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Rett syndrome

 
Sci-Tech Dictionary: Rett syndrome
 
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(′ret ′sin′drōm)

(psychology) An inherited developmental disorder observed only in females that is characterized by a short period of normal development, followed by loss of developmental skills (particularly purposeful hand movements) and marked psychomotor retardation. A brief autistic-like phase may be observed during the preschool period, but the subsequent course and clinical features are markedly different from autism.

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Neurological Disorder:

Rett syndrome

 
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Definition

Rett syndrome (RS) is a neurological disease of children that is also referred to as Rett's disorder or by the compound name of autism, dementia, ataxia, and loss of purposeful hand use. Named for the Austrian pediatrician who first described it, RS is sometimes grouped together with other childhood neurological disorders under the category of pervasive developmental disorders (PDDs) or autistic spectrum disorders. RS is classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), as a developmental disorder of childhood. More recently, Rett syndrome has been categorized along with Rubinstein-Taybi syndrome (RSTS), Coffin-Lowry syndrome (CLS), and several other rare disorders as a chromatin disease. Chromatin is the easily stained part of a cell nucleus that contains the cell's DNA, RNA, and several proteins that maintain its structure.

Description

RS was first described by an Austrian pediatrician, Andreas Rett, in 1966. His article attracted little attention, however, because it appeared in a German-language medical journal that was not widely read outside Europe. In 1983, a Swedish researcher named Bengt Hagberg published a follow-up study in the English-language Annals of Neurology, which led to worldwide recognition of RS as an identifiable neurological disorder.

RS has a distinctive onset and course. The affected child—almost always a girl—develops normally during the first five months of life. After the fifth month, head growth slows down and the child loses whatever purposeful hand movements she had developed during her first five months. After 30 months, the child frequently develops repetitive hand-washing or hand-wringing gestures; 50–80% of children with the disorder will eventually have seizures. RS is also associated with varying degrees of mental retardation.

The doctors who first studied RS attributed it to the breakdown or destruction of brain tissue. Later research indicated, however, that it is caused by the failure of the infant's brain to develop normally. This developmental failure is in turn associated with a genetic mutation affecting production of a key protein that organizes the structure of chromatin. Changes in chromatin structure lead to inappropriate activation of the genes that regulate brain development. About 80% of patients who meet the updated 2002 criteria for "classic" RS have this mutation on one of their two X chromosomes.

Demographics

According to the National Institute of Neurological Disorders and Stroke (NINDS), RS affects between one in 10,000 and one in 15,000 female infants. It is thought to occur in all races and ethnic groups with equal frequency. Although Rett syndrome is associated with a genetic mutation, less than 0.5% of reported cases are recurrences within families. Almost all cases represent sporadic (new) mutations of the gene responsible for the syndrome. The risk that the parents of a daughter with RS will have a second child with the disorder is less than 1%.

The reason that almost all patients with RS are female is that the mutation that causes the disorder is located on the X chromosome. While boys have an X and a Y chromosome, girls have two X chromosomes, only one of which is active in any given body cell. The other X chromosome is turned off in a process known as X inactivation, which helps to explain why the symptoms of RS vary from patient to patient. According to mathematical probability, the X chromosome with the mutation will be active in about half the girl's cells, with the healthy X chromosome active in the other half. If by chance a majority of the girl's cells have an active healthy X chromosome, she will have only mild symptoms of RS. On the other hand, if the X chromosome with the mutation is active in a majority of the girl's cells, she will have more severe symptoms. Since boys have only one X chromosome, they have no "backup" healthy X chromosome to compensate for one that contains the mutation. As a result, boys affected by the mutation usually die shortly before or after birth. The few cases of boys surviving with RS involve another genetic disorder known as Klinefelter's syndrome, in which the boy is born with three or more sex chromosomes, two or more Xs and a Y. If one of the X chromosomes contains the RS mutation, the boy may develop RS.

Causes and symptoms

RS is the first neurological disorder in humans to be traced to defects in a protein that controls the expression of other genes. The molecular cause of Rett's disorder is a genetic mutation on the long arm of the X chromosome (Xq28) at a locus known as MECP2. Dr. Huda Zoghbi at Baylor College of Medicine and her collaborator, Dr. Uta Francke at Stanford University, discovered the gene in 1999. The gene contains instructions for the formation of a protein known as methyl cytosine-binding protein 2 or MeCP2, which is crucial to the normal development of the human brain. The mutation associated with RS results in insufficient production of MeCP2. When this key protein is lacking, other genes are "turned on" or remain active at inappropriate points in the brain's development. These activated genes interfere with the normal pattern of brain maturation. The discovery of the MECP2 gene showed that RS should be understood as a genetic interference with normal brain development rather than the result of tissue loss or destruction.

