Rett Syndrome


Practice Essentials

Rett syndrome (RS) is a neurodevelopmental disorder that occurs almost exclusively in females and has a typically degenerative course. It is related to various mutations on the MECP2 gene, which codes for methyl-CpG binding protein-2 (MECP2). Recent studies suggest that MECP2 is expressed in neurons and glial cells and that it will someday be possible to reverse the disorder even after birth when behavioral symptoms occur.[1]

Signs and symptoms

RS progresses through 4 stages, typically reached at the following ages:

The history varies according to the clinical stage. Common symptoms reported include the following:

Physical findings also vary according to the clinical stage of the disorder. Common findings on physical examination include the following:

See Presentation for more detail.


The differential diagnosis varies according to the clinical stage of RS. Conditions that should receive particular consideration in each of the 4 stages of the syndrome are as follows:

Laboratory studies that may be warranted include the following:

Other studies that may be helpful include the following:

See DDx and Workup for more detail.


No medications are available specifically for treatment of RS. Agents that may be considered in RS patients include the following:

Nonpharmacologic therapy may include the following as appropriate:

Dietary measures may include the following:

Optimal management of RS involves early multidisciplinary evaluation and treatment, including the following:

Issues that may have to be addressed in long-term management of RS include the following:

See Treatment and Medication for more detail.


Rett syndrome (RS) is a neurodevelopmental disorder first reported in 1966 by Andreas Rett, an Austrian pediatric neurologist. It occurs almost exclusively in females and has a typically degenerative course. Before the discovery of RS, incidents were mistaken for many other neurologic disorders. The specific mutation on the gene related to RS (methyl-CpG binding protein-2 [MECP2]) was identified late in 1999.[2, 3, 4, 5, 6, 7, 8, 9, 10, 11]

Initially, RS patients have seemingly healthy development. In retrospect, however, it can be seen that girls were 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 RS also manifest a spectrum of symptoms, ranging from severe congenital encephalopathy, dystonia, apraxia, and retardation to psychiatric illness with mild intellectual disability. 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.

RS can be differentiated into 2 types, classic and variant (atypical). At least 200 different mutations have been found to be associated with the disease, including missense and truncating mutations. The common BDNF polymorphism may modify disease severity in RS,[12] and the severity of the phenotype varies depending on the MECP2 mutation type and locations.[13] The BDNF functional polymorphism (p.Val66Met; valine substitution with methionine at codon 66) may protect against early seizures.[14]

The regression phase in individuals with RS may occur acutely over a period of days or, more insidiously, 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 or 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.

After 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, the diagnosis of RS is made if the patient meets defined clinical criteria; it is not made through molecular genetic testing, though MECP2 mutations are frequently identified in individuals meeting the clinical criteria for RS.[15] As many as 20% of females who meet the full clinical criteria for RS may have no identified mutation, and some individuals have MECP2 mutations but do not have RS.[16]

Because no cure is available, treatment is palliative and supportive. A multidisciplinary approach to care is recommended.

Although RS is no longer listed as a DSM diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),[17] it is listed as a differential diagnosis for autism spectrum disorder. During the regressive phase of the syndrome, some young girls with RS may have a presentation that meets diagnostic criteria for autism spectrum disorder; however, after this period, autistic features generally cease to be a major area of concern.

Pathophysiology and Etiology

RS is a genetic disorder of neurodevelopmental arrest rather than a progressive process. The gene is located on the X chromosome. Females with a single mutated MECP2 gene are more likely to survive because 1 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 of them causing truncations and missense proteins. Mutations have been found in as many as 80% of analyzed cases of classic RS. The MECP2 protein may act as a transcriptional repressor or activator, depending on the target gene with which it associates.[1, 18]

The 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 the syndrome is reportedly less than 0.4%. However, recurrence in families can occur through mechanisms such as germline mosaicism.

