Welcome

Hello and welcome to my blog. My name is Leah and I am a junior at the University of Illinois. My hope is to one day become a Clinical Neuropsychologist, who uses genetics as a complement to the research and practice of clinical neuropsychology. This blog was designed with the general public in mind. My hope is to be able to provide easily accessible information about Rett Syndrome, so that they may better understand this genetic neurodevelopmental disorder. This blog is my final project for part of a summer class.

Brief Introduction, History, Symptoms, and Diagnosis

Brief Introduction

Rett is an autism spectrum disorder that mainly effects girls.

First, I want to provide you with a brief introduction to Rett Syndrome. Rett syndrome is classified as an autism spectrum disorder. It is a neurodegenerative disease, meaning that the child with the disorder will develop normally, hitting all major developmental milestones, for about 6 to 18 months. Then the child will regress, and lose verbal, motor, and cognitive abilities. Many people with Rett Syndrome are non-verbal, and communicate with an intense stare. There is also a hand wringing gesture, which becomes more common as the child loses purposeful hand movements. Many other symptoms, which will be discussed at a greater length, accompany this disorder.
The thing that intrigued me about Rett Syndrome is that it mainly occurs in girls. Most boys born with Rett syndrome will die prematurely. Genetic research  provided the answer as to why girls are able to survive with Rett while boys are typically unable to live with the condition.   It occurs in one in every 10,000 to 15,000 live female births. All socioeconomic, racial and ethnic groups are affected by this disorder. It is unlikely (about 1%) that a family will have a second daughter with Rett Syndrome. There are family cases of Rett Syndrome, which account for about 1% of all total cases of the disorder. There are many familial cases occur in Northern Tuscany, islands of Western Norway, and Sweden. If you have a child with Rett Syndrome prenatal testing is available, since we know the genetic cause of Rett Sydrome to detect if a second child has the disorder.

History

Rett syndrome was first described in 1966 by a doctor named Andreas Rett. . He noted two young girls rocking back and forth and constantly wringing their hands, which is the  stereotypical hand movement of Rett syndrome. He was able to find 6 other patients with similar symptoms. In 1966, he reported on studies of 22 different girls. A lack of an English description of the disease contributed to a lack of interest in the disorder. Dr. Rett contributed publications in Germany from 1966 to 19695. In 1972, a German publication recorded the disease as Rett Syndrome. In 1977, Dr. Rett provided a more extensive English description of the disorder. More cases of girls with similar symptoms awakened interest in the English speaking world, and the disorder received recognition. Today, it is a well-researched disorder that has a clear genetic origin and well described symptoms.

Example of the handwringing gesture observed by Dr. Rett. 

Diagnosis and Symptoms

Rett syndrome can either be diagnosed by assessing clinical criteria, or with genetic testing. Most commonly the physician will use the clinical criteria, and then may use a genetic test to confirm Rett Syndrome. The tests look for a mutant (altered) copy of the MeCp2 gene.

To diagnosis a child with typical or classical Rett Syndrome, there must be a period of growth followed by regression, there must be all of the Main criteria present, and none of the exclusion criteria, and it is likely that some of the supporting criteria is present, but it is not needed for a diagnosis of Classical Rett Syndrome. In contrast, a diagnosis of Aptypical Rett Syndrome involves a period of regression followed by a recovery or stabilization, at least 2 of 4 main criteria, and 5 of 11 of the supportive criteria. Below the main, exclusion, and supportive criteria are listed:

• Criteria Main Criteria
• Partial or complete loss of acquired purposeful hand skills
•  Partial or complete loss of acquired spoken language
•  Gait abnormalities: Impaired or absence of ability
•  Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing 
• Exclusion criteria for typical Rett
•  Brain injury after trauma , neurometabolic disease, or severe infection that causes neurological problems
•  Grossly abnormal psychomotor development in first 6 months of life
• Supportive criteria for Rett
•  Breathing disturbances when awake
•  Bruxism (clenching or grinding of teeth) when awake
•  Impaired sleep pattern
•  Abnormal muscle tone
•  Peripheral vasomotor disturbances (problems with cold, blue hands and feet)
• Scoliosis/kyphosis (curving of spine)
•  Growth retardation
•  Small cold hands and feet
• Inappropriate laughing/screaming spells
•  Diminished response to pain
• Intense eye communication

Typical Rett syndrome tends to follow a course, or stages. The stages are outlined below

At first, it is not obvious that a child has Rett.