The areas of the brain that are most severely affected by the lack of MeCP2 are the frontal, motor, and temporal portions of the brain cortex; the brain stem; the base of the forebrain; and the basal ganglia. These parts of the brain control such basic functions as movement, breathing, and speech. In addition, the disruption of the normal pattern of brain development in RS affects the child's emotions and ability to learn. RS is now known to be one of the most common causes of mental retardation in girls.

The symptoms of RS are usually described in terms of four stages in the child's development.

STAGE 1, EARLY ONSET (SIX TO 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. She may also be able to use single words or word combinations before she loses the ability to speak in stage 2. On the other hand, there may also be noticeable hand-wringing and slowing of head growth in this early stage.

STAGE 2, RAPID DETERIORATION (ONE TO FOUR YEARS) The second stage may be either rapid or gradual in onset. The child loses her ability to speak and to make purposeful hand movements—a condition known as apraxia. 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, air swallowing, and hyperventilating (rapid shallow breathing). The child may have trouble sleeping, and may become irritable or agitated. If she is able to walk, she will start to look unsteady on her feet (ataxia) and may have periods of trembling or shaking. Some girls completely lose the ability to walk in stage 2 and move by crawling or "bottom scooting." Slowed growth of the child's head is usually most noticeable during this stage.

STAGE 3, PLATEAU (TWO TO 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.

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. Seizures and breathing problems typically lessen in severity by late adolescence. The spine, however, begins to develop an abnormal sideways curvature (scoliosis), which is usually more severe in girls that have never learned to walk. The patient may also develop muscle rigidity, or spasticity. Puberty begins at the same age as in most girls.

Other symptoms associated with RS include a greater risk of bone fractures due to low bone density in spite of adequate calcium in the diet; constipation, which results from poor muscle tone in the digestive tract, scoliosis, and the side effects of anticonvulsant medications; excessive salivation and drooling; gastroesophageal reflux disease (GERD), which results from poor muscle tone in the esophagus; and crying or emotional agitation, which is thought to result from frustration with the inability to communicate.

Diagnosis

The diagnosis of RS is clinical, which means that it is based on external observation of the patient's symptoms rather than on the results of laboratory tests or imaging studies. In some cases, however, the child's doctor may order blood or urine tests or an electroencephalogram (EEG) to rule out epilepsy or other disorders. The doctor will observe the affected child—usually over a period of several hours or days at various intervals—and interview the parents. In most cases, the diagnosis cannot be made with certainty until the child is three to five years old. A diagnosis of RS 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. In addition to ordering genetic testing, a specialist who is evaluating a child for RS will use several different types of criteria.

Diagnostic criteria

The diagnostic criteria for RS, which were first established in 1985, were revised by an international committee in 2001–2002 in order to improve the consistency of diagnosis as well as take recent genetic discoveries into account. The criteria are divided into three groups: necessary criteria, which must be present for the doctor to make the diagnosis; supportive criteria, which are present in many patients with RS; and exclusion criteria, which rule out a diagnosis of RS.

Necessary criteria include the following:

  • child is apparently normal before and around the time of birth
  • psychomotor development (development of skills that involve the brain's regulation of motor activity) is either normal for the first six months or is slightly delayed from birth
  • circumference of child's head at birth is normal
  • head growth slows down after birth
  • child loses purposeful hand motions between six and 30 months
  • child makes repeated gestures, most commonly hand wringing or squeezing, clapping or tapping, and washing or rubbing motions
  • child withdraws socially, loses ability to communicate in words, and loses cognitive skills
  • ability to walk is impaired or lost

Supportive criteria include the following:

  • disturbed breathing (hyperventilation, air swallowing, breath holding) when awake
  • bruxism (grinding the teeth during sleep)
  • disturbed sleeping pattern from early infancy
  • muscle wasting and loss of muscle tone
  • scoliosis or kyphosis
  • retarded growth
  • hands and feet that are very small compared to the rest of the child's body
  • vasomotor disturbances

Exclusion criteria include the following:

  • enlargement of the internal organs or other signs of storage diseases
  • cataract formation or damage to the retina of the eye
  • evidence of brain damage before or shortly after birth
  • identification of a metabolic or other progressive neurological disorder
  • damage to the nervous system resulting from an infectious disease or head trauma

About 15% of children who are evaluated for RS have RS-like symptoms, or have the MECP2 mutation without fulfilling all the diagnostic criteria. These children are said to have "variant" or "atypical" RS. Children below the age of three years who show some of the signs of RS but do not yet meet the full criteria are said to have "provisional" RS.