About 70% of RS cases are due to 4 missense mutations (ie, R106W, R133C, T158M, R306C) and 4 nonsense protein-truncating mutations (ie, R168X, R255X, R270X, R294X), which are large deletions that cause significant gene destruction, resulting in greater severity. Another cluster of mutations near the end of the gene abrogate only the very end of the protein (C-terminal truncations). Physical therapy and speech therapy may result in intragroup differences, causing different outcomes.[19]

RS is the first human disease determined to be caused by defects in a protein that regulates gene expression through interaction with methylated DNA. Accordingly, it involves abnormal chromatin structure, with broad-ranging effects on expression of genes that are otherwise not mutated. The normal MECP2 gene encodes the MECP2 protein, which 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 appear to be crucial in nervous system development beyond the initial stages. Although the nervous system is the primary site, the specific target genes are not known. Astrocyte function is abnormal in RS, presumably owing to dysfunction of the MECP2 gene.[20]

A study of 974 RS patients was conducted using data from databases that employed multiplex ligation-dependent probe amplification (MLPA) to detect large deletions on MECP2.[21] Those with large deletions were less likely to have learned to walk, were not walking, and were more likely to have the most severe gross motor dysfunction and epilepsy; they also appeared to develop epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. These findings may help predict age of onset and symptom severity in RS.

Areas of research have included the study of insulinlike growth factor 1 (IGF-1), which may extend the life span and increase brain weight in mice with RS. In addition, IGF-1 may correct the deficit in brain synaptic maturation and reverse the reduction of PSD-95 in the motor cortex.[22]

Scoliosis may be associated wtih mutation or deletion of p.Arg255.[23]


United States and international statistics

The incidence of RS has been reported to be approximately 1 per 23,000 live female births.[24]

Wide variations in incidence have been reported in various countries; rates as high as 1 per 10,000 live female births have been reported.[25] One study in Japan found an incidence of 1 per 45,000 girls aged 6-14 years.[26] 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,[27] and preserved speech variants.

Age-, sex-, and race-related demographics

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

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.[3, 6, 8] 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.

No racial variations have been reported. In a study by Kozinetz et al, which included Latin Americans, Caucasians, and African Americans in Texas, no variations in the incidence or prevalence of RS were found.[28]


Developmental potential for patients with RS is difficult to predict. Some individuals with this syndrome achieve and maintain some functional skills. As many as 60% of RS patients may retain their abilities to ambulate; the remainder lose ambulation or never walk because of atrophy, dystonia, and scoliosis.

Survival rates 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 intellectual disability, which is associated with a 35-year survival rate of only 27%.

In a case study by Hagberg et al, the median age at death was 24 years; in most cases, death was sudden and unexpected.[29] However, subsequent experiences based on longer follow-up care indicated that with attention to nutritional needs and comprehensive programs of physical and occupational therapies, RS patients can be expected to survive long into adulthood. Most survive into the fifth or sixth decade of life, often with severe disabilities. Reports of women with RS in their sixth or even eighth decade of life are now available.

Although no cure for RS is available, accurate diagnosis has many advantages. Addressing scoliosis can prevent serious complications. Girls with RS may be able to retain some communicative skills with proper assistance. Dietary adjustments can be implemented to prevent malnutrition, for which RS patients are at substantial risk. The increased risk of sudden death (possibly from long-QT sequelae) can be taken into account. Finally, diagnosis can bring relief to parents and help to identify the scope of clinical problems that can be anticipated.

Unfortunately, recent studies show that seizure risk remains significant in Rett syndrome.[30]

Patient Education

Early identification of RS can facilitate educational efforts that may alleviate some parental concerns and help 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 the expected survival into adulthood, it is important to discuss provisions for guardianship and long-term care with parents and caregivers of individuals with RS.

The International Rett Syndrome Foundation (IRSF; 800-818-7388), supports international research and meetings of parents and professionals to improve knowledge of Rett syndrome. The Web site provides overviews of RS and highlights individuals living with RS. It also provides a discussion group for parents, doctors, and researchers; updated research findings; research contacts; an online library; specifics of how to obtain diagnostic sequencing of the MECP2 gene; and links to other RS-related sites.

