Rett disorder, which is also known as Rett syndrome or RS, belongs to a group of childhood disorders known as pervasive developmental disorders (PDDs) or autistic spectrum disorders. It is classified by the mental health professional’s handbook (the Diagnostic and Statistical Manual of Mental Disorders or the DSM-IV-TR) as a developmental disorder of childhood. Rett disorder is characterized by an early-onset slowing of the infant’s head growth and a reduction in brain size by as much as 30%. It is the leading cause of genetically based profound mental retardation in girls.
RS was first described by an Austrian physician, Andreas Rett, in 1966; prior to 1983, however, little was known about the syndrome because it was quite rare. Although RS was thought at first to result from the destruction or degeneration of brain tissue, genetic research has indicated that it is caused by the failure of the infant’s brain to develop normally. This developmental failure is in turn caused by a genetic mutation affecting production of a key protein that regulates brain development. In addition, it was previously
reported only in girls, but males who carry an extra X chromosome with a gene mutation related to the syndrome have also been identified as having characteristics of the disorder.
Rett disorder has a distinctive onset and course. In classic Rett syndrome, which occurs only in girls, the child develops normally during the first 6 to 18 months of life. In many cases, at around the fifth month, head growth slows or stagnates, and she loses whatever purposeful hand movements she had developed. Language and motor skills then regress rapidly. Purposeful hand use gives way to repetitive hand-washing or hand-wringing gestures. Seizures occur in up to 90% of affected girls, and 50-80% of children with the disorder will eventually develop epilepsy. Screaming fits and crying are features that arise by age 18 to 24 months. The disorder can also include characteristics of autism , tremors, and paniclike attacks. Rett disorder is also associated with severe or profound mental retardation.
Some atypical forms of Rett syndrome, including congenital, late-onset, and preserved-speech Rett, are now being diagnosed as people formerly diagnosed with other disorders, such as autism or learning disability, are confirmed to carry the genetic mutation linked to Rett syndrome. In addition, males who have inherited an extra X chromosome and are carrying the mutation, or in whom the gene is mutated very early in their development, can manifest a form of the disorder. The features of this form of Rett may not be as severe in nature because only some of the person’s cells will carry the mutation. Males normally inherit only one X chromosome. Those whose single X chromosome carries the mutation usually have such severe problems at birth that they do not survive into their second year.
A genetic mutation on the X chromosome is the cause of Rett syndrome. Because only a single copy of this mutated gene is required to give rise to the disease, it is an X-linked, dominant disorder. Given the severity of the features of classic Rett syndrome, it is not surprising that about 99.5% of cases of the syndrome arise from a new mutation in the egg or sperm cell line of a parent, rather than existing in the body cells of the parent. It is possible to be a carrier of an X chromosome with this mutation. Most cells in a woman’s body shut down one of her two X chromosomes. If most of the cells shut down the X carrying the disease-causing gene, she will not manifest the severe symptoms and may bear children, who have a 50% chance of inheriting the mutation-carrying X chromosome from her. Because Rett disorder usually is the result of a new mutation, however, multiple cases in a single family are rare, but if a mother is found to be an unaffected carrier or the couple has a child with the condition, prenatal testing is available.
The gene that causes Rett syndrome is MECP2, which lies on the long arm of the X chromosome. The protein it encodes is required for life and necessary for appropriate brain development. Its job is to turn off certain genes at specific developmental periods or to ensure that the correct form of a particular protein is made. Thus, its job in the brain is regulatory, and when it does not function right, the development of the brain does not occur in an appropriately regulated manner. The genes with which it interacts are thought to relate to nerve cell signaling, and the protein that MECP2 encodes exists at high levels in normal nerve cells. In its absence, the parts of the brain responsible for emotion, sensing, and movement do not communicate correctly with one another. As a result, affected parts of the brain exist in a permanently infantile developmental state.
The symptoms of Rett disorder have been described in terms of four stages in the child’s development.
STAGE 1, EARLY ONSET (6-18 MONTHS OF AGE) . The early symptoms of RS are not always noticeable in Stage 1. The infant may not make eye contact with family members and may not show much interest in toys. She may be considered a “good baby” because she is so calm and quiet. On the other hand, there may be noticeable hand-wringing and slowing of head growth.
