Rett Syndrome (RTT) is a unique neurodevelopmental disorder that manifests in infancy or early childhood . While it most commonly affects girls, it can also occur, albeit rarely, in boys. It is found in all races and ethnic groups worldwide.
The worldwide prevalence rate ranges from 1:10,000 to 1:23,000 live female births; meaning it is two to three times more common in women than phenylketonuria (PKU) , a congenital metabolic disorder for which every newborn in the US is tested. Rett is frequently associated with autism, cerebral palsy, and other related conditions. It is often misdiagnosed as palsy or nonspecific developmental delay. Although many healthcare professionals are not familiar with Rett’s disease , it is a relatively common cause of developmental delay in girls.
The probability and frequency of occurrence are similar in all races worldwide. It is not a disease specific to any particular race.
The clinical diagnostic phase , specialists will refer to a Rett Diagnostic Criteria Worksheet developed by leading authorities in Rett . Your child’s doctor will carefully examine early developmental milestones and their development during this period, and will assess their medical history and physical and neurological status. Finding a MeCP2 mutation is not mandatory at this stage. Your child may be evaluated in one of three categories:
Spoon Rett : those who meet the clinical diagnostic criteria.
Atypical Rett : Those who do not meet all of The classic diagnostic criteria for Rett Syndrome. Atypical. A diagnosis of Rett syndrome must include at least three of the primary criteria and five of the eleven supporting criteria. Atypical RTT accounts for 15-20% of all RTT
diagnoses.
Atypical RTT types include:
No. The stages of Rett Syndrome are provided only to facilitate understanding the natural history of the disorder. The course of Rett Syndrome is not predetermined, and the speed and severity of symptoms, as well as the age of onset, vary from child to child. Therefore, two girls of the same age can look very different from each other.
Rett syndrome was previously described as a neurodegenerative disorder with a poor prognosis and limited learning potential. Scientific research now defines Rett syndrome as a neurodevelopmental disorder that begins shortly before or immediately after birth, a crucial time for brain and synapse formation.
Studies have shown that although girls with Rett Syndrome have brains that are 30% smaller, they do not exhibit specific irregular formations, severe abnormalities, or signs of infection. There is an increased density of neuron clusters. This means that while cells should be spaced apart, in Rett Syndrome, because intercellular communication is poorly developed along the same pathway, the cells are very close together. Neuron sizes are reduced, and branching, which affects functions such as thinking, doing, and feeling, is diminished. The number of synapses (connections between brain cells) is about half of what it should be. The following clinical symptoms may result from abnormalities in multiple areas of the brain, but they have been observed in many girls with Rett Syndrome:
L- Dopa A synthetic form of dopamine . This drug has been shown to help prevent hardening (Stage 4) of motor retardation, but it does not provide sustained improvement .
Naltrexone ( Revia ) is an anti-drug medication used to calm the effects of drugs in addicts. It was tested in Rett Syndrome because girls with Rett Syndrome have high levels of naturally occurring brain chemicals called endorphins, which are drug-like substances, in their spinal fluid , and their reduced response to pain. Studies were limited to a dose of 1 mg per day and did not show dramatic results. However, independent studies have shown that using naltroxone in lower or higher doses can be beneficial in calming irregular breathing, seizures, and screaming fits. This may be due to the drug’s sedative effects. A negative aspect of this study was that during the periods when the drug was administered, there was a significant deterioration in Baylay tests, which measure child development, compared to patients given inert substances instead of medication, which is also likely due to the drug’s sedative effect. Another negative side effect is loss of appetite .
Bromocriptine ( Pardorel ) is a medication that enhances the function of the dopamine system in the brain . One trial resulted in improved communication, reduced agitation, and decreased hand movements in the first phase; however, symptoms reappeared when the medication was stopped, and the initial improvements were not repeated when the medication was restarted. This medication was found to be more effective in girls with milder symptoms.
Tyrosine ( dopamine and noradrenaline ) and Tryptophan ( serotonin ) They are amino acids and are used to stimulate neurotransmitter processes. Studies showed no difference in clinical performance or EEG patterns .
L- Carnitine is a derivative of essential amino acids and has frequently been found to be deficient in individuals taking anticonvulsants . In one single case, the child showed improvement in language and cognitive abilities. However, the child had atypical Rh factor ( RS) , and this situation did not recur in other cases. In a study of 35 girls, supplementation with carnitine (100 mg daily) did not lead to significant neurological improvement in the group as a whole. However, approximately 75% of the families participating in the study reported subtle but significant improvements in their quality of life during the period they used the medication, including increased attention, increased mobility, less daytime sleepiness, and a slight reduction in constipation. Some families reported that their daughters had spoken a word for the first time in several years. L- Carnitine It has been beneficial in increasing muscle tone in a large group of girls with RS . A beneficial side effect is loose stools. Experiments are still ongoing in large and diverse groups of girls with RS .
