Rett syndrome is a distinct neurodevelopmental disorder that emerges after a period of apparently normal early development. It is a rare condition, affecting approximately one in every 10,000 to 15,000 live female births, and is characterized by a progressive loss of motor and language skills. The disorder is almost exclusively caused by mutations in a specific gene known as MECP2. These genetic changes disrupt the normal course of brain development, leading to the wide-ranging symptoms associated with the condition.
The Normal Function of the MECP2 Gene
The MECP2 gene provides instructions for creating a protein called methyl-CpG-binding protein 2 (MeCP2). This protein is abundant in the brain and helps control the activity of other genes. The MeCP2 protein acts as a master regulator, binding to DNA to turn genes on or off, ensuring they produce proteins at the right time and in the correct amounts.
This regulatory function is important for the development and maturation of nerve cells (neurons). The MeCP2 protein plays a role in forming and maintaining synapses, the connections between neurons that allow them to communicate. By managing gene expression, the MeCP2 protein ensures the brain’s network develops and functions correctly. It is also involved in processes like alternative splicing, which allows a single gene to code for multiple proteins.
How MECP2 Mutations Lead to Rett Syndrome
In nearly all cases of Rett syndrome, a mutation in the MECP2 gene results in a MeCP2 protein that is either non-functional or produced in insufficient quantities. Without a properly working MeCP2 protein, the regulation of gene activity in the brain is lost. This disruption impairs the expression of other genes needed for brain development, which affects the growth, maturation, and connection of neurons.
The vast majority of these mutations are de novo, meaning they are spontaneous and not inherited from the parents. They occur randomly around the time of conception. Rett syndrome predominantly affects females because the MECP2 gene is on the X chromosome. Females have two X chromosomes, while males have one X and one Y.
In females with a MECP2 mutation, a process called X-chromosome inactivation randomly turns off one of the two X chromosomes in each cell. This means some cells use the healthy MECP2 gene, while others use the mutated copy. This mosaic pattern of gene expression allows for survival but results in the symptoms of Rett syndrome. For males who inherit a severe MECP2 mutation on their single X chromosome, the absence of a healthy copy is often not compatible with survival beyond early infancy.
Clinical Progression and Symptoms
The clinical course of classic Rett syndrome unfolds across four stages. The first signs can be subtle, appearing between 6 and 18 months of age. This initial phase, Stage I, is marked by a slowing of development, where a child may show less interest in play or make less eye contact.
Stage II, the rapid destructive stage, is when more recognized symptoms emerge. This period involves a significant regression, characterized by the loss of purposeful hand skills and spoken language. This stage is also when the hallmark symptom appears: stereotyped, repetitive hand movements, such as hand-wringing or clapping.
Following regression, the individual enters Stage III, the plateau stage. In this phase, some behavioral improvements may be seen, with less irritability. However, motor problems persist, and many individuals experience seizures and breathing irregularities. Apraxia, the inability to perform familiar movements on command, becomes more prominent, affecting coordination.
The final stage, Stage IV, is the late motor deterioration stage. Mobility becomes further reduced, and many individuals lose the ability to walk. Muscle weakness, rigidity, and spasticity can increase, leading to joint deformities and scoliosis. Despite the motor impairments, cognitive and receptive communication skills often remain, allowing individuals to express a wide range of emotions.
The Diagnostic Process
The diagnosis of Rett syndrome begins with clinical observation. A physician, often a pediatric neurologist, assesses a child’s developmental history for the characteristic pattern of symptoms. This involves noting the regression in skills, particularly the loss of purposeful hand use and spoken language.
To formalize the diagnosis, clinicians use established diagnostic criteria. These guidelines outline the features required for a diagnosis of typical or atypical Rett syndrome. The presence of repetitive hand movements and the loss of acquired skills are central to the clinical diagnosis, with supportive criteria including breathing disturbances and seizures.
While a clinical evaluation can strongly suggest Rett syndrome, a definitive diagnosis requires genetic testing. A blood test screens for mutations in the MECP2 gene, and finding a pathogenic mutation confirms the diagnosis in most cases. It is possible for an individual to meet the clinical criteria for Rett syndrome without an identifiable MECP2 mutation, as other gene mutations can cause similar symptoms.
Therapeutic Approaches and Research
There is no cure for Rett syndrome, so treatment focuses on managing symptoms and providing supportive care to improve quality of life. A multidisciplinary approach is necessary and includes:
- Physical therapy to address motor difficulties and prevent contractures.
- Occupational therapy to help with hand function and daily living activities.
- Speech-language therapy to foster non-verbal communication methods.
- Nutritional support to manage chewing and swallowing difficulties and ensure adequate growth.
- Medications to control seizures and manage other medical issues like breathing irregularities and gastrointestinal problems.
A significant development in treatment was the FDA approval of trofinetide (Daybue), the first drug specifically for Rett syndrome. This medication is thought to work by reducing inflammation in the brain and promoting the function of synapses, addressing some effects of the MeCP2 protein deficiency. Clinical trials showed it can help improve some core symptoms of the disorder.
Future research is focused on addressing the root genetic cause of Rett syndrome. Gene therapy is a promising area of investigation, with the goal of delivering a functional copy of the MECP2 gene to the brain’s cells. Other strategies being explored include RNA-based therapies that could help correct the errors in the message transcribed from the mutated gene. These approaches may provide more transformative treatments.