The Blue Bird Circle Rett Center of Baylor College of Medicine (713-798-RETT [7388] or 888-430-RETT) operates one of the largest RS clinics in the world. The Center is part of a Rett Consortium with the University of Alabama at Birmingham and the University of California at Los Angeles.

The Rett Syndrome Research Program of the Center for Genetic Disorders of Cognition and Behavior at the Kennedy-Krieger Institute, Johns Hopkins University School of Medicine (800-873-3377), can provide additional information.


The development of Rett syndrome (RS) progresses through 4 stages, which are typically reached at the following ages:

The history varies according to the clinical stage. Typical stage I symptoms are as follows:

Typical stage II symptoms are as follows:

Typical stage III symptoms are as follows:

Typical stage IV symptoms are as follows:

Physical Examination

Physical findings also vary according to the clinical stage of the disorder. Typical findings in stage I include the following:

Typical findings in stage II include the following:

Typical findings in stage III include the following:

Typical findings in stage IV include the following:

Laboratory Studies

Females who meet the clinical diagnostic criteria for Rett syndrome (RS) should undergo genetic testing. Several laboratories provide diagnostic sequencing of the MECP2 gene; details on how to order this testing are available from the International Rett Syndrome Foundation (IRSF). Patients with positive MECP2 mutational gene analysis need no further diagnostic testing.

Mutations in the MECP2 gene have been identified in a wide spectrum of clinical phenotypes, including girls with classic RS, girls with atypical or variant forms of RS, girls with autism spectrum disorder, healthy females (carriers), males with severe infantile encephalopathies, males with classic RS, and males with X-linked neurologic problems (eg, motor deficits or communication deficits).[33, 34]

Patients in whom no MECP2 mutation is found should undergo other diagnostic tests aimed at identifying other possible causes of their signs and symptoms. Such tests may include the following:

Barium Swallow or Overnight pH Probe Study

A barium swallow study or an overnight pH probe study may be performed to document gastroesophageal reflux (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.


Neuroimaging may be useful. Magnetic resonance imaging (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.


Findings on electrocardiography (ECG) may include an inverted T wave and a prolonged QT interval.[35] Studies have demonstrated that the incidence of sudden death in persons with RS is greater than that in the general population. Patients with RS may also have significantly lower heart rate variability. These cardiac abnormalities may increase through the successive stages of the syndrome.


Abnormal results on electroencephalography (EEG) are common.[36] Seizures are reported in 60-90% of patients with RS. Differentiation from Landau-Kleffner syndrome (acquired epileptic aphasia) should be made clinically and secondary to response to therapy. Patients also frequently have epileptiform abnormalities that appear to be age-related and to occur most frequently during clinical stage III, as well as 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. 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 (EMG) studies are typically normal and need not be completed, except for the purpose of excluding other conditions.


Electroretinography (ERG), in conjunction with EEG and the continued decline observed 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

Polygraphic respiratory recordings may demonstrate a pattern of disorganized breathing characterized by periods of apnea or hyperventilation and significant oxygen desaturation and clinical cyanosis.

Normal breathing occurs during sleep in persons with RS. Total sleep time may be decreased. Patients may demonstrate prolonged periods (≥18 h) of wakefulness or sleep. Nighttime awakenings with frequent laughing are reported. Screaming episodes may also occur at night; however, the possibility of other medical problems (eg, GER) must also be considered.

Psychometric Testing

Generally, the results of psychometric testing in patients with RS are indicative of profound intellectual disability. However, standard instruments that depend on the use of hands and oral language may be inadequate for full assessment of these individuals. Specialized tests, such as the Gilliam Autism Rating Scale or the Children’s Autism Rating Scale, can be helpful for detailing autisticlike symptomatology.

Histologic Findings

Morphologic features in individuals with RS 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, and limbic correlates), with preservation in the visual cortex and decreased organ weights proportional to height and weight.

Neurochemical findings include the following:

Approach Considerations

To maximize the abilities of patients with Rett syndrome (RS) requires the adoption of a comprehensive team approach.