Genetic testing

It is important to understand that even though RS is associated with mutations in the MECP2 gene, the syndrome sometimes occurs without the mutation. Conversely, the mutation can occur without producing the symptoms of RS. Genetic testing can identify about 80% of RS cases but is not sufficient to use alone to make the diagnosis. Researchers think that the remaining 20% of cases may be caused either by mutations in other parts of the gene or by genes that have not yet been identified.

Treatment team

Treatment for patients with RS is highly individualized because the severity of specific symptoms varies from patient to patient; for example, some may never have seizures. In almost all cases, however, the treatment team for a child with RS will include a neurologist, an orthopedic surgeon, a physical therapist, an occupational therapist, a dietitian, and a speech-language therapist in addition to a pediatrician and a dentist. In some cases, the treatment team may include a psychiatrist who specializes in childhood and adolescent psychiatry. Most patients will also have a case manager to coordinate treatments.

When the patient reaches puberty, she should be seen by a developmental pediatrician and an orthodontist. Respite and in-home caregivers may also be added to the treatment team for adults with RS.

Treatment

There is no cure for RS; treatment is intended to ease the symptoms and to keep the patient mobile as long as possible. It will include most or all of the following:

  • Medications. A patient with RS may be given drugs for breathing problems and difficulties with muscle control. One medication that is useful is baclofen (Lioresal), a muscle relaxant. Patients with seizures are given anticonvulsant (anti-seizure) medications.
  • Special diets. Many patients with RS have a poor appetite and problems swallowing. The patient may need an assessment by a dietitian to plan meals that are appealing as well as nutritionally sound. Patients with seizures that cannot be controlled by medications may benefit from a special high-fat, low-carbohydrate diet known as a ketogenic diet.
  • Physical therapy. Physical therapy of patients with RS is focused on maintaining or improving the patient's balance and ability to walk; maintaining full range of motion whenever possible; and preventing the muscle contractures that lead to deformities in adult life.
  • Splints and braces. Hand or elbow splints may be used to reduce repetitive hand movements and increase the child's purposeful use of her dominant hand. Patients who develop kyphosis (humpback) or scoliosis may be fitted for spinal braces.
  • Occupational therapy.
  • Speech therapy. Some patients with RS are taught to communicate with body language; others use eye blinking, communication boards, or electronic devices.
  • Complementary and alternative therapies. Music therapy has been successfully used in patients with RS, as well as hydrotherapy, equine therapy (horseback riding), and acupuncture.

Clinical trials

As of late summer 2003, there are no open clinical trials for RS at the National Institutes of Health (NIH). There are, however, two medical centers funded by the NIH that evaluate patients for RS and conduct research on the disorder; contact information for the Blue Bird Circle Rett Center and the Kennedy Krieger Institute is listed under Resources.

Prognosis

It is difficult to predict the severity or the course of RS in any specific individual. Although the symptoms of RS are disabling, most patients survive into the 40s and 50s. Little is known about patients' long-term prognosis after age 40 because the disorder has been studied intensively only since the mid-1980s.

What is known about the short-term prognosis of middle-aged adults with RS is encouraging, however. Their mental state stabilizes and they are often able to continue to learn as well as improve the use of their hands. They make better eye contact with others. In addition, patients are usually less irritable, sleep better, and have fewer seizures and breathing problems. The chief additional problem for adults with RS is decreased mobility. After the early adult years, the patient's muscles may become rigid or spastic, causing joint deformities and increased difficulty in walking.

Special concerns

Educational and social needs

Most patients with RS can benefit from special educational programs. Education in the public schools is available in most areas until the patient is 21. After that age, the patient may be able to attend sheltered workshops or day centers, depending on where she lives. In the last few years, some young women with milder forms of RS have been able to attend classes at local community colleges or find employment with the help of a job coach.