Clinical Evidence
Supporting Neurobiological Evidence
Rett syndrome is a neurodevelopmental disorder, not a degenerative disorder. Survival into adulthood is expected, provided there is no disease or complications.
Because MECP2 is an X-linked gene, it was previously thought that Rett Syndrome only affected girls. However, more is now known about the circumstances under which Rett Syndrome is diagnosed in boys.
Three possible genetic mutations that cause Rett Syndrome may occur in males:
MECP2 Duplication Syndrome
MECP2 duplication syndrome is a condition characterized by moderate to severe intellectual disability, more common in males than females. Most individuals with this condition have poor muscle tone , feeding difficulties, little or no speech ability, seizures that cannot be corrected with treatment, and muscle stiffness ( spasticity ) in infancy. Individuals with MECP2 duplication syndrome experience delayed development of motor skills such as sitting and walking. Some individuals may lose previously acquired skills (developmental regression). Approximately one-third of individuals with this condition cannot walk without assistance. Many individuals with MECP2 duplication syndrome experience recurrent respiratory infections . These infections are a significant cause of death in affected individuals, with nearly half succumbing to them by the age of 25.
MECP2-related severe neonatal encephalopathy
MECP2-related severe neonatal Encephalopathy is a neurological disorder primarily affecting males and causing impaired brain function. Affected males have a small head size ( microcephaly ), weak muscle tone ( hypotonia ) in infancy , movement disorders, stiffness (in muscles), and seizures. While infants appear normal at birth, severe encephalopathy develops in the first week of life. This condition leads to feeding problems, failure to gain weight, and stunted growth, resulting in developmental delay. Severe neonatal encephalopathy associated with MECP2 is a common symptom. Encephalopathy patients have severe intellectual disability. Affected males have respiratory distress, some with slowed or brief cessation of breathing ( apnea ). As the child gets older, apnea becomes more frequent, especially during sleep. Infants with this condition often use a breathing machine (mechanical ventilation ) to help regulate their breathing . Severe neonatal encephalopathy associated with MECP2. encephalopathy Most male infants born under this condition do not live to be two years old due to respiratory failure.
Atypical without MECP2 mutations What is known about Rett Syndrome?
CDKL5 Malfunction – http://cdkl5.com/ About -CDKL5/ Default . aspx
FoxG1 Syndrome – http://foxg1.com/ about -foxg1/
Dr. Steven from Greenwood Genetics Center can be found at the following link. You can listen to or view Skinner’s presentation titled “What are MECP2, CDKL5, and FOXG1 related to each other?” delivered at the 2016 Hope for Families conference .
Audio File: https://www.dropbox.com/s/ab4khjhqvxol31i/genetics%20101%20Skinner%20Fri%203pm.mp3?dl=0
Presentation: http://www.rettsyndrome.org/document.doc?id=345
Other possible disorders that may resemble Rett syndrome should be ruled out. These include Angelman syndrome and neuronal disorders. steroid lipofuscinosis Infantile forms are included. Girls with Rett syndrome often have autism and cerebral palsy. It is often misdiagnosed as palsy . Careful clinical evaluation can differentiate these disorders
The MECP2 gene mutation is most commonly found in Rett syndrome . Some children with this type of mutation may exhibit more typical features of autism. Rett syndrome is predominantly seen in girls, while autism is more common in boys. In both cases, speech and emotional contact are weakened. However, children who meet the criteria for Rett syndrome exhibit signs seen in autism , such as slowed head growth rate, loss of purposeful hand skills, and hyperactivity or irregular breathing patterns. Hand flapping is common in autism , while the repertoire of aimless hand stereotypes seen in Rett syndrome is not present in autism. A child with Rett syndrome almost always prefers people to objects, but the opposite is true in autism; that is, girls with Rett syndrome tend to form warmer relationships with people, while the opposite is true in autism. Unlike autism, a child with Rett syndrome is generally endearing. Children with Rett syndrome often exhibit autistic-like traits at an early age, but these traits disappear as they get older.
Most parents know their children better than anyone else. Often, parents who review the diagnostic criteria for Rett Syndrome can immediately recognize if the symptoms match their child’s. Review the Diagnostic Criteria Guidelines; if your child meets 3 of the main criteria and 5 of the secondary criteria, you can largely conclude that your child has Rett Syndrome. A definitive diagnosis requires expert opinion from genetic and neurodevelopmental specialists.
