AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Rett syndrome (RS) is a pervasive developmental disorder first reported in 1966 by Andreas Rett, an Austrian pediatric neurologist. RS occurs almost exclusively in females and has a typically degenerative course. Before the discovery of RS, incidents were mistaken for many other neurologic disorders, especially in females. The gene related to RS (methyl-CpG binding protein-2 [MECP2]) was identified late in 1999.^{1, 2, 3, 4, 5, 6, 7, 8, 9, 10}

Patients with RS initially have seemingly healthy development. However, in retrospect, girls are frequently reported to have been placid as infants, with low tone and subtle slowing of development. An early clinical feature is deceleration of head growth that begins when the individual is aged 2-4 months. A period of developmental stagnation is followed by a period of regression. Males with this disorder also manifest a spectrum of symptomatology, ranging from severe congenital encephalopathy, dystonia apraxia, and retardation to psychiatric illness with mild mental retardation. Individuals who are less severely affected may tolerate or even prefer interpersonal contact, show affection to others, and suffer from learning disabilities and speech fragmentation related to breathing irregularity.

The regression phase in individuals with RS may occur acutely over a period of days or, more insidiously, over months. Regression is characterized by loss of purposeful hand skills and oral language and the development of hand stereotypies and gait dyspraxia. Other problems include breath holding and apnea during wakefulness with normal breathing during sleep, epilepsy, oral-motor dysfunction with gut motility problems (eg, constipation, gastroesophageal reflux [GER]), scoliosis, autonomic dysfunction (cold, blue extremities), and somatic growth failure. During the regression period, individuals with RS demonstrate screaming episodes, sleep disturbances, and poor social interactions.

Following the regression period, people with RS demonstrate no further cognitive decline, become more interactive with their environment and other persons, and may demonstrate some improvements in hand and communication skills. They progress through puberty and survive to adulthood; however, they never regain significant purposeful hand use or oral language skills.

Currently, diagnosis of RS is made if the patient meets defined clinical criteria. The diagnosis is supported by a positive mutational analysis of MECP2. However, as many as 20% of females who meet the full clinical criteria for RS may have no identified mutation. Because no cure is available, treatment is palliative and supportive. A multidisciplinary approach to care for persons with RS is recommended.

Pathophysiology

RS is a genetic disorder of neurodevelopmental arrest rather than a progressive process. The gene for RS is located on the X chromosome. Females with one mutated MECP2 gene are more likely to survive because one X chromosome is activated randomly in each cell. The symptoms and severity of RS may depend on both the percentage of activated defective genes and the type of mutation. Multiple mutation types have been found in the 3 coding regions of the MECP2 gene, with most mutation types causing truncations and missense proteins. Mutations have been found in as many as 80% of analyzed cases of classic RS.

RS is the first human disease discovered that is caused by defects in a protein that regulates gene expression through interaction with methylated DNA. Therefore, RS involves abnormal chromatin structure, with broad-ranging effects on expression of genes that are otherwise not mutated. The normal MECP2 gene encodes a protein (also called MeCP2) that binds to methylated DNA in conjunction with a corepressor. This causes activation of histone deacetylase. Mutations in the MECP2 gene produce loss of function of this protein and unregulated expression of the genes that it normally affects, some of which, apparently, are crucial in nervous system development beyond the initial stages. Although the nervous system is the primary site, the specific target genes are not known.

Frequency

United States

The incidence has been reported to be approximately 1 per 23,000 live female births.¹¹

International

Wide variations in the incidence of RS have been reported among various countries. Rates as high as 1 per 10,000 live female births have been reported.¹² One study in Japan found an incidence of 1 per 45,000 girls aged 6-14 years.¹³ Variations in incidence may be partly accounted for by the inclusion of atypical or variant forms of RS. These atypical forms include congenital RS, milder forms with later onset of regression,¹⁴ and preserved speech variants.