If seizurelike activity is noted, video-electroencephalographic (EEG) monitoring may be necessary to identify epileptic seizures for which antiepileptic drugs (AEDs) are appropriate. The vacant spells noted in RS patients 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 and valproic acid) to newer AEDs (eg, topiramate and lamotrigine), a ketogenic diet, and vagal nerve stimulation.

Pharmacologic Therapy

No medications are available to treat persons with RS. Bromocriptine and carbidopa-levodopa, which are dopamine agonists, have been tried as treatments for motor dysfunction in persons with RS; however, benefits are neither substantial nor long lasting. Case reports have suggested that levocarnitine may be effective. Double-blind placebo-controlled trials of folate and betaine have not demonstrated objective evidence of improvement, despite the theory that methyl-group pools might promote transcriptional repression.[37]

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

Sarizotan, a 5HT1A agonist and D2 agonist/antagonist, has been associated with a 70-85% reduction of apneas and hyperventilation episodes in preclinical testing with both acute and chronic dosing.[38] Sarizotan has been designated orphan drug status by the U.S. Food and Drug Administration and the Committee for Orphan Medicinal Products (COMP) from the European Medicines Agency (EMA).

Nonpharmacologic Therapy

Vagal nerve stimulation has generally been safe and well tolerated, with few surgical complications, increased alertness, and improved ability to participate in activities.[39]

If seizures are well controlled, addition of the Snoezelen multisensory approach, with or without hydrotherapy, may be considered.[40, 41, 42]

If an RS patient cannot manage oral intake of food, a gastrostomy tube may be placed to minimize the risk of aspiration or recurrent pneumonias. Many girls with RS may experience significant somatic growth failure. Female RS patients aged 4-8 years may demonstrate poor or no weight gain despite apparently adequate caloric intake. In such cases, supplemental feeding is warranted, either orally or via a gastrostomy tube.

If GER is refractory to medical treatment, a fundoplication may be necessary.

Scoliosis in individuals with RS often does not respond to orthotics. Surgery should be considered in patients with Cobb angles more than 40-45° or curves that cause pain or loss of function.[43]


Many RS patients experience poor weight gain, despite excellent appetites. 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.

Osteoporosis is common in persons with RS. Treatment with vitamin D, calcium supplements, and bisphosphonate may be warranted.

The ketogenic diet may be helpful in patients with epilepsy that does not respond to usual pharmacologic treatments. Its utility in epilepsy syndromes of various etiologies suggests that this approach may have multiple mechanisms of action.[44]


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.


Optimal management of RS involves early multidisciplinary evaluation and treatment, including communication assessment, oral motor assessment, and various other assessments and therapies.

Most girls with RS lose expressive language; however, some may retain 1-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 for maximizing the potential of individuals with RS. Devices such as picture boards may be helpful.

Feeding disorders occur in more than 80% of RS patients aged 4-8 years. Causative factors include abnormal tongue movements and tone, skeletal misalignment, and rigidity,[45] underscoring the importance of oral motor assessment. Treatments may range from simple positioning and rigidity-decreasing therapy to more complex interventions.

Music, hydrotherapy, hippotherapy (ie, horseback riding), and massage are sometimes helpful. Other needs include psychosocial support for families and the creation and implementation of an appropriate educational plan with schools. Parents may require help in accessing community resources for items (eg, wheelchairs or ramps) and services that allow home care of RS patients.

Long-Term Monitoring

Issues that may have to be addressed in long-term management of RS include the following:

Perhaps reflecting attempts to communicate, agitation and screaming are common and are often distressing to families. RS patients need gradual transitions and may find it very difficult to communicate physical problems to physicians. The clinician should perform careful evaluation to exclude clinical problems and pain. If no clinical reason for the agitation can be found, treatment may include warm baths, massage, music, or a quieter and less stimulating environment.

For management of sleep disturbances in RS, short-acting nonbenzodiazepine receptor agonists (eg, zaleplon and zolpidem) may be helpful without exerting untoward effects on daytime functioning. Other approaches to sleep problems have included the administration of melatonin 2.5-7.5 mg and the application of behavioral techniques.