It is important for patients with RS to participate in community activities and social events precisely because they have a fairly long life expectancy. Personal accounts of adults with RS indicate that they enjoy travel, church or synagogue activities, volunteer work, swimming, camping, music, sports events, and similar outings.

Legal issues

The most pressing long-term concern for patients with RS is working out a life plan for ongoing care, since many are likely to outlive their parents. The parents of a girl diagnosed with RS should consult an estate planner, an attorney, and a certified public accountant (CPA) in order to draft a life plan and letter of intent. A letter of intent is not a legally binding document, but it gives the patient's siblings and other relatives or caregivers necessary information on providing for her in the future. The attorney can help the parents decide about such matters as guardianship as well as guide them through the legal process of appointing a guardian, which varies from state to state.

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. Washington, DC: American Psychiatric Association, 2000.

Martin, John H. Neuroanatomy: Text and Atlas, 3rd ed. New York: McGraw-Hill, 2003.

Parker, James N., MD, and Philip M. Parker, PhD, eds. The Official Parent's Sourcebook on Rett Syndrome. San Diego, CA: ICON Health Publications, 2002.

"Psychiatric Conditions in Childhood and Adolescence." The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

Thoene, Jess G., editor. Physicians'Guide to Rare Diseases. Montvale, NJ: Dowden Publishing Company, 1995.

PERIODICALS

Amir, R. E., I. B. Van den Veyver, M. Wan, et al. "Rett Syndrome Is Caused by Mutations in X-Linked MECP2, Encoding Methyl-CpG-Binding Protein 2." Nature Genetics 23 (October 1999): 185–188.

Ausio, J., D. B. Levin, G. V. De Amorim, et al. "Syndromes of Disordered Chromatin Remodeling." Clinical Genetics 64 (August 2003): 83–95.

Bumin, G., M. Uyanik, I. Yilmaz, et al. "Hydrotherapy for Rett Syndrome." Journal of Rehabilitation Medicine 35 (January 2003): 44–45.

Chen, R. Z., S. Akbarian, M. Tudor, and R. Jaenisch. "Deficiency of Methyl-CpG Binding Protein-2 in CNS Neurons Results in a Rett-Like Phenotype in Mice." Nature Genetics 27 (March 2001): 327–331.

Hagberg, B., J. Aicardi, K. Dias, and O. Ramos. "A Progressive Syndrome of Autism, Dementia, Ataxia, and Loss of Purposeful Hand Use in Girls: Rett's Syndrome: Report of 35 Cases." Annals of Neurology 14 (October 1983): 471–479.

Hagberg, B., F. Hanefeld, A. Percy, and O. Skjeldal. "An Update on Clinically Applicable Diagnostic Criteria in Rett Syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, September 11, 2001." European Journal of Paediatric Neurology 6 (2002): 293–297.

Hendrich, Brian, and Wendy Bickmore. "Human Diseases with Underlying Defects in Chromatin Structure and Modification." Human Molecular Genetics 10, no. 20 (2001): 2233–2242.

Isaacs, J. S., M. Murdock, J. Lane, and A. K. Percy. "Eating Difficulties in Girls with Rett Syndrome Compared with Other Developmental Disabilities." Journal of the American Dietetic Association 103 (February 2003): 224–230.

Kadyan, V., A. C. Clairmont, R. J. George, and E. W. Johnson. "Intrathecal Baclofen for Spasticity Management in Rett Syndrome." American Journal of Physical Medicine and Rehabilitation 82 (July 2003): 560–562.

Liebhaber, G. M., E. Riemann, and F. A. Baumeister. "Ketogenic Diet in Rett Syndrome." Journal of Child Neurology 18 (January 2003): 74–75.

Magalhaes, M. H., J. Y. Kawamura, and L. C. Araujo. "General and Oral Characteristics in Rett Syndrome." Special Care in Dentistry 22 (July-August 2002): 147–150.

Moldavsky, M., D. Lev, and T. Lerman-Sagie. "Behavioral Phenotypes of Genetic Syndromes: A Reference Guide for Psychiatrists." Journal of the American Academy of Child and Adolescent Psychiatry 40 (July 2001): 749–761.

Rett, A. "Rett Syndrome. History and General Overview." American Journal of Medical Genetics. Supplement 1 (1986): 21–25.

Rett, A. "On an Unusual Brain Atrophy Syndrome in Hyperammonemia in Childhood." [in German] Wiener medizinische Wochenschrift (1946) 116 (September 10, 1966): 723–726.