Rett Syndrome begins and the severity of symptoms vary from person to person. Children with Rett Syndrome exhibit normal or near-normal characteristics until 6-18 months after birth, when they begin to lose acquired abilities. After this period of normal development, a regression occurs, characterized by loss of communication skills, limited hand use, and slowed head growth . Stereotypical hand movements and gait disturbances also begin. Other problems that may arise during this period include breathing irregularities and seizures while awake. They may experience periods of extreme irritability or inconsolable crying. While motor problems increase over time , their eye contact and communication may improve, and improvements in seizures and irregular breathing may occur. Many individuals with RTT require intensive support to maintain their daily lives.
The most basic daily care activities will include feeding, bathing, dressing, toileting, and administering daily medications. We may need to lift and carry them, or help them walk, frequently change their positions, or change their bibs to address drooling. We may need to learn programs that improve communication with children. For this, we need to know how to use technological devices such as DVDs or MP3 players . We will need to learn how to find the right professionals, schedule appointments and therapies, research the right schools or programs, and arrange for special equipment.
We really need to pay close attention to how we do things and how those things affect us and the rest of our families. While we can’t eliminate RTT ( Random Threat to Things) today , we are facing the problems it creates. It’s important to do everything we can, but we also need to accept that we can’t do everything, that we can’t keep up with everything. We must keep in mind that accepting we can’t do everything and asking for help from others, from those close to us and our family, can make significant changes that will create a positive difference in our daily lives.
Rett Syndrome will need help with most activities necessary for daily living, but she can learn some independent skills. Many girls learn to use the toilet, and most can feed themselves with their hands or with some assistance, using a tool. Some girls can learn to use devices designed for communication. Despite their challenges, girls with Rett Syndrome continue to learn and can live happily with family and friends well into middle age and beyond. They experience all emotional stages and can express their personalities and themselves in social, educational, and recreational activities at home and in their environment.
RTT results from a chain of events beginning with a genetic mutation in MECP2. Mutations are always naturally present in everyone and usually don’t cause problems. A MECP2 mutation results in a deficiency or absence of the normal MeCP2 protein, which is necessary for the regulation or direction of other genes. These other genes affect or control the normal development of brain regions responsible for sensory, emotional, motor, and autonomic function , during the critical period when significant developments are expected to occur as the baby’s development begins . Development appears normal in early infancy until MeCP2-related regulation or control becomes necessary (until the MeCP2 protein is needed). Without these regulators (MeCP2 protein), proper development in selected brain regions will not occur. This explains why a child develops normally in the first few months of life.
The discovery of the MECP2 gene made it possible to develop a blood test for RTT. However, diagnosis of the disorder is still based on symptoms and clinical history.
Currently, approximately 85% of all patients diagnosed with RTT test positive for a MECP2 mutation in genetic testing. This does not mean that the remaining 15% do not have RTT . While a positive test result for a mutation confirms the diagnosis, it is not sufficient. It is possible that mutations are present in an as yet unsequencing area of MECP2, or that other genes contribute to the development of RTT even without MeCP2 mutations.
By 2004, the majority of mutations in MECP2 were identified by analyzing DNA sequences. This gene mutation was found in 80-85% of children who met the diagnostic criteria for RTT.
If we think of the MECP2 gene as a book with four chapters, mutations represent missing pages , extra pages , or pages in the wrong order. In some cases, one or two chapters may be missing. The correct term for chapters is exons ( exon = axis = codon = node). Most mutations have been found in exons 3 and 4 (MECP2 has four exons , but exon 1 is thought to be silent. (Translator’s Note: Girls have two X chromosomes; one becomes active and the other becomes passive during fetal development in the womb, in a way whose mechanics and causes are not yet known. This passive chromosome and the genes on it are called “silent” . In our girls, the MeCP2 on the active chromosome is mutated, but there is another properly functioning, unmutated one on the silent chromosome. Some of the treatment research focuses on trying to activate these silent genes.)
in MeCP2 that cause RTT have been identified. However, eight specific mutations are the most common, accounting for more than half of all individuals
with RTT . Since 2004 , a small number of mutations have been identified in exon 1 , but more importantly, the presence of large deletions has been detected. These large deletions mean the loss of one or more exons . These large deletions can be detected using a completely different method. Combining all this new information, it has become possible to detect MeCP2 mutations in 95% or more of girls undergoing genetic testing. In addition, MeCP2 mutations are now beginning to be identified in boys with RTT characteristics. MeCP2 mutations in boys can lead to more serious problems, including premature death.