Mortality/Morbidity

Most patients with RS survive into the fifth or sixth decade of life, often with severe disabilities. Survival rates of RS decline in individuals older than 10 years; the 35-year survival rate is 70%. Death may be sudden and often is secondary to pneumonia. Risk factors include seizures, loss of mobility, and difficulties with swallowing. The life expectancy is more favorable in patients with RS than in other individuals with profound mental retardation, which is associated with a 35-year survival rate of only 27%.

Race

No racial variations have been reported. In a study by Kozinetz et al, which included Latin Americans, Caucasians, and African Americans in Texas, no variation in incidence or prevalence of RS was found.¹⁵

Sex

Most patients identified are female because the disease is X-linked. Many males with RS are believed to die in utero. However, a few reports have detailed males with mutations in MECP2 and RS-like symptoms.^{2, 5, 7} Excess male fetal loss has not been demonstrated in families with a history of RS; thus, an alternative explanation for female predominance may be noted.

Age

RS generally becomes clinically evident by the time the individual is aged 2-4 years; however, the underlying neurodevelopmental arrest probably starts in children aged 6-18 months or younger.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

History varies by clinical stage as follows:

• Stage I - Developmental arrest (typically in children aged 6-18 mo)
• • Parents may report gross motor development delay, disinterest in play, and loss of eye contact.
  • Hypotonia may be noted.
  • Hand wringing, a hallmark of the disease, typically appears.
  • Infants may be reported as placid and calm when compared with healthy infants.
  • Early symptoms are often very vague and nonspecific.
• Stage II - Rapid deterioration or regression (typically in children aged 1-4 y)
• • Deterioration may be rapid.
  • Sometimes, parents can report specific dates after which their child was no longer healthy.
  • In other cases, deterioration may be slow in onset.
  • This stage can last weeks to months and may be characterized by reports of autisticlike behavior, such as a loss of social interaction and communicative skills, loss of oral language, and loss of purposeful finger and hand use.
  • Parents may note stereotypic hand movements during wakefulness. These are usually midline and consist of hand wringing, clapping, washing, or hand-to-mouth movements.
  • Parents or caregivers may also report episodes of breathing irregularities, such as hyperventilation¹⁶ or breath holding.
  • Patients with Rett syndrome (RS) may also have seizures and vacant spells that resemble seizures.
  • Other problems that may be noted are sleep disorders, intermittent strabismus, and irritability.
• Stage III - Pseudostationary (typically in children aged 2-10 y)
• • Some improvement in behavior, hand use, and communication skills may occur.
  • Patients may make good eye contact and make their intent known with whatever communicative skills that remain.
  • Despite the improvement, mental impairment and hand stereotypies continue.
  • Increasing rigidity, bruxism, and involuntary tongue movements may be reported.
  • Motor dysfunction and seizures are frequently reported.
  • Episodes of hyperventilation or breath holding may continue.
  • Although the child has a good appetite, weight gain is poor.
  • Feeding may become more difficult, and almost all individuals with RS have some degree of oral motor dysfunction.
• Stage IV - Late motor deterioration (typically >10 y).
• • No additional deterioration of cognitive skills, communication skills, or hand skills occurs; however, increasing motor problems may occur, including hypertonia, dystonia, and Parkinson symptoms (eg, bradykinesia, rigidity, retropulsion).
  • Some patients stop walking.
  • Seizure frequency may be reduced.

Physical

Disease development progresses through 4 stages, which are typically reached at the ages indicated below. Physical findings vary by clinical stage as follows:

• Stage I - Developmental arrest (typically in children aged 6-18 mo)
• • Findings may include gross motor development delay, loss of eye contact, deceleration in head growth (can occur by age 3 mo), deceleration in weight growth (can occur by age 4 mo), deceleration of height growth (can occur by age 16 mo), hypotonia, and hand wringing.
  • Infants with RS may appear placid and calm when compared with healthy infants.
  • Cutaneous findings, such as the presence of hypopigmented macules, are not observed when examined with a Wood lamp.
• Stage II - Rapid deterioration or regression (typically in children aged 1-4 y)
• • Findings may include autisticlike behavior (ie, loss of social interaction and communicative skills with no oral language).
  • Midline hand wringing, clapping, hand washing, or hand-to-mouth movements may be present, along with episodes of hyperventilation or breath holding.
  • Seizures and vacant spells that resemble seizures may also occur, along with intermittent strabismus and irritability.
• Stage III - Pseudostationary (typically in children aged 2-10 y): Findings may include hand stereotypies, rigidity, hyperventilation, breath holding, bruxism, involuntary tongue movements, poor weight gain, and scoliosis.
• Stage IV - Late motor deterioration (typically in individuals >10 y)
• • Findings may include dystonia, rigidity, muscle wasting, quadriparesis, scoliosis or kyphoscoliosis, loss of ambulation, growth retardation, hyperventilation, and seizures.
  • Improvements may be observed in frequency and intensity of hand movements.
  • Eye contact continues to be preserved and may be the only avenue by which emotions and needs can be communicated.
• Rett syndrome diagnostic criteria: Diagnosis of classic RS requires that patients meet certain necessary, supportive, and exclusionary characteristics as outlined below.
• Atypical or variant incidents of RS may occur because of the heterogeneity of the syndrome. Inclusion criteria for these are presented below. In a girl aged 10 years or older with mental retardation of unexplained origin who does not demonstrate the exclusion criteria listed below, atypical or variant RS can be diagnosed if at least 3 of the 6 primary criteria are present. In addition, at least 5 of 11 supportive manifestations must be met.

Causes

See Pathophysiology. Mutations that cause RS are almost all sporadic. In families with a girl who has RS, the increased risk of having a second girl with RS is reportedly less than 0.4%. However, recurrence in families can occur through mechanisms such as germline mosaicism.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Differential diagnosis varies by clinical stage as follows:

Stage I - Developmental arrest (typically in children aged 6-18 mo)
Benign congenital hypotonia
Cerebral palsy
Prader-Willi syndrome
Angelman syndrome
Metabolic disorders (eg, fetal alcohol syndrome, trisomy 13)

Stage II - Rapid deterioration or regression (typically in children aged 1-4 y)
Autism
Angelman syndrome
Encephalitis
Hearing and/or visual disturbance
Landau-Kleffner syndrome
Psychoses
Slow virus panencephalopathy
Tuberous sclerosis
Metabolic disorders (eg, phenylketonuria, ornithine transcarbamoylase deficiency)
Infantile neuronal ceroid lipofuscinosis

Stage III - Pseudostationary (typically in children aged 2-10 y)
Spastic ataxia
Cerebral palsy
Spinocerebellar degeneration
Leukodystrophies
Neuroaxonal dystrophy
Lennox-Gastaut syndrome
Angelman syndrome (likely not Kabuki because patients would have macrocephaly)

Stage IV - Late motor deterioration (typically in patients >10 y)
Other degenerative disorders

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Females who meet the clinical diagnostic criteria should undergo genetic testing.

• Several laboratories provide diagnostic sequencing of the MECP2 gene. Specifics of how to obtain this testing can be found on the International Rett Syndrome Association Web site.
• Patients with positive MECP2 mutational gene analysis need no further diagnostic testing.
• Patients in whom no mutation is found should undergo other diagnostic tests to identify other possible causes of their signs and symptoms. These include tests for serum lactate, ammonia, pyruvate, and amino acids as well as urine organic acids and chromosomal studies, including specific tests for Angelman syndrome (chromosome 15). Rarely, urinary tests for uroporphobilinogen to rule out intermittent porphyria can be helpful.
• Mutations in the MECP2 gene have been identified in a wide spectrum of clinical phenotypes, including girls with classic Rett syndrome (RS), girls with RS variant forms, girls with autism, healthy females (carriers), males with severe infantile encephalopathies, males with classic RS, and males with X-linked neurologic problems (eg, motor deficits, communication deficits).^{17, 18}

Imaging Studies

Neuroimaging may be useful.

• MRI may help include or exclude other causes of a patient's signs and symptoms.
• Although RS is associated with a significant decrease in cerebral cortex size, cerebellar atrophy, and a brain weight that is approximately 70-90% of normal, these findings are not specific for the diagnosis of RS.
• Changes may also be observed in the corticospinal tracts with reduced myelin and some gliosis.

