Rett, Zoghbi, and the History of Rett syndrome

By Nelson Tang

What is Rett syndrome? This article will go over the causes, symptoms, and commonality associated with Rett syndrome and the treatments that are required. It will also take a look at how the lives of individuals with Rett syndrome are impacted by it. Lastly, the article will discuss who made the discovery of Rett syndrome and the contributions that these people have made to the field.

Rett syndrome is a rare neurodevelopmental genetic disorder that affects the development of one’s brain, which can result in severe mental and physical disability. Data shows that females are more likely to have this manifest compared to males, with 1 in every 10,000 females born each year having Rett syndrome. [3]. Despite this, males with Rett syndrome are shown to be more severely affected than females. Nearly all cases are linked to a single cause, which is the result of a mutation. This mutation occurs in the methyl CpG binding protein 2, or MECP2, which contains the synthesis of a protein called methyl cytosine binding protein 2. Furthermore, this protein is needed for brain development and acts as a biochemical switch that activates and deactivates gene functions. In some cases, there have been other cases for Rett syndrome, which include partial gene deletion, mutation in only parts of MECP2, and other causes that have not been identified. Even though Rett syndrome is a genetic disorder, only 1% of all recorded cases show that it passed on from one generation to the next making the mutations random and spontaneous.[4].

When it comes to the symptoms, it varies from person to person with some being more severely affected than others. The age at which symptoms first appear varies and the condition may change with age. Rett syndrome can best be described in four stages where certain characteristics do overlap. During the first stage, a child will usually develop and grow normally at least for the first six months, but there can be subtle signs. This stage occurs between 6 to 18 months with the symptoms lasting several months or more and sometimes referred to as “stagnation.” Symptoms include low muscle tone (hypotonia), difficulty in feeding, unusual, repetitive hand movements, or jerky limb movements, mobility problems such as with sitting, crawling, or walking, a delay in speech development, or a lack of interest in toys. The second stage is also referred to as “regression” or “the rapid destruction stage” where certain abilities are lost. This stage usually occurs between the ages of 1 and 4 years old and lasts from 2 months and up to 2 years. This is where severe problems will gradually begin to start with some of the characteristics being similar to autism. The child will struggle with communication and language, memory, mobility, coordination and other brain functions.

The third stage is also referred to as the “plateau” and begins between the ages of 2 to 10 years old and can last for years as those with Rett syndrome are in this stage for most of their lives. In this stage, some of the symptoms of stage 2 may see improvement such as improved behavior. Other areas of improvement include a greater interest in people and their surroundings, improvement in alertness, attention span and communication or walking ability. However, there are some negative symptoms such as being prone to seizures, or irregular breathing patterns, or difficulties in gaining and maintaining weight. The fourth and final stage involves deterioration in movement and lasts from several years to decades. Individuals can develop a curvature in their spines or scoliosis, lose the ability to walk, or have weakening and spasticity of muscles. [3]. As one can see, it can be a difficult road ahead for people afflicted with this condition. 

There are two ways in which Rett syndrome can be diagnosed by the doctors. It can either be done through a genetic blood test in finding the mutation of the MECP2 gene or simply by observing the development of the child and looking for the symptoms that are associated with it. Currently, there is no cure for Rett syndrome, but there are several ways to treat the condition. In 2023, a drug called Trofinetide was approved by the FDA in treating those with Rett syndrome. Trofinetide works by reducing swelling in the brain, increasing the amount of a protective protein in the brain, and stopping some cells from becoming too active and it is given to those who are two years old and older. [4]. Other treatments include speech and language therapy, physical therapy, physiotherapy, occupational therapy, hydrotherapy, music therapy, a back or leg brace, a hand splint, spinal surgery, or medicine.[3]. Treatment depends on the symptoms, as different solutions are needed for different issues.

The two people who made the discovery of Rett syndrome are Andreas Rett and Huda Zoghbi. In 1954, Dr. Andreas Rett, who was a pediatrician in Vienna, Austria, took note while observing two girls making the same repetitive hand-washing motions. Rett saw their clinical and developmental histories were very similar. He would go on to discover six other girls with similar behavior and even made a film about it. He also traveled throughout Europe to find children with similar symptoms and published his findings in 1966 in several German medical journals. Dr. Bengt Hagberg noticed some of the same symptoms present in some girls in 1960 and wrote an article on Rett syndrome naming it after Andreas and brought attention and raised the profile of this disease. [2]. Huda Zoghbi would be the one to discover the genetic basis of Rett syndrome. In 1983, she was able to diagnose two girls who had this disorder based on Dr. Hagberg’s depictions and it was a breakthrough because there were no clinical cases in the United States at that time.

Zoghbi published her first clinical studies in 1985 in determining the causes and risk factors. She developed an interest in genetic studies wanting to go down that path and found a mentor in Dr. Arthur Beaudet. Between 1991 and 1992, Zoghbi and other researchers were able to pinpoint the specific region where the gene mutation occurred after meticulous analysis. In 2000, they were able to find and determine that the underlying cause of Rett syndrome was the result of mutations in the methyl-CpG-binding protein MECP2.[1]. Thanks to the research and developments made, there is a better understanding of Rett syndrome and how to treat those with it. With more effective treatment, the life expectancy of those with Rett syndrome has increased and hopefully there will be a cure found one day. 

References:

[1]. Elliott, Ellen. “Women in Science: Huda Zoghbi Discovered the Genetic Basis of Rett Syndrome.” The Jackson Laboratory, www.jax.org/news-and-insights/jax-blog/2018/march/women-in-science-huda-zoghbi-autism#

[2.] “History of Rett.” International Rett Syndrome Foundation, 28 Feb. 2023, www.rettsyndrome.org/about-rett-syndrome/history-of-rett/

[3]. NHS Choices, NHS, www.nhs.uk/conditions/rett-syndrome/

[4.] “Rett Syndrome.” National Institute of Neurological Disorders and Stroke, U.S. Department of Health and Human Services, www.ninds.nih.gov/health-information/disorders/rett-syndrome