolerability of triheptanoin in participants with Rett syndrome using laboratory values, electrocardiogram, rate of adverse events (AE), and physical exam. This study also seeks to evaluate the efficacy of UX007 (triheptanoin) in improving overall seizure frequency, dystonia severity, and quality of life. Eligible participants will take triheptanoin daily. Participation in the primary arm of this study will last up to 8.5 months, with an optional 36-month extension.

Title: Assessing Emerald and MC10 Biostamp nPoint Biosensors for Rett Syndrome

Stage: Recruiting

Principal Investigator:  David Lieberman, MD, PhD

Boston Children’s Hospital

Boston, MA

The study consists of two sequential cohorts with a total of approximately 20 patients enrolled. Patients in each cohort may participate for up to 4 weeks. Each participant will have up to 2 Emerald devices installed in their home to monitor sleep, breathing, and movement and will use between 3 and 9 nPoint patches to determine proper patch placement for detecting breathing signals.

The study will consist of a Screening visit, an Observation period, and a follow-up phone call. The Screening Period will be one day in clinic, the Observation period will be up to 4 weeks at home, and the follow-up phone call will be performed at the completion of the Observation Period.