If a child previously had a negative MeCP2 mutation test, it is recommended that they repeat the test in light of these new developments.
Mutations in another gene on the X chromosome known as CDKL5 (cyclin-dependent kinase -like 5) can cause an atypical Rett Syndrome called the early-onset seizure variant. These individuals usually have a negative MeCP2 mutation test result. Not everyone with a CDKL5 mutation will appear as atypical RTT; other CDKL5 disorders include Infantile Spasms, West Syndrome, Early-Onset Seizures, and Autism. CDKL5 mutation testing is not routinely available at most diagnostic laboratories . If you think your child should have this test, it is recommended that you discuss it with your pediatrician, neurologist, or geneticist. For more information… http://www.cdkl5.com
As with any other disorder, the level of disability ranges from mild to severe. It is difficult to predict the intensity of symptoms in any given child. While most children begin walking at the expected time, others may be significantly delayed or unable to walk independently. Some children begin walking and lose this ability later in life, while others continue to walk throughout their lives. Some children do not walk until late childhood or adolescence.
The clinical features of a particular trait or disorder constitute an individual’s phenotype . The gene for a specific trait or disorder leads to a person’s genotype . By comparing the two, we can correlate clinical features with a particular mutation. In Rett syndrome, this can allow us to make some predictions about the likelihood of developing scoliosis or epilepsy in the future , but much more data needs to be collected before we can make these predictions.
One way to grow our knowledge base is to contribute to InterRett – IRSF Rett. Phenotype Database https://interrett.ichr.uwa.edu.au/
This project, Rett It collects information from parents and clinicians about the characteristics of the syndrome . Then, this information is compiled to create an online searchable database.
The chance of having more than one child with Rett is less than 1%. This means that with a probability of more than 99.5%, the mutation will not recur in a family. In general, the bottom line on recurrence risks is: If you have one affected child and no other relatives with the condition, the risk of recurrence for your family (you and your children) is much lower than 1%. The situation is different for families with more than one child with Rett , and their condition needs to be addressed individually through a specialist genetic counselor.
Both parents can be tested for germline mutations before deciding to have another child. If a mother has a germline mutation, her daughters, who may appear unaffected, may also need to be tested when they reach reproductive age, as they could also be asymptomatic or silent carriers. Finally, prenatal testing of babies born into a family where Rett syndrome occurred is also an option. All of these options should be explored individually through a specialist genetic counselor.
Apraxia ( dyspraxia ), the inability (or reduced ability) of the body to program itself to perform gross motor movements (such as walking, running, climbing stairs, squatting, or fine motor movements like holding a spoon or touching with a finger), is the most fundamental and serious disadvantage of Rett’s . The mutation can interfere with every bodily movement , including vision and speech, making it difficult for individuals with Rett’s to accomplish what they want . Because of this apraxia and speech impediment, accurately assessing their intelligence is very difficult. Most traditional testing methods require them to use their hands and/or speak, which may be impossible for individuals with Rett’s . Their mobility may be delayed, and they may have difficulty crawling or walking.
Rett Syndrome is rare, little is known about long-term predictions and survival time. Most identified patients are under 18 years of age. Older girls or women are difficult to identify due to the lack of infant and childhood records, but studies indicate that a girl with Rett Syndrome has a 95% chance of surviving to age 20-25. This is comparable to the 98% survival rate for the general female population in the USA. The survival rate for ages 25-40 in Rett Syndrome drops to 69%, compared to 97% for the general female population in the USA. The average life expectancy for a girl diagnosed with Rett Syndrome can exceed 45 years. While there are likely many women in their 40s and 50s with Rett Syndrome, the number of women over 40 studied is very small, allowing for reliable predictions. These statistics show that while life expectancy in Rett Syndrome is lower, it is not as low as in similar neurological disorders.
It is important to note that only 5% of cases reported to IRSA have resulted in death. This means that 95% of those diagnosed are still alive. The most frequently reported deaths (about a quarter of the total) do not have a clear cause such as acute injury or infection; they are more often reported as “sudden death” or “death of unknown cause”. Factors that increase the risk of “sudden, unexplained death” in Rett Syndrome include uncontrollable seizures, swallowing difficulties, and lack of movement. In cases of sudden unexplained death, it does not matter whether there is physical or functional therapy, nutrition, or lifestyle. Among the reported deaths, pneumonia is the most common cause. Factors leading to death from pneumonia include lung dysfunction due to scoliosis and difficulty swallowing. Other causes of death include malnutrition, bowel perforation or twisting, as well as accidents and illnesses.
