ABOUT RETT
Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder that occurs almost exclusively in females; even rarer in males. It is estimated that 1 in 10,000 are affected by RTT, usually caused by a mutation of the MECP2 gene on the X chromosome. It leads to severe impairments, affecting nearly every aspect of the individual’s life: their ability to speak, walk, eat, and even breathe easily. Other medical issues encountered include seizures, muscle stiffness, osteoporosis and scoliosis. The hallmark of RTT is near constant repetitive hand movements. RTT is usually recognized in children between 6-18 months as they begin to miss developmental milestones or lose abilities they had gained also known as regression. RTT is not a degenerative disease. Many individuals with RTT live long into adulthood. There is currently no cure however, medical advancements are being made on medication to help with symptom control.
*Health Canada has approved the 1st drug for RTT in October 2024, Daybue, that will be available to Canadian families early 2025.
HOW TO DIAGNOSE
RTT is diagnosed through a clinical examination that looks for specific signs and behaviours; it is confirmed through genetic testing. It can occur, however, without any of the currently known genetic mutations. As with any medical condition there is a large amount of variation in people with Rett syndrome. For example, some individuals learn to walk, although in an abnormal way, while others are never able to walk independently. There are two types of diagnoses to be made: typical/classic RTT and atypical/variant RTT.
Typical/classic RTT is characterized by a period of regression followed by recovery or stabilization. It requires the presence of 4 main criteria:
- partial or complete loss of acquired purposeful hand skills
- partial or complete loss of acquired spoken language, gait abnormalities and stereotypical hand movements
- no brain injury secondary to trauma
- no grossly abnormal psychomotor development in the first six months of life.
Some other supportive criteria are often present in this type of RTT but they are not required for the diagnosis.
For Rett syndrome to be considered atypical/variant, a period of regression must be present followed by recovery or stabilization and 2 of the 4 main criteria above must be met as well as 5 of 11 supportive criteria. These supportive criteria are:
- breathing disturbances when awake
- teeth grinding when awake
- impaired sleep pattern
- abnormal muscle tone
- peripheral vasomotor disturbances
- curvature of the spine – scoliosis/kyphosis
- delayed growth
- small, cold hands and feet
- inappropriate laughing/screaming spells
- diminished response to pain
- intense eye communication – eye pointing
In Ontario, a diagnosis is done by a clinical geneticist. A referral should be made by your primary care physician or pediatrician.
After diagnosis, a referral should be made to one of the Ontario Rett clinics.
SYMPTOMS OF RETT SYNDROME
Loss of Hand Skills – Children may lose the ability to use their hands for purposeful movements and develop repetitive hand-wringing, clapping, or tapping.
Loss of Speech – They may stop speaking words they previously learned and struggle to communicate.
Motor and Movement Issues – Walking becomes difficult, with some children losing the ability to walk altogether. Coordination problems and muscle weakness are common.
Breathing Problems – Irregular breathing patterns such as breath-holding, hyperventilation, or shallow breathing can occur.
Slowed Growth – Slower head, hand, and foot growth compared to peers.
Seizures – Many individuals with Rett syndrome experience epilepsy and seizures.
Cognitive and Social Changes – While they may not speak, children with Rett syndrome often recognize their caregivers and may still show interest in social interaction through eye contact and facial expressions.
Sleep Issues – Trouble falling or staying asleep, along with irregular sleep patterns.
Digestive Problems – Constipation, reflux, and other gastrointestinal issues are common.
HISTORY OF RETT SYNDROME
Dr. Andreas Rett, an Austrian neurologist, first identified Rett syndrome in 1966. He noticed a pattern while observing two girls in his clinic who displayed the same unusual hand-washing movements. Intrigued, he searched for more cases and found several other young patients with similar symptoms, including loss of speech, difficulty walking, and developmental regression after a period of normal growth. Dr. Rett published his findings in a German medical journal, but his work remained largely unnoticed until 1983, when Swedish researcher Dr. Bengt Hagberg and colleagues published an article in an English-language journal describing the syndrome. This brought international attention to the disorder, which was then named “Rett syndrome” in honor of Dr. Rett’s discovery.
MECP2 IN SIMPLE TERMS
MECP2 is a gene that acts like a “boss” for other genes in the brain, helping to control how brain cells work and communicate. It gives instructions on when to turn certain genes on or off, which is important for brain development and function.
In RTT, there is a change (mutation) in the MECP2 gene, which causes it to stop working properly. This leads to problems with brain signaling, making it harder for the body to control movement, speech, and other functions. Because MECP2 is so important for brain activity, when it doesn’t work as it should, it leads to the challenges seen in Rett syndrome.
RETT SYNDROME IN MALES
During conception if all goes well with the fertilization process the cells in a human carry the DNA instructions (genes) on 23 pairs of chromosomes. The mother gives the fetus 23 chromosomes and the father gives the fetus 23 chromosomes creating 46 chromosomes in each person. The special pairs of chromosomes that determine fetal sex are called the X & Y chromosomes.
Females typically have two X chromosomes whereas males typically have an X and a Y chromosome. Over the years, we have learned that RTT is caused by loss of the MECP2 gene function which is located on the X chromosome. This gene provides instructions for making a protein called MECP2 that helps regulate how and when our cells use different genes. If the MECP2 gene is mutated this causes the protein to not function properly, causing signs of RTT to appear.
In females, classical RTT occurs when one MECP2 gene is mutated and the other copy of the gene (on the other X chromosome) functions normally. The healthy copy of MECP2 acts as a vital crutch to support development and growth.
RTT in males is very rare due to the fact that most males only have one X chromosome, and if a mutation occurs in their only copy of MECP2, the fetus usually doesn’t survive, or is very sick at birth and may not live very long. Some males defy the odds and can survive without a normal copy of MECP2; however, they are usually quite severely delayed from birth and are severely disabled. Some boys have RTT in addition to another condition which provides a second X chromosome with a working copy of MECP2. These boys typically look very similar to girls with RTT. The first condition is known as Klinefelter syndrome, where males have two X chromosomes and one Y chromosome. The second is when the fetus is mosaic for the MECP2 mutation; there is a mix of two different populations of cells (one of which has a normal MECP2 gene). These conditions allow one functioning copy of the MECP2 gene to support development and growth.
For more information about genetics and the MECP2 gene you may refer to “The Rett Syndrome Handbook” written by Kathy Hunter.
Mark Jorgensen
1973 - 2017
Mark Jorgensen and his mother Barb Wentworth have been part of the Rett syndrome community in Ontario since Mark’s diagnosis in 2012. Mark was originally diagnosed with cerebral palsy (CP) and developmental delay. At the time, it was thought that Rett syndrome occurred exclusively in females. An earlier diagnosis could have made a positive difference in Mark’s care and helped to explain symptoms that did not fit with his CP diagnosis.
Mark will be remembered for his contagious laugh, his ability to strike up a conversation with anyone and his love of music and animals.