Van den Veyver, I. B., and H. Y. Zoghbi. "Genetic Basis of Rett Syndrome." Mental Retardation and Developmental Disabilities Research Reviews 8 (2002): 82–86.

Yasuhara, A., and Y. Sugiyama. "Music Therapy for Children with Rett Syndrome." Brain and Development 23 (December 2002) (Suppl 1): S82–S84.

ORGANIZATIONS

American Academy of Child and Adolescent Psychiatry. 3615 Wisconsin Avenue, NW, Washington, DC 20016-3007. (202) 966-7300. Fax: (202) 966-2891. (February 25, 2004). http://www.aacap.org.

Blue Bird Circle Rett Center, Baylor College of Medicine, Department of Pediatrics, One Baylor Plaza, Room 319C, Houston, TX 77030. (888) 430-7388 or (713) 798-RETT. (February 25, 2004).http://bluebirdrett.bcm.tmc.edu.

International Rett Syndrome Association (IRSA). 9121 Piscataway Road, Suite 2-B, Clinton, MD 20735. (301) 856-3334 or 1-800-818-RETT. Fax: (301) 856-3336. (February 25, 2004). http://www.rettsyndrome.org

Kennedy Krieger Institute, Department of Neurogenetics, 707 North Broadway, Baltimore, MD 21205. (800) 873-3377 x 29-409 or (443) 923-2778. (February 25, 2004). http://www.kennedykrieger.org.

National Institute of Child Health and Human Development (NICHD). National Institutes of Health (NIH), Bldg. 31, Room 2A32, Bethesda, MD 20892-2425. (800) 370-2943 or (301) 496-5133. (February 25, 2004). http://www.nichd.nih.gov.

National Organization for Rare Disorders (NORD). 55 Kenosia Avenue, P. O. Box 1968, Danbury, CT 06813-1968. (800) 999-6673 or (203) 744-0100. Fax: (203) 798-2291. (February 25, 2004). http://www.rarediseases.org.

Rett Syndrome Research Foundation (RSRF). 4600 Devitt Drive, Cincinnati, OH 45246. (513) 874-3020. Fax: (513) 874-2520. (February 25, 2004). http://www.rsrf.org.

OTHER

National Institute of Neurological Disorders and Stroke (NINDS). Rett Syndrome Fact Sheet. NIH Publication No. 01-4863. Bethesda, MD: NINDS, 2003.


Rebecca J. Frey, PhD


 
Medical Dictionary: Rett's syndrome
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Home > Library > Health > Medical Dictionary
(rĕts)
n.

A progressive brain disorder occurring principally in girls, characterized by autism, dementia, ataxia, and purposeless hand movements, and associated with abnormally high levels of ammonia in the blood.

 
Wikipedia: Rett syndrome
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Rett syndrome/r
Classification and external resources
ICD-10 F84.2
ICD-9 330.8
OMIM 312750
DiseasesDB 29908
eMedicine med/3202 
MeSH C10.574.500.775

Rett syndrome (also called Retts disorder) is a neurodevelopmental disorder that is classified as a pervasive developmental disorder by the DSM-IV. It was first described by Austrian neurologist Andreas Rett in 1966. The clinical features include a deceleration of the rate of head growth (including microcephaly in some) and small hands and feet. Stereotypic, repetitive hand movements such as mouthing or wringing are also noted. Symptoms of the disorder include cognitive impairment and problems with socialization, the latter during the regression period. Socialization typically improves by the time they enter school. Girls with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures.[1] They typically have no verbal skills, and about 50% of females are not ambulatory. Scoliosis, growth failure, and constipation are very common and can be problematic. Many argue that it is misclassified as a pervasive developmental disorder, just as it would be to include such disorders as fragile X syndrome, tuberous sclerosis, or Down syndrome where one can see autistic features.[2] The symptoms of this disorder are most easily confused with those of Angelman syndrome, cerebral palsy and autism.

Contents

Cause

Rett syndrome (symbolized RTT) is caused by mutations in the gene MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations.

Sporadic mutations

Rett syndrome is usually caused (95% or more) by a de novo mutation in the child (so it is NOT inherited from either parent. Parents are generally genotypically normal, i.e. one without a MECP2 mutation).

In sporadic cases of Rett syndrome, it is thought that the mutated MECP2 is usually derived from the male copy of the X chromosome. [3] It is not yet known what causes the sperm to mutate, and such mutations are rare.