Constipation is common in RS patients. Treatment involves adequate fluid intake, high fiber intake, and exercise. Stool softeners may be necessary; however, continuous laxatives, suppositories, and enemas must be avoided. Long-term mineral oil use interferes with the absorption of certain fat-soluble vitamins. Regular oral milk of magnesia can be used.

Scoliosis occurs in more than 50% of RS patients, usually between the ages of 8 and 11 years. It may progress rapidly, especially if early hypotonia, dystonia, or loss of ambulation is present. Close monitoring is necessary to determine whether bracing or surgery is needed.

Osteopenia with possible fractures may occur for multiple reasons; it can be minimized through physical therapy, good nutrition, and close observation.[46]

In most girls with RS, puberty occurs at the same age as it does in girls without RS. Discussions regarding birth control should be held with the patient’s guardians.

Deterrence and Prevention

A study done in Italy of 164 patients analyzed immune function as stratified between three groups: those with Rett syndrome (RS), those with nonRS pervasive developmental disorders, and healthy controls, and found that RS patients could be distinguished from the other groups by a consistent and significant increase of the serum IgM fraction via antibody agglutination and correlated with the CSF114 (Glc)-based assay. This suggests that this change might reflect a common underlying mechanism involving neuroinflammation either as a cause or an effect of the immune dysfunction to other neurological diseases such as observed in multiple sclerosis, meningitis, and encephalitis.[47]

A 2014 study using MeCP2 gene knockout mice showed that earlier identification of RS might be possible with detection of subtle gait parameter changes as reflected by changes in treadmill overlap distance, stance width, step angle, and gait symmetry.[48]

Another study using MeCP2 gene knockout mice suggested that prevention of seizures due to RS might be possible as MeCP2 deletion from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. This is possibly related to the reduction of the number of GABAergic synapses in the cortex and enhancement of excitability of layer 5 pyramidal neurons with GABAergic transmission reduction in neurons without MeCP2 due to the role that MeCP2 plays in cortical excitatory neurons regulating GABAergic transmission and cortical excitability.[49]

Medication Summary

No medications are available specifically for treatment of Rett syndrome (RS). Antiepileptic drugs (AEDs) may be prescribed to control seizurelike activity. Antireflux agents may be given to treat gastroesophageal reflux (GER). There is some evidence that levocarnitine may be effective. Sedative-hypnotic agents are used to treat sleep disturbances. Caution should be used if propranolol is used to reduce autonomic tone as paradoxical hypertension is possible.[50]

Carbamazepine (Tegretol, Epitol, Carbatrol)

Clinical Context:  Carbamazepine may block posttetanic potentiation by reducing summation of temporal stimulation. After a therapeutic response is achieved, the dosage may be reduced to the minimum effective level, or treatment may be discontinued at least once every 3 months.

Valproic acid (Depakote, Stavzor)

Clinical Context:  Valproic acid is chemically unrelated to other drugs that treat seizure disorders. Although the mechanism of action is not established, the drug's activity may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channels, or exert a direct membrane-stabilizing effect.

For conversion to monotherapy, the concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 weeks. This reduction may start at the initiation of therapy or may be delayed by 1-2 weeks if there is concern that seizures may occur with reduction. During this period, patients should be closely monitored for increased seizure frequency.

As adjunctive therapy, divalproex sodium may be added to the patient's regimen at a dosage of 10-15 mg/kg/day, which may be increased by 5-10 mg/kg/day every week to achieve an optimal clinical response. Ordinarily, an optimal clinical response is achieved at dosages lower than 60 mg/kg/day.

Topiramate (Topamax)

Clinical Context:  Topiramate is a sulfamate-substituted monosaccharide with broad-spectrum antiepileptic activity that may have state-dependent sodium channel-blocking action, which potentiates the inhibitory activity of GABA. It may block glutamate activity.

It is not necessary to monitor topiramate plasma concentrations to optimize therapy. Coadministration with phenytoin may necessitate adjustment of the phenytoin dosage to achieve an optimal clinical outcome.