STAGE 2, RAPID DETERIORATION (1-4 YEARS OLD) . This stage may be either rapid or gradual in onset. The child loses her ability to speak and to make purposeful hand movements. Hand-to-mouth movements may appear, as well as hand-wringing or hand-clapping gestures. These movements may be nearly constant while the child is awake but disappear during sleep. There may be noticeable episodes of breath holding and hyperventilating (rapid shallow breathing). The child may have trouble sleeping, and may become irritable. If she is able to walk, she will start to look unsteady on her feet and may have periods of trembling or shaking. Slowed growth of the head is usually most noticeable during this stage.
STAGE 3, PLATEAU (2-10 YEARS) . Motor problems and seizures often appear during this stage. The child’s behavior, however, often shows some improvement, with less irritability and crying. She may show greater interest in her surroundings, and her attention span and
communication skills often improve. Many patients with RS remain in stage 3 for most of their lives.
STAGE 4, LATE DETERIORATION OF MOTOR SKILLS (USUALLY AFTER 10 YEARS OF AGE) . In stage 4, patients with RS gradually lose their mobility; some stop walking while others have never learned to walk. There is, however, no loss of cognitive or communication skills, and the repetitive hand movements may decrease. The spine begins to develop an abnormal sideways curvature (scoliosis), and the patient may develop muscle rigidity. Puberty begins at the same age as in most girls.
RS is less common than the other PDDs. Recent estimates of its prevalence range between 1:10,000 births and 1:15,000 female births. Little is known about its prevalence across different racial and ethnic groups.
Rett syndrome can be diagnosed based on either the diagnostic criteria established in the DSM-IV-TRor based on testing of the MECP2 gene for mutations. Molecular analysis of the MECP2 gene for mutations will identify at least four out of five females who have classic Rett disorder.
Diagnoses based on DSM-IV-TRcriteria are made after observation of the child—usually over a period of several hours or days—and interviews with the parents. The diagnosis can be made by a pediatrician or primary care physician, but should be confirmed by a pediatric neurologist (specialist in disorders of the nervous system in children) or developmental pediatrician. After the examiner has excluded the possibility of other developmental disorders, there are six criteria that must be met for a diagnosis of the classic form of Rett disorder, and a secondary group of supportive criteria that are frequently observed in RS patients but are not necessary to make the diagnosis.
Diagnostic criteria according to the DSM-IV-TR
The diagnostic criteria for RS include the following:
- a period of apparently normal development before 6-18 months of age
- a normal-sized head at birth followed by slowing of head growth between 5 months and 4 years
- severe impairment in the use of language and loss of purposeful hand motion
- repetitive hand movements that include one or more of the following: hand-washing, hand-wringing, or hand-clapping gestures
- shaking of the chest or torso, particularly when the child is agitated or upset
- in children able to walk, an unsteady, stiff-legged, wide-based gait
Supportive criteria are criteria that are not essential to the diagnosis of a particular disorder (because some people with the disorder do not have them). Supportive criteria are nonetheless strong evidence that a person who exhibits these criteria does in fact have the disorder. Supportive criteria for Rett disorder include:
- dysfunctional breathing, which may include hyper-ventilation, breath holding, and air swallowing
- abnormal electroencephalogram (EEG) patterns
- difficulties in chewing and swallowing
- muscle rigidity and contracting of the joints that increase with age
- scoliosis (curvature of the spine from side to side)
- teeth grinding (bruxism)
- small feet in relation to overall height
- slow overall growth
- loss of body fat and muscle mass
- abnormal sleeping patterns combined with irritability or agitation
- poor circulation in the feet and legs
These supportive criteria do not always appear in young children with RS but are often observed as the child grows older.
Variant Rett syndrome
Because genetic testing has revealed some gradations in the manifestation of Rett syndrome, there also is a list of suggested criteria for the variant form of the condition. These include a set of main criteria, of which three must be met:
- reduction or lack of hand skills
- reduction or complete loss of speech, including
- presence of stereotyped hand movements
- lost or diminished communication abilities
- slowed head growth from early childhood
- regression that is followed by recovery of interaction.
