Rett's disorder

Definition

Rett's disorder, which is also known as Rett's 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's disorder is characterized by an early-onset slowing of the infant's head growth and a reduction in brain size, as much as 30%.

Description

RS was first described by an Austrian physician, Andreas Rett, in 1966; prior to 1983, however, little was known about the syndrome because its occurrence is 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.

Rett's disorder has a distinctive onset and course. The 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 develop epilepsy. Rett's disorder is also associated with severe or profound mental retardation .

Causes and symptoms

Causes

The cause of Rett's disorder is a genetic mutation on the long arm of the X chromosome (Xq28) at a locus known as MECP2. The gene was discovered in 1999, and it produces a protein known as MeCP2, which is essential to life and crucial to the normal development of the human brain. The mutation that causes Rett's disorder allows other genes to become or remain active at inappropriate points in the brain's development. These activated genes interfere with the normal pattern of development and maturation of the brain's functions. Although Rett's disorder was previously thought to result from degeneration or deterioration of brain tissue, the discovery of the Rett's gene provides evidence that the disorder may be due to a failure of normal brain development. The sensory, motor, and emotional functions of the brain are not integrated in Rett's patients as they are in persons without the mutation. Certain regions of the brain in Rett's patients essentially remain at an infantile stage of development.

RS is classified by geneticists as an X-linked dominant disorder with a high rate of new mutations. Most of these mutations (99.5%) occur while the fetus is developing in the mother's womb; only 0.5% of cases of Rett's disorder are recurrences within families. One of the most important aspects of the discovery of the Rett gene is that RS is the first disorder in humans to be traced to defects in a protein (MeCP2) that controls the expression of other genes through its interaction with methylated DNA. The discovery uncovered a new class of genetic disease that might extend far beyond RS in its applications to other disorders related to developmental failures of the nervous system.

Symptoms

The symptoms of Rett's disorder have been described in terms of four stages in the child's development.

STAGE ONE, EARLY-ONSET (SIX–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 TWO, RAPID DETERIORATION (ONE–FOUR YEARS). 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 THREE, PLATEAU (TWO–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 FOUR, 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.

Demographics

RS is less common than the other PDDs. Recent estimates of its prevalence range between 1:10,000 births and 1:15,000 births. As of 2002, little is known about its prevalence across different racial and ethnic groups.

Until 2000, Rett's disorder was thought to occur only in girls, but at least two cases have been reported in boys as well. Since RS is caused by a mutation on the X chromosome that affects the production of a protein essential to life, and the Y chromosome that determines male sex cannot compensate for a damaged X chromosome, a male fetus with a defective X chromosome does not usually survive. The two known cases of RS in boys involve one child who has two X chromosomes as well as a Y, and a child whose X chromosome is faulty in some of the cells in his body but not all. This condition is known as mosaicism.

Diagnosis

The diagnosis of Rett's disorder is made on the basis of observation of the child—usually over a period of several hours or days—and interviews with the parents. There are no laboratory or diagnostic imaging tests for RS. 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 Rett's 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

The diagnostic criteria for RS include the following:

• a period of apparently normal development before six–18 months of age
• a normal-sized head at birth followed by slowing of head growth between five months and four 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
• 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

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's disorder include:

• dysfunctional breathing, which may include hyperventilation, breath holding, and air swallowing
• abnormal electroencephalogram (EEG) patterns
• seizures
• difficulties in chewing and swallowing
• constipation
• muscle rigidity and contracting of the joints that increase with age
• scoliosis (curvature of the spine from side to side)
• teeth grinding
• 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.

Treatments

There is no single treatment regimen that is applicable to all patients with Rett's disorder. Some patients benefit from medications for muscular rigidity or for specific mood or behavioral problems, such as anxiety or irritability. A child psychiatrist should be consulted in regard to medications.

The degree of mental retardation associated with RS means that patients with this disorder will not benefit from psychotherapy . 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 U. S. National Institute of Mental Health (NIMH) is presently conducting research studies of psychosocial approaches to treatment of Rett's and other PDDs as well as studies of medications given for these disorders. Readers who would like more information about this research may contact NIMH Public Inquiries at 6001 Executive Boulevard, Rm. 8184, MSC 9663, Bethesda, MD 20892-9663. (301) 443-4513; Fax (301) 443-4279; TTY (301) 443-8431.

Prognosis

It is important to note that current information about the prognoses of children with Rett's syndrome is derived from treatments given to patients in the 1970s or 1980s. As knowledge of effective treatments continues to accumulate, children with RS are receiving treatment earlier than they did two decades ago. It is likely that future prognoses for the disorder will reflect these improvements.

As of 2002, the prognosis for RS patients is poor. In most cases, there is a steady loss of cognition, 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.

Prevention

As of 2002, there are no effective strategies for preventing Rett's disorder, since most cases result from new mutations of the MECP2 gene rather than transmission of a defective gene from the parents.

Resources

BOOKS

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

"Psychiatric Conditions in Childhood and Adolescence." Section 19, Chapter 274. In 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

Gura, T. "Gene Defect Linked to Rett Syndrome." Science 286 (October 1, 1999): 27.

Jan, M., J. M. Dooley, and K. E. Gordon. "A Male Rett Syndrome Variant: Application of Diagnostic Criteria." Pediatric Neurology 20 (1999): 238-240.

Rett Syndrome Diagnostic Criteria Work Group. "Diagnostic Criteria for Rett Syndrome." Annals of Neurology 23(1988): 425-428.

Smith, Jill C., MD. "Rett Syndrome in Boys." The Rett Gazette (Winter 2001): 1-2.

ORGANIZATIONS

Institute for Community Inclusion/UAP. 300 Longwood Avenue, Boston, MA 02115. (617) 355-6506. TTY (617) 355-6956. E-mail: ici@a1.tch.harvard.edu.

International Rett Syndrome Association (IRSA). 9121 Piscataway Road, Suite 2-B, Clinton, MD 20735. (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.

OTHER

"Gene Today, Gone Tomorrow." Baylor College of Medicine press release, September 30, 1999.

Willard, Huntington F., and Brian D. Hendrich. "Breaking the Silence in Rett Syndrome." Manuscript circulated by the Department of Genetics, Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, OH, January 2002.

Rebecca J. Frey, Ph.D.