Lamotrigine (Lamictal)

Clinical Context:  Lamotrigine is a phenyltriazine that is chemically unrelated to existing AEDs. The mechanism of action is unknown. Studies suggest that the drug inhibits voltage-sensitive sodium channels, stabilizing neuronal membranes and modulating presynaptic transmitter release of excitatory amino acids. The dose should be rounded down to the nearest 5-mg increment.

Class Summary

AEDs are used to control seizure activity.

Levocarnitine (Carnitor)

Clinical Context:  Levocarnitine can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl CoA esters.

Class Summary

Vagal nerve stimulators are amino acid derivatives synthesized from methionine and lysine. They are required in energy metabolism.

Metoclopramide (Reglan, Metozolv)

Clinical Context:  Metoclopramide increases GI motility, increases resting esophageal sphincter tone, and relaxes the pyloric sphincter.

Class Summary

Prokinetic agents are used to augment cholinergic activity and improve motility in the gastrointestinal (GI) tract for treatment of reflux.

Zaleplon (Sonata)

Clinical Context:  Zaleplon is a nonbenzodiazepine hypnotic of the pyrazolopyrimidine class. Its chemical structure is unrelated to those of benzodiazepines, barbiturates, and other hypnotic drugs, but it interacts with GABA-BZ receptor complex. Zaleplon binds selectively to the omega1 receptor situated on the alpha subunit of the GABA-A receptor complex in the brain. It potentiates t-butyl-bicyclophosphorothionate binding.

Zolpidem (Ambien, Edluar, Intermezzo, Zolpimist)

Clinical Context:  Zolpidem is structurally dissimilar to benzodiazepines but similar in activity, with the exception of its reduced effects on skeletal muscle and seizure threshold.

Class Summary

Sedative and hypnotic agents are used to induce sleep.


Bettina E Bernstein, DO, Distinguished Fellow, American Academy of Child and Adolescent Psychiatry; Distinguished Fellow, American Psychiatric Association; Clinical Assistant Professor of Neurosciences and Psychiatry, Philadelphia College of Osteopathic Medicine; Clinical Affiliate Medical Staff, Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia; Consultant to Gemma Services, Private Practice; Consultant PMHCC/CBH at Family Court, Philadelphia

Disclosure: Nothing to disclose.


Daniel G Glaze, MD, Medical Director, Blue Bird Circle Rett Center; Professor, Departments of Pediatrics and Neurology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Caroly Pataki, MD, Health Sciences Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.


Joseph H Schneider, MD Assistant Professor of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School

Joseph H Schneider, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Texas Medical Association, and Texas Pediatric Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.