•  Stage 1 – Early Onset Stagnation Period
• Starts at 6 to 18 months 
•  Not often noticed
•  Less eye contact, less interest in toys, may need less attention, may be irritable and restless
•  May be delays in skills like sitting or crawling, but it is not very noticeable
• Lasts for a few months, but can last for over a year
• Stage 2- Rapid Development Regression Period
• Starts between 1 year to 4 years
• Can last weeks or months
• Hand skills and expressive language can be lost
•  Abnormal Hand movements begin
• Breathing irregularities and irritability
•  Loss of social interaction and communication
•  May have unsteady walking gait and trouble starting movements
•  May develop seizures
• Decline of head growth can be noticed
• Stage 3- Pseudo-stationary Period
•  Starts between 2 and 10 years
•  Lasts most of life
• Apraxia, or being unable to perform complex movements and seizures are common
•  Impairments in hand functioning become more obvious
• Behavior like irritability and crying may improve
•  May have more interest in outside world
• May make better eye contact and use gaze to communicate
•  May start to learn about new things

  

  A child  who has lost mobility due to Rett.

• Stage 4- Late Motor Deterioration Stage
•  Can last for years or decades
•  Starts when ability to move around is lost
•  Characterized by muscle weakness, rigidity (stiffness), spasticity (uncontrolled muscle activity), dystonia (increased muscle tone with abnormal posturing of extremity or trunk) and scoliosis (curvature of the spine)
•  Hand movements become less intense
•  Eye gaze continues

MeCP2 and Treatment

MeCP2

The development of genetic and genomic research has clarified much of the mystery surrounding Rett syndrome. Rett syndrome is a purely genetic disease. Because of genetic research, we know how Rett syndrome occurs, and why symptoms occur. In the coming years, new treatments and gene therapies will be developed to reduce symptoms and potentially provide a cure. 
Through genomic research, Rett Syndrome has been linked to the X chromosome, which is one of the sex chromosomes. A chromosome is a large strand of DNA. DNA is like an instruction booklet for an organism. DNA has an alphabet of A,T, C and G. Most cases a mutation occurs in the MeCp2 gene. A gene is a specific set of instructions, written in the A, T, C, and G alphabet, that serves a specific purpose. A mutation is a change in that specific set of instructions. There is no single type of mutation that causes Rett Syndrome. It has been revealed that MeCp2 is a highly important gene, so important that it has remained the same in other species like rats and mice. Because we know that MeCp2 is linked to Rett syndrome. Researchers can cause mutations in other species like mice, to make a model for the disease. Mouse models have been very useful revealing how an organism develops with a mutated copy of MeCp2.Mice that have a mutation in MeCp2 develop tremors, breathing abnormalities, jaw misalignment, and have smaller less dense neurons, which are brain cells, similar to humans with the disease. 

Examples of other organisms withe MeCp2.

Since research has shown that it is a mutation in MeCp2 that causes Rett Syndrome. Rett is not condition that is typically passed down through families. Most of the time the mutation occurs in father’s X-chromosome, in the sperm cell. This means that the mutated cell is only passed on to the child, but is not present in the parent. However, there are familial cases, but it is only in 1% of the cases. Fortunately, most cases are sporadic and not inherited. Typically, having one child with Rett does not signal that another child is at risk for having the disorder. 
The MeCp2 gene produces a very important protein that is a necessity in regulation of genes. MeCp2 protein binds to certain genes to block DNA from being transcribed, which means copied into RNA which is then translated, or made into proteins, which perform many different functions in the cell. With a properly functioning copy of MeCp2, protein is made in the proper ratios for a healthy organism.