Although your daughter was more susceptible to life-threatening conditions such as pneumonia, choking, and seizures, she will most likely live a long life. However, we all carry the risk of many accidents and unexpected illnesses. The time will come when we will all die. Researchers are ready to listen, learn, and share. You can help us in our research to understand Rett Syndrome. Please consider participating in the autopsy investigations; this will be your daughter’s legacy to us all, and also a gift of help and hope to thousands of families.
Deep breathing means the body expels more carbon dioxide than normal, so hyperventilation causes carbon dioxide levels to drop. Carbon dioxide is a normal waste product of the body, carried in the blood. Its purpose is to maintain acid/alkali balance for the normal functioning of cells. When carbon dioxide levels drop, cells cannot function properly. Hyperventilation can lead to dizziness and tingling in the fingers.
When she holds her breath, the oxygen level in her blood vessels drops. This can cause her to feel like she is about to faint.
Abnormal breathing patterns can resemble epileptic seizures, but they are not seizures. Sometimes what is thought to be a seizure is not a seizure, and some seizures may go unnoticed while the person is asleep or even awake.
In most girls, irregular breathing becomes less noticeable as they get older. Hyperventilation is more common in younger girls with Rett Syndrome, while a type of breathing technique called Valsalva maneuver is more frequently seen in older girls .
Valsalva maneuver is the act of taking long breaths in and exhaling while keeping the airway closed (mouth and nose). It is performed by divers to regulate inner ear pressure. This causes a sudden change in blood pressure and heart rate. It is performed involuntarily by all people in situations such as ear blockage or breath-holding.
In cases of breath-holding, while it can be very worrying for parents to watch their children, these episodes are always followed by regular breathing. Observing irregular breathing can cause great anxiety, but parents specializing in Rett Syndrome suggest reacting more calmly, as they know that girls get used to these irregular breaths and regular breathing will return soon . Even though it may feel like it lasts forever, it’s important to remain calm and in control. Much research is being conducted to find answers to the causes of irregular breathing.
Rett Syndrome, irregular breathing usually occurs only while awake and is generally not observed during sleep. Abnormal breathing while awake is likely due to the immaturity of neurons that regulate breathing mechanisms. During sleep, changes in bodily function ensure regular and continuous breathing. In some girls with Rett Syndrome, abnormal breathing during sleep is often of the type that obstructs breathing and is usually caused by swollen tonsils. Airway obstruction may be due to mechanical problems in the breathing passages. Mouth breathing, snoring, and frequent ear infections may indicate that your daughter has a problem that requires evaluation by an ENT specialist.
From a parental perspective, monitoring this can be alarming and may disturb your daughter in some way, but it is not thought to cause permanent damage. It is not known why normal breathing during sleep, which is common in Rett Syndrome, leads to EEG abnormalities, and why abnormal breathing while awake appears normal on the EEG. Cessations of breathing during sleep are not typically seen in Rett Syndrome. However, if your child’s breathing stops briefly while sleeping, you should consult their doctor. Testing may be necessary to determine if there is an airway obstruction (such as adenoids or swollen tonsils). This is a separate, treatable problem from Rett Syndrome.
Swallowing air can be difficult. Air may be swallowed in small amounts with each meal, or in smaller amounts throughout the day. Sometimes it’s easy to hear the air being swallowed. If your upper abdominal area swells shortly after eating, you may be swallowing air. Below you will find some signs and symptoms of swallowing air.
If a large amount of air temporarily remains in the stomach, it leads to sudden swelling of the upper abdominal area. The stomach stretches, creating a certain tension. If a girl with Rett Syndrome cannot burp or pass gas, the intestines may thin over time. This is especially true for those who are not well-nourished. Excessive swelling of the stomach wall can lead to rupture. Many cases of gastric rupture have been reported in girls with RS . A single rupture of the stomach or intestines can lead to peritonitis , an acute burning and infection of the abdominal cavity. Peritonitis can be fatal if not treated immediately. However, although gastrointestinal problems are common in RS2, severe cases are rare.
If air passes properly into the intestines, gastric bloating is less of a problem. However, it can collect in the middle of the intestine and cause abdominal swelling and uncomfortable cramps. Medications that slow constipation and stool passage can worsen abdominal bloating.
Your child should have an ECG at age 5. If it’s normal, it should be repeated every two years. If it’s abnormal, a cardiologist, an expert in the electrical function of the heart, should be consulted.
If irregularities appear on the electrocardiogram, you can consult a cardiologist. Unclear ECG changes will likely not require medication.