Germline mutations

It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MECP2.[4] MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of Rett syndrome, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Rett syndrome affects one in every 12,500 female live births by age 12 years.

Gender and Rett syndrome

It almost exclusively affects girls—male fetuses with the disorder rarely survive to term. Development is typically normal until 6–18 months, when language and motor milestones regress, purposeful hand use is lost and acquired deceleration in the rate of head growth (resulting in microcephaly in some) is seen. Hand stereotypies are typical and breathing irregularities such as hyperventilation, breathholding, or sighing are seen in many. Early on, autistic-like behavior may be seen.

Most individuals with Rett syndrome are female. Because the disease-causing gene is located on the X chromosome, a female born with a MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins in addition to the abnormal proteins caused by a MECP2 mutation, the XY karyotype male fetus is unable to check the development of the disease, hence the failure of many male fetuses with a MECP2 mutation to survive to term. Females with a MECP2 mutation, however, have a non-mutant chromosome that provides them enough normal protein to survive at least to birth. Research shows that males with Rett syndrome almost all have Klinefelter's syndrome as well (in which the male has an XXY karyotype).[5] Thus, a non-mutant MECP2 gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.

There have, however, been several cases of 46,XY Karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age.[6] The incidence of Rett syndrome in males is unknown, partly due to low survival of male fetuses with the Rett syndrome associated MECP2 mutations, and partly to differences between symptoms caused by MECP2 mutations and those caused by Rett's.[7][8]

The severity of Rett syndrome in females can vary depending on the type and position of the mutation of MECP2 and the pattern of X-chromosome inactivation. It is generally assumed that 50% of a female's cells use the maternal X chromosome while the other 50% uses the paternal X chromosome (see X-inactivation). However, if most cells in the brain activate the X chromosome with the functional MECP2 allele, the individual will have very mild Rett syndrome; likewise, if most neurons activate the X chromosome with the mutated MECP2 allele, the individual will have very severe Rett syndrome just as males with MECP2 mutations do[citation needed] (as they only have one X chromosome).

Development and symptoms

The infant with Rett syndrome often avoids detection until 6–18 months due to a relatively normal appearance and some developmental progress. However closer scrutiny reveals disturbance of the normal spontaneous limb and body movements that are thought to be regulated in the brainstem. The brief period of developmental progress is followed by stagnation and regression of previously acquired skills. During regression some features are similar to those of autism. It is, hence, easy to mistakenly diagnose Rett syndrome for autism.

Symptoms of Rett syndrome that are similar to autism:

  • screaming fits
  • panic attack
  • inconsolable crying
  • avoidance of eye contact
  • lack of social/emotional reciprocity
  • general lack of interest
  • markedly impaired use of nonverbal behaviors to regulate social interaction
  • loss of speech
  • Balance and coordination problems, including losing the ability to walk in many cases

Symptoms of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion should rarely be made):

Symptoms may stabilize for many decades, particularly for interaction and cognitive function such as making choices. Anti-social behavior may change to highly social behavior. Motor functions may slow as rigidity and dystonia appear. Seizures may be problematic, with a wide range of severity. Scoliosis occurs in most and requires corrective surgery in about 10%. Those who remain ambulatory tend to have less progression of scoliosis.

Treatment and prognosis

 Please help improve this section by expanding it. Further information might be found on the talk page. (February 2007)

Currently there is no cure for Rett syndrome, but studies have shown that restoring MECP2 function may lead to a cure.[9] One area of research is in the use of Insulin-like Growth Factor 1 (IGF-1), which has been shown to partially reverse symptoms in MeCP2 mutant mice.[10] Such a treatment works because the neuronal cells have not atrophied, but rather are in an immature state.

Treatment of Rett syndrome includes:

The challenge of developing therapies for MECP2 disorders[11]

The recent studies (funded by the International Rett Syndrome Foundation) demonstrating that neurological deficits resulting from loss of MeCP2 can be reversed upon restoration of gene function are quite exciting because they show that neurons that have suffered the consequences of loss of MeCP2 function are poised to regain functionality once MeCP2 is provided gradually and in the correct spatial distribution. This provides hope for restoring neuronal function in patients with RTT. However, the strategy in humans will require providing the critical factors that function downstream of MeCP2 because of the challenges in delivering the correct MeCP2 dosage only to neurons that lack it, given that the slightest perturbation in MeCP2 level is deleterious. Thus, therapeutic strategies necessitate the identification of the molecular mechanisms underlying individual RTT phenotypes and picking out the candidates that can be therapeutically targeted. The next phase of research needs to assess how complete the recovery is. Clearly, lethality, level of activity, and hippocampal plasticity are rescued, but are the animals free of any other RTT symptoms such as social behavior deficits, anxiety, and cognitive impairments? Since postnatal rescue results in viability, it will be important to evaluate if even the subtler phenotypes of RTT and MECP2 disorders are rescued when protein function is restored postnatally. This is particularly important given emerging data about early neonatal experiences and their long-term effects on behavior in adults.