Other Tests

• Electrocardiography
• • Findings may include an inverted T wave and a prolonged QT interval.¹⁹
  • Studies have demonstrated that the incidence of sudden death in persons with RS is greater than that of the general population.
  • Patients with RS may also have significantly lower heart rate variability.
  • These cardiac abnormalities may increase with advancing stages of RS.
• Barium swallow study or overnight pH probe study
• • These tests can be used to document GER, which is present in approximately 15% of patients with RS. GER may cause weight loss, discomfort with meals, vomiting after eating, obstructive apnea, or recurrent respiratory congestion and problems.
  • Swallowing studies frequently document poor oral motor skills and risk of aspiration.
• EEG
• • Abnormal results are common.²⁰
  • Seizures are reported in 60-90% of patients with RS.
  • Differentiation from Landau-Kleffner syndrome should be made clinically and secondary to response to therapy.
  • Patients also frequently have epileptiform abnormalities that appear to be age related with greatest frequency during clinical stage III and with abnormalities that can be noted earlier during nonrapid eye movement (NREM sleep).
  • Video-EEG polygraphic monitoring may be required to determine whether antiepileptic therapy is indicated because many reported seizure episodes are nonepileptic behavioral events, whereas actual seizures may be underrecognized because they occur during sleep.
• Neurophysiologic testing
• • Auditory brainstem-evoked response testing generally demonstrates normal hearing with a delayed conduction time.
  • Somatosensory-evoked responses demonstrate spinal cord and brainstem conduction abnormalities.
  • Electromyographic studies are typically normal and need not be completed, except to exclude other conditions.
• Electroretinography
• • Electroretinography plus the EEG and the continued decline of children with infantile neuronal ceroid lipofuscinosis can help differentiate RS from infantile neuronal ceroid lipofuscinosis.
  • Both disorders cause rapid regression of psychomotor development and the development of hand and finger stereotypes in children aged 1-2 years.
• Polygraphic respiratory recordings
• • These studies may demonstrate a pattern of disorganized breathing characterized by periods of apnea and/or hyperventilation and significant oxygen desaturation and clinical cyanosis.
  • Normal breathing occurs during sleep in persons with RS.
  • Total sleep time may be decreased in patients with RS.
  • Individuals with RS may demonstrate prolonged periods (³18 h) of wakefulness or sleep.
  • Nighttime awakenings with frequent laughing are reported.
  • Screaming episodes may also occur at night; however, consider the possibility of other medical problems (eg, GER).
• Psychometric testing
• • Generally, results in psychometric testing scores are indicative of profound mental retardation.
  • However, standard instruments that depend on the use of hands and oral language may be inadequate to fully assess individuals with RS.
  • Specialized tests such as the Gilliam Autism Rating Scale or the Children's Autism Rating Scale can be helpful to detail autisticlike symptomatology.

Histologic Findings

Morphologic features include reduced brain weight, including reduced volume of the frontal cortex and caudate, reduced neuronal size, and dendritic arborizations in certain areas (frontal correlates, motor correlates, limbic correlates) with preservation in the visual cortex and decreased organ weights proportional to height and weight.

Neurochemical findings include the following:

• Reduced levels of catecholamines in the substantia nigra
• Reduced dopamine D2 receptors and dopamine reuptake in the caudate nucleus
• Reduced choline acetyltransferase in the hippocampus, caudate, and thalamus
• Reduced acetylcholine vesicles or transporters in the putamen and thalamus
• Reduced benzodiazepine receptor binding in the frontal and temporal cortex
• Reduced beta-endorphins in the thalamus and cerebellum but increased beta-endorphins in the cerebrospinal fluid (CSF)
• Increased glutamate in the CSF
• Reduced melanin in the substantia nigra
• Decreased substance P levels in the CSF

Diagnostic Criteria 

The diagnostic criteria for RS are as follows:

• Necessary criteria
• • Apparently normal prenatal and perinatal period
  • Apparently normal development through at least the first 5-6 months of life
  • Normal head circumference at birth
  • Deceleration of head growth (age 3 mo to 3 y)
  • Loss of acquired skills (age 3 mo to 3 y), including learned purposeful hand skills, acquired babble and/or learned words, and communicative abilities
  • Appearance of obvious mental deficiency
  • Appearance successively of intense hand stereotypies, including hand wringing or squeezing; hand washing, patting, or rubbing; and hand mouthing or tongue pulling
  • Gait abnormalities among ambulant girls, including gait apraxia, dyspraxia, or both and jerky truncal ataxia, body dyspraxia, or both
  • Diagnosis tentative until the individual is aged 2-5 years
• Supportive criteria
• • Breathing dysfunction, including periodic apnea during wakefulness, intermittent hyperventilation, breath-holding spells, and forced expulsion of air or saliva
  • Bloated and/or marked air swallowing
  • EEG abnormalities, including slow waking background and intermittent rhythmic slowing (3-5 Hz) and epileptiform discharges, with or without clinical seizures
  • Epilepsy (various seizure forms)
  • Spastic signs, later muscle wasting, and/or dystonic traits
  • Peripheral vasomotor disturbances
  • Neurogenic scoliosis
  • Hypotrophic small and cold feet
  • Growth retardation
• Exclusion criteria
• • Organomegaly or other signs of storage disease
  • Retinopathy or optic atrophy
  • Microcephaly at birth
  • Existence of identifiable metabolic or other neurodegenerative disorder
  • Acquired neurologic disorder resulting from severe infections, head trauma, or toxic ingestion
  • Evidence of intrauterine growth retardation
  • Evidence of perinatally acquired brain damage

The diagnostic criteria for atypical or variant RS syndrome are as follows:

• Primary criteria
• • Loss of (partial or subtotal) acquired fine finger skills in late infancy or early childhood
  • Loss of acquired single words or phrases and/or nuanced babble
  • RS hand stereotypies, hands together or apart
  • Early deviant communicative ability
  • Deceleration of head growth of 2 standard deviations (SD), even when within the reference range
  • RS disease profile (ie, a regression period [stage II] followed by a certain recovery of contact and communication [stage III] in contrast to slow neuromotor regression through school age and adolescence)
• Supportive criteria
• • Breathing irregularities (hyperventilation and/or breath holding)
  • Bloating and/or marked air swallowing
  • Characteristic RS teeth grinding
  • Gait dyspraxia
  • Neurogenic scoliosis or high kyphosis (ambulant girls)
  • Development of abnormal lower limb neurology
  • Small blue and/or cold impaired feet, autonomic and/or trophic dysfunction
  • Characteristic RS EEG development (as noted)
  • Unprompted sudden laughing and/or screaming spells
  • Impaired and/or delayed nociception
  • Intensive eye communication with eye pointing

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Adopt a comprehensive team approach to maximize the abilities of patients with Rett syndrome (RS).
• If seizurelike activity is noted, video-EEG monitoring may be necessary to identify epileptic seizures for which antiepileptic drugs (AEDs) are appropriate. Vacant spells of patients with RS may not be seizures, and seizures may be less common than reported. However, true seizures may go unrecognized during sleep. Various treatments have been used to manage epilepsy in persons with RS. Treatments range from conventional AEDs (eg, carbamazepine, valproic acid) to newer AEDs (eg, topiramate, lamotrigine), a ketogenic diet, and a vagal nerve stimulator (VNS). Vagal nerve stimulation has generally been safe and well tolerated, with few surgical complications, increased alertness, and improved ability to participate in activities.²¹
• If seizures are well controlled, consider the addition of the Snoezelen multisensory approach, with or without hydrotherapy.^{22, 23, 24}

Surgical Care

• If the patient with RS cannot manage oral intake of food, consider a gastrostomy tube (G-tube) to minimize the risk of aspiration or recurrent pneumonias. Many girls with RS may experience significant somatic growth failure. Girls aged 4-8 years with RS may demonstrate poor or no weight gain despite apparently adequate caloric intake. In such persons, supplemental feeding is warranted either orally or by G-tube.
• If GER is refractory to medical treatment, a fundoplication may be necessary.
• Scoliosis in individuals with RS often does not respond to orthotics. Consider surgery in patients with Cobb angles more than 40-45° or curves that cause pain or loss of function.