There are also 11 suggested supportive criteria for the variant form of Rett disorder, with the dictate that at least 5 must be present:
- breathing irregularities
- abnormal locomotion
- spinal deformity that results in a hunched appearance (kyphosis) or scoliosis (curvature of the spine)
- loss of muscle in the lower limbs
- feet that are cold, discolored, and small Sleep disturbances, including nighttime screaming
- unexpected episodes of screaming or laughing
- the appearance of a reduced awareness of pain
- intense eye contact
There is no single treatment regimen that is applicable to all patients with Rett disorder. A suite of therapies that may be useful will include speech, occupational, and physical therapy. While these therapies will not cure Rett, they may help ameliorate some aspects of the disorder. Some patients benefit from medications for muscular rigidity or for specific mood or behavioral problems, such as anxiety or irritability. Because of the increased risk of a potentially deadly irregular heartbeat, females with RS should avoid drugs that can exacerbate the problem, including antipsychotics, anesthetics, and some antibiotics. A child psychiatrist should be consulted in regard to medications.
Parents of children with RS, however, are often helped by supportive therapy groups for parents of children with PDDs. Another type of program that is helpful for parents is learning skills for coping with the behaviors of RS children. These programs are usually led by a behavioral psychologist .
The prognosis for RS patients is poor. In most cases, there is a steady loss of cognition, and of movement-related, social, and behavioral skills throughout the patient’s lifetime. Some patients, however, make modest developmental gains in adolescence. The average life expectancy of patients with RS has not yet been determined, although some are presently middle-aged. Females with the classic form of Rett syndrome usually live to adulthood, but there is a high incidence of sudden death among this group, possibly because of irregular heartbeat.
Hyperventilation —A pattern of rapid, shallow breathing that is frequently found in patients with Rett disorder.
Mosaicism —A genetic condition in which some cells in an organism have one set of chromosomes and other cells have a different set.
Mutation —A spontaneous change in the sequence of nucleotides in a chromosome or gene. Mutations may affect the number and structure of chromosomes or cause deletions of part of a chromosome. Rett disorder is caused by a mutation on the long arm of the X chromosome.
Pervasive developmental disorders (PDDs) —A category of childhood disorders that includes Asperger’s syndrome and Rett disorder. The PDDs are sometimes referred to collectively as autistic spectrum disorders.
Scoliosis —An abnormal lateral (sidewise) curvature of the spine. Many patients with RS develop scoliosis after puberty.
Children who have RS can and do attend school. Some attend special school targeting children with their disabilities, while others attend neighborhood schools and participate in the general classroom environment. In the United States, the Individuals with Disabilities Education act ensures that children can be eligible for early intervention services in a Birth-to-Three program if they are diagnosed before the age of three.
Because most cases result from new mutations of the MECP2 gene rather than transmission of a defective gene from the parents, there are no known strategies for preventing Rett disorder.
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Angelman, Rett and Prader-Willi Syndromes Consortium Registry, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza Room T619, Houston, TX 77030.Telephone: (713) 798-4795. Fax: (713) 798-7773. http://rarediseasesnetwork.epi.usf.edu/arpwsc/takeaction/registrymenu.htm.
Institute for Community Inclusion/UAP, 300 Longwood Avenue, Boston, MA 02115. Telephone: (617) 355-6506. TTY (617) 355-6956. E-mail: [email protected] harvard.edu.
International Rett Syndrome Association (IRSA), 9121 Piscataway Road, Suite 2-B, Clinton, MD 20735. Telephone: (301) 856-3334 or (800) 818-RETT. Fax: (301) 856-3336. www.rettsyndrome.org
National Association of Rare Disorders (NORD), P.O. Box 8923, New Fairfield, CT 06812-8923. (800) 999-NORD or (203) 746-6518.
Rett Syndrome Research Foundation (RSRF), 4600 Devitt Drive, Cincinnati, OH 45246. http://www.rsrf.org, Telephone: 513-874-3020, Fax: 513-874-2520.
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The U.S. government provides a database of ongoing clinical trials, including those that address Rett’s. To see which trials are ongoing, visit the Web site at http://clinicaltrials.gov/ct/search;jsessionid=7EA72CF4829AFE0ACE3A61A70A84DB38?term=rett%27s.
Rebecca Frey, PhD
Emily Jane Willingham, PhD