Mortality

Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have an extra X chromosome (often described as Klinefelter syndrome), or have somatic mosaicism.

Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:

A high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:

  • spontaneous brainstem dysfunction
  • cardiac arrest
  • seizures
  • cardiac conduction abnormalities - abnormally prolonged QT interval on ECG
  • gastric perforation

Depiction in popular culture

  • The movie "Society's Child" (2002), starring Jessica Steen and Margot Kidder, is about a mother of a 10-year-old girl with Rett syndrome and a social worker who tries to help her. [12]
  • Jacob Appel's short story, A Thanatology for Mollusks, features a girl with Rett syndrome whose mother falls in love with her special education instructor.[13]
  • "Silent Angels: The Rett Syndrome Story" (2000) is a moving documentary narrated by Julia Roberts which tells the story of courageous families and determined genetic researchers as they strive to find answers to this debilitating neurological </ref>http://www.rettsyndrome.org
  • Clint Black, a popular country singing star, was a contestant on the 2009 season of the Celebrity Apprentice and played to win money for the International Rett Syndrome Foundation. His niece had been diagnosed with Rett Syndrome and died at the age of 16. [14]
  • "So You Think You Can Dance" (Season 4), Jean Marc Généreux choreographed a Viennese waltz for Kherington Payne and Stephen Twitch Boss that he dedicated to daughter Francesca who suffers from Rett syndrome. [15]

Notes

  1. ^ "Predictors of Seizure Onset in Rett Syndrome" Le Jian et al. [1]
  2. ^ "Is Rett Syndrome a Subtype of Pervasive Developmental Disorders" Tsai, L.Y., Journal of Autism and Developmental Disorders
  3. ^ Trappe R, Laccone F, Cobilanschi J, et al. (May 2001). "MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin". American journal of human genetics 68 (5): 1093–101. doi:10.1086/320109. PMID 11309679. 
  4. ^ "Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2" Amir, R. et al.
  5. ^ Schwartzman, J.S., et al. Rett Syndrome in a Boy with 47,XXY Karyotype Confirmed by a Rare Mutation on the MECP2 Gene. 2001. Neuropediatrics 32:162-164
  6. ^ Hardwick, S.A. et al. Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband. 2007. European Journal of Human Genetics. 15(12):1218-29
  7. ^ "New Study Reveals Rett Syndrome Can Strike Males" ScienceDaily, August 12, 2006
  8. ^ Moog, U., et al. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). 2003. European Journal of Paediatric Neurology 07:5-12
  9. ^ "Autism-like disorder 'reversible'", BBC News, 8 February 2007.
  10. ^ "Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice", Proceedings of the National Academy of Sciences, vol 106, no 6, 2029–2034
  11. ^ "The Story of Rett Syndrome: From Clinic to Neurobiology." Chahrour et al. Neuron, Vol 56, 422-437, 08 November 2007
  12. ^ http://www.jessicasteen.com/jsp_society.html
  13. ^ Flyway, Iowa State University, Volume 5, No. 1-2.
  14. ^ http://www.rettsyndrome.org/index.php?option=com_content&task=view&id=487&Itemid=629
  15. ^ http://well.blogs.nytimes.com/2008/06/19/reality-dance-show-puts-rett-syndrome-in-the-spotlight/

References

Further reading

  • Ben Zeev Ghidoni B (2007). "Rett syndrome". Child Adolesc Psychiatr Clin N Am 16 (3): 723–43. doi:10.1016/j.chc.2007.03.004. PMID 17562589. 
  • Bittner JG, et al. (2008). "Rett Syndrome and gastric perforation". Am Surg 74 (4): 315–317. 

Rett Disorder and the Developing Brain. edited by Alison Kerr & Ingegerd Witt Engerstrom Oxford University Press ISBN 0-19-856815-0, 2005

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