MeCP2 binds to BDNF promotor III. This represses function of the BDNF gene, which is involved in brain development. It is required for the development and maturation of neurons. Mecp2 binds to genes in a methylation-dependent manner. This means that methylation, which is the addition of methyl group to a gene,  acts like a chemical tag that signals to MeCP2 to bind to that gene.

An illustration of MeCp2 binding to DNA

The mouse on the right has been altered to have Rett Syndrome. It has odd paw movements, and over grooms

The FXYD1 promotor  is a target for MeCP2 to bind to. In mice models it was found that there was increased expression of FXYD1 is found in those with Rett Syndrome, and it is associated with poorer quality brain cells . MECP2 also represses the ANT1 gene. It has also been found in mice that those with a mutated MeCP2 allele had more anxiety and an abnormal stress response, similar to Rett patients. In mice, mutant MeCP2 did not bind to the promoter of CrH. Too much CrH may be related to Rett Syndrome. MeCp2 is not working properly, there is widespread abnormal gene transcription, leading to Rett Syndrome .
RTT syndrome is mainly found in females. Females are able to survive with impairment as they have a functional copy of MeCP2, as females have two X-chromosomes. The mutant copy MeCP2 causes more damage to development, as they only have one x chromosome. This normally results in death in infancy or early childhood.

Structurally, there are two main parts that have a main function for MeCP2. One is 85 amino acid, which is the substances that make up proteins, long methyl-CpG binding domain (MBD). MBD is essential for binding to DNA. The second is a 104 amino acid long transcriptional repression domain (TRD). TRD causes transcriptional repression, which prevents RNA copies from being made. . When a mutation occurs, the MBD can change and the function will be interfered with. Many mutations lead to partial or complete loss of functioning of MeCP2.

Twin studies have revealed interesting information about Rett syndrome It has pointed to the fact that Rett syndrome may be lethal in males. It has also been used to investigate the different types of mutations of MeCp2. Interestingly, the severity of Rett syndrome is linked with the type of mutation in MeCp2. This has been discovered due to DNA sequencing technology. Mutations in which a single A, T, C or G is changed, added, or missing, are linked with a relatively less severe case. In contrast, mutations that cause a large change in sequence size to the MeCp2 sequence lead to a more severe case of Rett Syndrome. The studies have also shown that twins can have the same mutation of MeCP2, and have slightly different cases of Rett Syndrome.



Illustration of the MeCP2 gene

Treatment

Many people with Rett have scoliosis or curving of the spine.

There are no cures for Rett syndrome. It can be managed, and the symptoms can be reduced. Physical therapy is used to improve or maintain mobility, and balance, and to reduce misshapen limbs, and back. Occupational therapy is used to improve use of hands, to reduce the hand-wringing gesture, and to teach the girls how to do self-directed activities, like eating or brushing hair . Dietary changes include the use of calcium and minerals to slow scoliosis and strengthen bones, the implementation of high fat, high calorie diets in increase height and weight, and a feeding tube. Braces and surgery are used to correct scoliosis and splints to adjust hand movements. Medication is used to reduce breathing problems, eliminate abnormal heart rhythm, relieve indigestion and diarrhea, and to control seizures.

Animal models are being used to come up with therapy. In a mouse model, researchers were able to find that loss of function of MeCp2 causes abnormal brain cell growth. A potential gene therapy has been found using mouse models. It was found that injecting mice with AAV9, may stabilize the symptoms or reverse them. Another study found that fat metabolism is perturbed in brains and livers of mice with Rett Syndrome. Drugs were able to improve fat metabolism, improve motor functioning and help with longevity in the mice. Additionally improvement was found in mouse models when given the drugs Levodopa and Dopa-Decarboxylase Inhibitor. Mouse models are often used to investigate the role of oxidiate stress, or damage caused by reactive oxygen in the body, in  those with Rett Syndrome, and to develop interventions. There needs to be more research done to come up with a cure in humans.

This mouse has been genetically modified to have Rett Syndrome.