  1. Kubota T, Miyake K, Hirasawa T. Role of epigenetics in Rett syndrome. Epigenomics. 2013 Oct. 5(5):583-92. [View Abstract]
  2. 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. 1999 Oct. 23(2):185-8. [View Abstract]
  3. Dayer AG, Bottani A, Bouchardy I, Fluss J, Antonarakis SE, Haenggeli CA, et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. 2007 Jan. 29(1):47-50. [View Abstract]
  4. Hoffbuhr K, Devaney JM, LaFleur B. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001 Jun 12. 56(11):1486-95. [View Abstract]
  5. Huppke P, Laccone F, Kramer N, et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. 2000 May 22. 9(9):1369-75. [View Abstract]
  6. Kankirawatana P, Leonard H, Ellaway C, et al. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. 2006 Jul 11. 67(1):164-6. [View Abstract]
  7. Kerr AM, Archer HL, Evans JC, et al. People with MECP2 mutation-positive Rett disorder who converse. J Intellect Disabil Res. 2006 May. 50(Pt 5):386-94. [View Abstract]
  8. Moog U, Smeets EE, van Roozendaal KE, et al. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003. 7(1):5-12. [View Abstract]
  9. Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev. 2006 Jun. 16(3):276-81. [View Abstract]
  10. Philippe C, Villard L, De Roux N, et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006 Jan-Feb. 49(1):9-18. [View Abstract]
  11. Wan M, Lee SS, Zhang X, et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec. 65(6):1520-9. [View Abstract]
  12. Zeev BB, Bebbington A, Ho G, Leonard H, de Klerk N, Gak E, et al. The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology. 2009 Apr 7. 72(14):1242-7. [View Abstract]
  13. Temudo T, Ramos E, Dias K, Barbot C, Vieira JP, Moreira A, et al. Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type. Mov Disord. 2008 Jul 30. 23(10):1384-90. [View Abstract]
  14. Nectoux J, Bahi-Buisson N, Guellec I, Coste J, De Roux N, Rosas H, et al. The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome. Neurology. 2008 May 27. 70(22 Pt 2):2145-51. [View Abstract]
  15. Percy AK, Neul JL, Glaze DG, et al. Rett syndrome diagnostic criteria: lessons from the Natural History Study. Ann Neurol. 2010 Dec. 68(6):951-5. [View Abstract]
  16. Suter B, Treadwell-Deering D, Zoghbi HY, Glaze DG, Neul JL. Brief Report: MECP2 Mutations in People Without Rett Syndrome. J Autism Dev Disord. 2013 Aug 7. [View Abstract]
  17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 5th. Arlington, VA: American Psychiatric Association; 2013. 57.
  18. Monteggia LM, Kavalali ET. Rett syndrome and the impact of MeCP2 associated transcriptional mechanisms on neurotransmission. Biol Psychiatry. 2009 Feb 1. 65(3):204-10. [View Abstract]
  19. Zhang Y, Minassian BA. Will my Rett syndrome patient walk, talk, and use her hands?. Neurology. 2008 Apr 15. 70(16):1302-3. [View Abstract]
  20. Maezawa I, Swanberg S, Harvey D, LaSalle JM, Jin LW. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J Neurosci. 2009 Apr 22. 29(16):5051-61. [View Abstract]
  21. Bebbington A, Downs J, Percy A, Pineda M, Zeev BB, Bahi-Buisson N, et al. The phenotype associated with a large deletion on MECP2. Eur J Hum Genet. 2012 Apr 4. [View Abstract]
  22. Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A. 2009 Feb 10. 106(6):2029-34. [View Abstract]
  23. Downs J, Torode I, Wong K, Ellaway C, Elliott EJ, Christodoulou J, et al. The Natural History of Scoliosis in Females With Rett Syndrome. Spine (Phila Pa 1976). 2016 May. 41 (10):856-63. [View Abstract]
  24. Glaze DG, Schultz RJ. Rett Syndrome: Meeting the Challenge of This Gender-Specific Neurodevelopmental Disorder. Medscape Womens Health. 1997 Jan. 2(1):3. [View Abstract]
  25. Sampieri K, Meloni I, Scala E, et al. Italian Rett database and biobank. Hum Mutat. 2007 Apr. 28(4):329-35. [View Abstract]
  26. Terai K, Munesue T, Hiratani M, Jiang ZY, Jibiki I, Yamaguchi N. The prevalence of Rett syndrome in Fukui prefecture. Brain Dev. 1995 Mar-Apr. 17(2):153-4. [View Abstract]
  27. Huppke P, Maier EM, Warnke A, et al. Very mild cases of Rett syndrome with skewed X inactivation. J Med Genet. 2006 May 11. [View Abstract]