Consultations

Patients with RS need early multidisciplinary evaluation and therapy, including the following:

• Communication assessment
• • Most girls with RS lose expressive language; however, some may retain one-word expressions, and others may attempt to communicate through eyes and body language.
  • Careful assessment of the patients' communication abilities and the parents' response to the patients' communication is important to maximize their potential.
  • Devices such as picture boards may be helpful.
• Oral motor assessments
• • Feeding disorders occur in more than 80% of patients with RS when aged 4-8 years.
  • Factors include abnormal tongue movements and tone, skeletal misalignment, and rigidity.²⁵
  • Treatments may range from simple positioning and therapy to decrease rigidity to more complex interventions.
• Other assessments and therapy
• • Music, hydrotherapy, hippotherapy (ie, horseback riding), and massage are noted by some to be helpful.
  • Other needs include psychosocial support for families and the creation and implementation of an appropriate educational plan with schools.
  • Parents may require help accessing community resources for items (eg, wheelchairs, ramps) and services that allow home care of patients with RS.

Diet

Despite excellent appetites, weight gain is poor in many patients with RS.

• Improved weight gain and better seizure control have been reported when girls were given a high-calorie diet, with approximately 70% of calories from fats and 15% each from carbohydrates and proteins (see Surgical Care).
• Osteoporosis is common in persons with RS. Osteoporosis in individuals with RS may need to be treated with vitamin D, calcium supplements, and bisphosphonate.

Activity

Therapy that promotes ambulation, balance, and hand use is important.

• Hand splints and other devices that decrease hand stereotypies may make girls with RS more focused and may decrease agitation and self-injurious behavior.
• Hinged ankle-foot orthoses and physical therapy may be beneficial in treating toe walking that results from increased heel cord tone.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No medications are available to treat persons with Rett syndrome (RS). Bromocriptine and carbidopa-levodopa, which are dopamine agonists, have been tried as a treatment for motor dysfunction in persons with RS; however, benefits are neither substantial nor long lasting. Case reports have suggested the effectiveness of levocarnitine.

Individuals with GER may respond to conservative medical treatment with antireflux agents (eg, metoclopramide), thickened feeding solutions, and semiupright positioning at bedtime (see Gastroesophageal Reflux). AEDs may be prescribed to control seizurelike activity.

Drug Category: Antiepileptic agents

These agents are used to control seizure activity.

Drug Category: Vagal nerve stimulators

These agents are amino acid derivatives synthesized from methionine and lysine. They are required in energy metabolism.

Drug Category: Prokinetic agents

These agents are used to augment cholinergic activity and improve motility in the GI tract for treatment of reflux.

Drug Category: Sedative and hypnotic agents

These agents are used to induce sleep.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Agitation and screaming
• • Perhaps as attempts to communicate, agitation and screaming are common and are often distressing to families.
  • Patients with Rett syndrome (RS) need gradual transitions and may have great difficulty communicating physical problems to physicians.
  • The clinician should perform careful evaluation to exclude clinical problems and pain.
  • If a clinical reason cannot be found for agitation, treatment may include warm baths, massage, music, or a quiet less-stimulating environment.
• Sleep disturbances
• • For management of sleep disturbances, short-acting nonbenzodiazepine receptor agonists (eg, zaleplon, zolpidem) may be helpful without untoward effects on daytime functioning.
  • Other approaches to sleep problems have included use of melatonin with dosage range of 2.5-7.5 mg and behavioral techniques.
• Constipation
• • Constipation is common in patients with RS.
  • Order adequate fluid intake, high fiber intake, and exercise.
  • Stool softeners may be necessary; however, avoid continuous laxatives, suppositories, and enemas.
  • Long-term mineral oil use interferes with the absorption of certain fat-soluble vitamins.
  • Regular oral milk of magnesia can be used.
• Scoliosis
• • Scoliosis occurs in more than one half of patients with RS, usually when aged 8-11 years.
  • Scoliosis may progress rapidly, especially if early hypotonia, dystonia, or loss of ambulation is present.
  • Close monitoring is necessary to determine if bracing or surgery is needed.
• Osteopenia with possible fractures: Possibly occurring for multiple reasons, osteopenia with possible fractures can be minimized through physical therapy, good nutrition, and close observation.²⁶
• Birth control
• • In most girls with RS, puberty occurs at the same age as girls without RS.
  • Discussions of birth control should occur with the patient's guardians.

