Rett Syndrome

Rett syndrome is an early-onset neurodevelopmental disorder that results in severe cognitive and physical disabilities. It predominately affects females, with symptoms often initially presenting in infancy after a period of typical development.

It is estimated that 1 in 12,000 girls are born with Rett syndrome every year, and it is the second most common cause of female intellectual disability (after Down syndrome). However, Rett syndrome is often undiagnosed or misdiagnosed due to its rarity and certain symptomatic similarities with other conditions, such as cerebral palsy and autism. Therefore, it is difficult to determine the true frequency of Rett syndrome in the general population.

What Causes Rett Syndrome?

Approximately 90% of cases are attributed to mutations in the MECP2 gene which is found on the X chromosome. The MECP2 gene produces a protein (MECP2) which is present throughout all human tissue but is particularly abundant in neurons in the brain, playing an important role in neuronal activity and brain development. Currently, approximately 800 different Rett-causing MECP2 gene mutations have been identified. The mechanism of how MECP2 gene mutations lead to the clinical features of Rett syndrome remains uncertain.

Symptoms and Stages of Rett Syndrome

The severity and age of onset vary between children with Rett syndrome, but there are 4 stages of classical Rett Syndrome:

  1. First signs (6–18 months old) – Initially babies with Rett syndrome appear to develop and grow as expected, although there may be subtle signs which become apparent with hindsight e.g., difficulty feeding, mobility problems, jerky limb movements, and low muscle tone. This stage often lasts several months.
  2. Regression (1–4 years old) – Symptoms start to deteriorate with gradual or sudden development of communication, memory, mobility, and coordination problems e.g., repetitive hand movements, social withdrawal, periods of distress, and unsteadiness when walking. This stage may last from 2 months to upwards of 2 years.
  3. Plateau (2–10 years old) – Stage 2 symptoms may improve, with the child demonstrating interest in their surroundings, reduced irritability, and improved communication and walking. However, seizures and irregular breathing patterns can worsen. This stage often lasts for many years, with children remaining at this stage for most of their lives.
  4. Movement deterioration – Main symptoms include the development of scoliosis, muscle weakness, and the inability to walk. Communication, language skills, and brain function do not tend to worsen. This stage can last years/decades. 

Why Does Rett Syndrome Mainly Affect Women?

There is usually no family history of Rett syndrome; almost all cases are spontaneous with the mutation occurring randomly. Girls have 2 X chromosomes (only one is active in any given cell), therefore these patients will be heterozygous for the mutation, carrying one normal and one mutated copy of the gene. The severity of Rett syndrome in girls is partly determined by the percentage of cells that express the mutated copy of the MECP2 gene. Meanwhile, boys only have 1 X chromosome. With no backup copy that can compensate for a defective MECP2 gene, boys experience severe problems when they are first born and die shortly after birth.

Living with Rett Syndrome

Currently, there is no cure for Rett syndrome and treatment focuses on symptomatic relief for patients through a multidisciplinary approach.

Some symptoms requiring management include epilepsy, behaviour changes, sleep disorders, breathing irregularities, cardiac dysfunction, gastrointestinal dysfunction, and bone fractures. Consequently, people with Rett syndrome are often provided with anti-epileptic drugs, beta-blockers, occupational therapy, speech and language therapy, and physiotherapy for example.

Although some people with Rett syndrome retain a certain degree of hand control, walking ability, and communication skills, most will be dependent on 24-hour care throughout their lives. Many people with Rett syndrome reach adulthood, and those with mild forms of the disease can live into old age. However, complications can often occur such as heart rhythm abnormalities, pneumonia, and epilepsy which result in some people with Rett syndrome dying at a young age.

The Gender Research Gap of Rett Syndrome

One of the most recent and promising advances is NGN-401, new gene therapy in the pipeline from Neurogene. NGN-401 has been demonstrated as a safe therapy in mice with a form of Rett syndrome that prolongs lifespan and reduces disease burden. However, it must be noted that this study exclusively used male mice – this is commonplace in Rett syndrome research despite the disorder primarily affecting girls.

Historically, women were often excluded from clinical studies because sex wasn’t considered a major health factor and women were deemed too variable to study due to their monthly hormonal cycle. For years researchers have generalised data collected from men and applied it to women despite fundamental biological differences. The women’s health movement has pushed against this, and today, more than half of the National Institute of Health (NIH) funded clinical trial participants are women.

However, in preclinical work with animals and cells, the preference for male models is still strong. Familiar reasons are cited for the general exclusion of female animals, such as their regular hormonal fluxes making data unreliable due to less predictable behaviour and physiology. However, these characteristics have been further investigated and can now be accounted for in preclinical trial results, negating this as a valid reason for the omission of female subjects.

Like men and women, male and female rodents have unique sex-based characteristics. Specifically, regarding Rett syndrome, male mice are often preferred because symptoms are more severe, develop sooner, and are easy to detect. The varying proportion of normal vs. mutated copies of the MECP2 gene in female mice can also result in male mice being chosen for mechanistic research. This bias may lead to researchers overlooking valuable data regarding Rett syndrome. Rett mutations usually take longer to affect female mice and this slow onset, similar to that seen in human Rett syndrome patients, provides an important opportunity to study how Rett syndrome changes behaviour and brain function over an entire lifetime.

Ultimately, Rett syndrome is an incredibly complex disorder, and it is believed that an eventual cure will rely on multiple treatments including gene therapy, medication, and neurohabilitative therapies. Further research is required to elucidate the mechanisms that underlie this disorder to be able to move a step closer to developing a cure for Rett syndrome, as well as novel therapies for symptom management and diagnostic methods.

Raising Awareness of Rett Syndrome

Rett syndrome is a life-long debilitating condition which requires round-the-clock care, therefore we must be advocates for these girls and women who often cannot raise awareness of their experiences and condition themselves. Not only does it have a gruelling effect on the patient, but their families who provide continuing care also require support to be able to deal with this physical and emotional challenge. Further research, education, and awareness are key to helping improve the futures of those with Rett syndrome and their families.

Links to Learn More:

For more information and support: https://www.rettuk.org/

Discover Ms. Coenraads determination to find a cure for her daughter: https://www.nytimes.com/2020/07/07/health/rare-diseases.html

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