  28. Kozinetz CA, Skender ML, MacNaughton N, et al. Epidemiology of Rett Syndrome: a population-based registry. Pediatrics. 1993. 91(2):445-50. [View Abstract]
  29. Hagberg B, Berg M, Steffenburg U. Rett Syndrome - an odd handicap afffecting girls. A current 25-year follow-up in western Sweden. Lakartidningen. 1999. 96(49):5488-90. [View Abstract]
  30. Tarquinio DC, Hou W, Berg A, Kaufmann WE, Lane JB, Skinner SA, et al. Longitudinal course of epilepsy in Rett syndrome and related disorders. Brain. 2017 Feb. 140 (Pt 2):306-318. [View Abstract]
  31. Kerr AM, Julu PO. Recent insights into hyperventilation from the study of Rett syndrome. Arch Dis Child. 1999 Apr. 80(4):384-7. [View Abstract]
  32. Vignoli A, La Briola F, Canevini MP. Evolution of stereotypies in adolescents and women with Rett syndrome. Mov Disord. 2009 Jul 15. 24(9):1379-83. [View Abstract]
  33. Amir RE, Sutton VR, Van den Veyver IB. Newborn screening and prenatal diagnosis for Rett syndrome: implications for therapy. J Child Neurol. 2005 Sep. 20(9):779-83. [View Abstract]
  34. Ham AL, Kumar A, Deeter R. Does genotype predict phenotype in Rett syndrome?. J Child Neurol. 2005 Sep. 20(9):768-78. [View Abstract]
  35. Ellaway CJ, Sholler G, Leonard H, et al. Prolonged QT interval in Rett syndrome. Arch Dis Child. 1999 May. 80(5):470-2. [View Abstract]
  36. Glaze DG, Schultz RJ, Frost JD. Rett syndrome: characterization of seizures versus non-seizures. Electroencephalogr Clin Neurophysiol. 1998 Jan. 106(1):79-83. [View Abstract]
  37. Glaze DG, Percy AK, Motil KJ, Lane JB, Isaacs JS, Schultz RJ, et al. A study of the treatment of Rett syndrome with folate and betaine. J Child Neurol. 2009 May. 24(5):551-6. [View Abstract]
  38. Abdala AP, Lioy DT, Garg SK, Knopp SJ, Paton JF, Bissonnette JM. Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome. Am J Respir Cell Mol Biol. 2014 Jun. 50 (6):1031-9. [View Abstract]
  39. Wilfong AA, Schultz RJ. Vagus nerve stimulation for treatment of epilepsy in Rett syndrome. Dev Med Child Neurol. 2006 Aug. 48(8):683-6. [View Abstract]
  40. Chung JC, Lai CK, Chung PM, French HP. Snoezelen for dementia. Cochrane Database Syst Rev. 2002. CD003152. [View Abstract]
  41. Lavie E, Shapiro M, Julius M. Hydrotherapy combined with Snoezelen multi-sensory therapy. Int J Adolesc Med Health. 2005 Jan-Mar. 17(1):83-7. [View Abstract]
  42. Lotan M. Management of Rett syndrome in the controlled multisensory (Snoezelen) environment. A review with three case stories. ScientificWorldJournal. 2006. 6:791-807. [View Abstract]
  43. Downs J, Young D, de Klerk N, Bebbington A, Baikie G, Leonard H. Impact of scoliosis surgery on activities of daily living in females with Rett syndrome. J Pediatr Orthop. 2009 Jun. 29(4):369-74. [View Abstract]
  44. Hartman AL. Does the effectiveness of the ketogenic diet in different epilepsies yield insights into its mechanisms?. Epilepsia. 2008 Nov. 49 Suppl 8:53-6. [View Abstract]
  45. Motil KJ, Schultz RJ, Browning K, et al. Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome. J Pediatr Gastroenterol Nutr. 1999 Jul. 29(1):31-7. [View Abstract]
  46. Leonard H, Thomson MR, Glasson EJ, et al. A population-based approach to the investigation of osteopenia in Rett syndrome. Dev Med Child Neurol. 1999 May. 41(5):323-8. [View Abstract]
  47. PapiniAM, Nuti F, Real-Fernandez F, Rossi G, Tiberi C, Sabatino G, et al. Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N (Glc) IgM Antibody Fraction. J of Immunology Research. 2014. 1-6.
  48. Gadalla KKE, Ross PD, Riddell JS, Bailey MES, Cobb SR. Knockout Mouse Model of Rett Syndrome Reveals Early-Onset and Progressive Motor Deficits. PLoS One. 2014. 9(11):1-5.
  49. Zhang W, Peterson M, Beyer B, Frankel WN, Zhang ZW. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures. J of Neuroscience. Feb 2014. Feb 12:2754-2763.
  50. Santosh PJ, Bell L, Lievesley K, Singh J, Fiori F. Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report. BMC Pediatr. 2016 Nov 29. 16 (1):194. [View Abstract]