Prognosis

• Development
• • Developmental potential for patients with RS is difficult to predict.
  • Some individuals with RS achieve and maintain some functional skills.
  • Of patients with RS, as many as 60% may retain their abilities to ambulate; the remainder lose ambulation or never walk because of atrophy, dystonia, and scoliosis.
• Lifespan
• • In a case study by Hagberg et al of 54 patients, the median age at death was 24 years.²⁷ In most cases, death was sudden and unexpected.
  • However, more recent experiences based on longer follow-up care indicate that, with attention to nutritional needs and comprehensive programs of physical and occupational therapies, individuals with RS can be expected to survive long into adulthood.
  • Reports of women with RS in their sixth and even eighth decade of life are now available.
• Diagnosis
• • Although no cure for RS is available, accurately identifying the diagnosis has many advantages. For example, girls with RS may be able to retain some communicative skills with proper assistance.
  • Because persons with RS are at significant risk of malnutrition, enact steps to adjust their diets to avoid malnutrition.
  • Individuals with RS are at risk of sudden death, possibly from long-QT sequelae; therefore, identifying patients with this condition is important.
  • Finally, diagnosis can bring relief to parents and help to identify the scope of clinical problems that can be anticipated.

Patient Education

• International Rett Syndrome Association
• • International Rett Syndrome Association, Clinton, MD (800-818-7388), supports international research and meetings of parents and professionals to improve knowledge of RS.
  • The Rett Syndrome Web site is available in multiple languages.
  • The Web site provides overviews of RS and highlights individuals living with RS.
  • The site also provides a discussion group for parents, doctors, and researchers, updated research findings, research contacts, an online library, and links to other RS-related sites.
  • Several laboratories provide diagnostic sequencing of the MECP2 gene. Specifics of how to obtain this testing can be found on the International Rett Syndrome Association Web site.
• Blue Bird Circle Rett Center
• • The Blue Bird Circle Rett Center of Baylor College of Medicine (Houston, TX; 713-798-RETT [7388] or 888-430-RETT), operates one of the largest RS clinics in the world.
  • The Blue Bird Circle Rett Center Web site contains additional information.
  • The Blue Bird Circle Rett Center is part of a Rett Consortium with the University of Alabama at Birmingham and the University of California at Los Angeles.
• The Rett Program: The Rett Program at the Kennedy-Krieger Institute, Johns Hopkins University School of Medicine (Baltimore, MD; 800-873-3377) can provide additional information.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Diagnosis of Rett syndrome (RS) is initially difficult; however, the observant pediatrician may note deceleration of head, weight, and height growth.
• Although no cure is available for this disorder, early identification of RS may help with parental concerns and maximize the girl's potential, which is influenced by an active lifestyle, good nutrition, and the amount of effective physical therapy received.
• In view of expected survival into adulthood, discuss provisions for guardianship and long-term care with parents and caregivers of individuals with RS.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet. Oct 1999;23(2):185-8. [Medline].
2. Dayer AG, Bottani A, Bouchardy I, et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. Jul 14 2006;[Medline].
3. Hoffbuhr K, Devaney JM, LaFleur B. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. Jun 12 2001;56(11):1486-95. [Medline].
4. Huppke P, Laccone F, Kramer N, et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. May 22 2000;9(9):1369-75. [Medline].
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Article Last Updated: Mar 13, 2008