What is Rett Syndrome?
Rett syndrome, often abbreviated as RTT, is a disorder affecting brain development. This condition causes children to lose skills they had learned after a period of normal development. Some of the many symptoms of RTT can include slower head growth, walking difficulties, and loss of hand movements which are often replaced with repetitive motions like hand-wringing. Other symptoms may include loss of speech and irregularities in breathing.
RTT is a complicated condition and can show itself in different ways. There are typical, atypical, and variant forms of RTT. About 90% of the known cases of RTT are due to changes (mutations) in a specific gene called the methyl-CpG-binding protein 2 (MECP2). Changes in a different gene, known as cyclin-dependent kinase-like 5 (CDKL5), can lead to some atypical cases of RTT.
Changes in the MECP2 gene can interfere with the development of nerve cells and the connections between them. In 1986, neuropathologists, scientists who study diseases of the nervous system, Jellinger and Seitelberger were the first to identify and describe the physical changes or pathology, of RTT. They observed that the brains of RTT patients weighed less, and the nerve cells in a part of the brain called the substantia nigra pars compacta had less melanin compared to people of the same age who do not have RTT.
Interestingly, while RTT was initially thought to only affect females, males with the same gene mutations and symptoms are now being identified.
What Causes Rett Syndrome?
Rett syndrome (RTT) is a medical condition that mostly occurs with a genetic mutation that is inherited in a manner linked to the X chromosome. This means it can have lethal outcomes for boys who only have one X chromosome. Most classic RTT cases happen due to mutations in a gene known as MECP2. However, new studies have found that two other genes, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1), also play a role in bringing about RTT.
There are different types of genetic alterations linked with RTT, including missense, nonsense, and frameshift mutations. Missense mutations are when one DNA code letter is mistaken for another, nonsense mutations are when an alteration in the genetic code leads to an early stop signal and frameshift mutations are when genetic code letters are deleted or inserted changing the reading frame. It’s important to realize the effects of the mutations can vary significantly. For example, mutations affecting the region known as NLS in the MECP2 gene or early truncating mutations generally lead to a more serious form of RTT compared to missense mutations. Also, mutations that lead to the loss of a part at the end of the gene (C-terminal deletions) are often associated with less severe forms of RTT. In particular, a specific mutation known as R133C often results in a less severe form of RTT, with patients often retaining the ability to speak.
The MECP2 protein, which is created by the MECP2 gene, has two main functions at the cell level. The first is the methyl-binding domain that specifically attaches to chemically marked (methylated) sites in our DNA. The second function is the transcription repression domain that helps attract proteins that block the process of turning genes into functioning proteins. A mutation in another gene on the X chromosome known as CDKL5 can cause a form of RTT where seizures are a major symptom.
A critical point to remember is that the severity of the disease can vary widely depending on the type of mutation. Close to 30 different types of mutations can potentially cause Rett Syndrome.
Risk Factors and Frequency for Rett Syndrome
Rett Syndrome (RTT) is a prominent cause of mental disability among girls, with 1 in every 10,000 to 15,000 girls affected. A study conducted in Texas found that, among every 22,800 females aged between 2 and 18, 1 suffers from the classic form of RTT. Initially, this disorder was believed to only affect females, and males diagnosed with RTT were presumed to be non-survivable. Hence, more studies are required to understand the occurrence rate and prevalence of RTT in males. A review in 2015 reported 57 cases of male RTT patients in Texas, showing that no specific racial group is more predisposed than others.
- Rett Syndrome (RTT) is a common cause of mental disabilities in girls, affecting 1 out of every 10,000 to 15,000.
- A Texas-based study found that 1 in every 22,800 girls aged 2-18 develop classic RTT.
- RTT was historically thought to only affect girls.
- More studies are needed to determine the prevalence of RTT in boys.
- A 2015 review found 57 cases of RTT in boys in Texas.
- No specific racial group has a higher risk of developing RTT in males.
Testing for Rett Syndrome
Just having MECP2 mutations doesn’t guarantee a diagnosis of Rett syndrome (RTT). This condition is usually diagnosed based on observed symptoms, and can be divided into typical or atypical forms.
For typical Rett syndrome, certain symptoms must be present. There has to be a noticeable decline or regression in using hands purposefully or loss of spoken language, which usually leads to repetitive movements like hand-wringing and abnormal walking patterns. After this regression period, the condition generally stabilizes and sometimes even shows slight improvements. Also, it’s important to note that not everyone with typical Rett syndrome will experience slowed head growth after birth.
In atypical Rett syndrome, regression is still a requirement, but diagnosis needs two out of four main symptoms and five out of eleven supporting symptoms.
These diagnostic criteria apply to both men and women.
Treatment Options for Rett Syndrome
Rett syndrome (RTT) is a condition currently without a cure, but its symptoms can be managed through various medical approaches. Many patients with RTT experience symptoms like seizures, behavioral changes, sleep problems, unusual breathing patterns, heart issues, digestive difficulties, and bone fractures.
About 60% of people with RTT have some form of seizures. Medicines such as valproate, lamotrigine, levetiracetam, carbamazepine, and AEDs can help manage these seizures. Regarding behavioral changes, which often include anxiety, certain medications called serotonin reuptake inhibitors (SSRIs) can be beneficial.
Patients with RTT often struggle to fall asleep and tend to wake up many times at night. A combination of good sleep habits and certain medicines like trazodone can help, once other causes such as obstruction in the airway have been eliminated.
Unusual breathing patterns, including not breathing (apnea), fast breathing (hyperventilation), or holding the breath, often occur in RTT. It’s tricky to manage these problems, but it’s recommended to avoid medications that might further alter breathing patterns, like opioids.
Patients with RTT may also have heart problems, like a longer gap in the heartbeat (prolonged QT interval). The treatment for this in RTT patients can be more complex than in typical patients. Certain medications, like macrolides, should be avoided because they can further prolong the QT interval. Bone fractures are more frequent in people with RTT than in the general population, so it’s crucial to check vitamin D levels regularly and add supplements if necessary. Digestive problems like gastroesophageal reflux disease (GERD, a chronic disease where stomach acid goes into the esophagus) and constipation are common, but can be managed with calcium carbonate, histamine H2 receptor blockers (but cimetidine should be avoided), and an increased intake of fiber.
Physical therapy, speech therapy, occupational therapy, and psychosocial support for families can also be beneficial for those with RTT. By effectively managing these symptoms, the quality of life of those living with RTT can significantly improve.
What else can Rett Syndrome be?
Rett syndrome (RTT) is a medical condition that can sometimes be mistaken for other disorders. It’s important for medical professionals to consider and rule out other possibilities, such as:
- Cerebral palsy
- Autism
- Angelman syndrome
- General developmental delays
What to expect with Rett Syndrome
The lifespan of someone with Rett syndrome (RTT) can differ based on the specific type of MECP2 mutation they have. This mutation refers to changes in a specific gene that affects brain development and function. Generally, people with RTT live into middle age. However, recent research suggests they may live even longer.
