Rett Syndrome 

Updated: Feb 06, 2017
Author: Bettina E Bernstein, DO; Chief Editor: Caroly Pataki, MD 

Overview

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:

  • Stage I - Developmental arrest (6-18 months)

  • Stage II - Rapid deterioration or regression (1-4 years)

  • Stage III - Pseudostationary (2-10 years)

  • Stage IV - Late motor deterioration (>10 years)

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

  • Stage I - Gross motor development delay, disinterest in play, and loss of eye contact; hypotonia; hand wringing; unusual placidity and calmness; vague and nonspecific early symptoms; breath-holding spells

  • Stage II - Deterioration; autisticlike behavior; stereotypic hand movements during wakefulness; breathing irregularities; seizures and vacant spells that resemble seizures; sleep disorders, intermittent strabismus, and irritability

  • Stage III - Some improvement in behavior, hand use, and communication skills; good eye contact and attempts to communicate intent; continued mental impairment and hand stereotypies; increasing rigidity, bruxism, and involuntary tongue movements; motor dysfunction and seizures; continued breathing irregularities; poor weight gain despite good appetite; difficult feeding and some degree of oral motor dysfunction

  • Stage IV - No additional deterioration of cognitive skills, communication skills, or hand skills; increased motor problems; cessation of walking; possible reduction of seizure frequency

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

  • Stage I - Gross motor development delay; loss of eye contact; deceleration of head, weight, and height growth; hypotonia; hand wringing; abnormal placidity and calmness; no cutaneous findings on Wood lamp examination

  • Stage II - Autisticlike behavior; midline hand wringing, clapping, hand washing, or hand-to-mouth movements; episodes of hyperventilation or breath-holding; seizures and vacant spells that resemble seizures; intermittent strabismus and irritability

  • Stage III - Hand stereotypies, rigidity, hyperventilation, breath holding, bruxism, involuntary tongue movements, poor weight gain, and scoliosis

  • Stage IV - Dystonia, rigidity, muscle wasting, quadriparesis, scoliosis or kyphoscoliosis, loss of ambulation, growth retardation, hyperventilation, and seizures; improved frequency and intensity of hand movements; preserved eye contact

See Presentation for more detail.

Diagnosis

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:

  • Stage I - Benign congenital hypotonia, cerebral palsy, Prader-Willi syndrome, Angelman syndrome, and metabolic disorders (eg, fetal alcohol syndrome and trisomy 13)

  • Stage II - Autism spectrum disorder, Angelman syndrome, encephalitis, hearing or visual disturbance, Landau-Kleffner syndrome, psychoses, slow virus panencephalopathy, tuberous sclerosis, metabolic disorders (eg, phenylketonuria and ornithine transcarbamoylase deficiency), and infantile neuronal ceroid lipofuscinosis

  • Stage III - Spastic ataxia, cerebral palsy, spinocerebellar degeneration, leukodystrophies, neuroaxonal dystrophy, Lennox-Gastaut syndrome, and Angelman syndrome (probably not Kabuki makeup syndrome, because patients would have macrocephaly)

  • Stage IV - Other degenerative disorders

Laboratory studies that may be warranted include the following:

  • Genetic testing (for all patients who meet the clinical diagnostic criteria for RS)

  • Serum lactate, ammonia, pyruvate, and amino acids

  • Urinary organic acids

  • Chromosomal studies, including specific tests for Angelman syndrome (chromosome 15)

  • Urinary tests for uroporphobilinogen to rule out intermittent porphyria (rarely helpful)

Other studies that may be helpful include the following:

  • Barium swallow study or overnight pH probe study

  • Neuroimaging (eg, MRI)

  • Electrocardiography (ECG)

  • Electroencephalography (EEG)

  • Neurophysiologic testing (auditory brainstem-evoked responses, somatosensory-evoked responses, electromyography [EMG])

  • Electroretinography (ERG)

  • Polygraphic respiratory recordings

  • Psychometric testing

See DDx and Workup for more detail.

Management

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

  • Antiepileptic drugs (AEDs) for epilepsy

  • Antireflux drugs for GER

  • Levocarnitine

  • Sedative-hypnotics

Nonpharmacologic therapy may include the following as appropriate:

  • Vagal nerve stimulation

  • Snoezelen multisensory approach, with or without hydrotherapy

  • Placement of a gastrostomy tube

  • Fundoplication, if GER is refractory to medical treatment

  • Surgical treatment of scoliosis, if the condition does not respond to orthotics

Dietary measures may include the following:

  • High-calorie diet, with approximately 70% of calories from fats and 15% each from carbohydrates and proteins

  • Vitamin D, calcium supplements, and bisphosphonate for osteoporosis

  • Ketogenic diet

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

  • Communication assessment

  • Oral motor assessment

  • Other assessments and therapies, such as music, hydrotherapy, hippotherapy (ie, horseback riding), massage, psychosocial support for families, educational planning with schools, and help with accessing community resources for home care

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

  • Agitation and screaming

  • Sleep disturbances

  • Constipation

  • Scoliosis

  • Osteopenia with possible fractures

  • Birth control

See Treatment and Medication for more detail.

Background

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]

Epidemiology

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]

Prognosis

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.

 

Presentation

History

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

  • Stage I - Developmental arrest (6-18 months)

  • Stage II - Rapid deterioration or regression (1-4 years)

  • Stage III - Pseudostationary (2-10 years)

  • Stage IV - Late motor deterioration (>10 years)

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

  • 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

  • Breath-holding spells, including apneustic breathing and hyperventilation, can occur early

Typical stage II symptoms are as follows:

  • 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

  • Stage II can last weeks to months and may be characterized by reports of autisticlike behavior (eg, 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 hyperventilation[31] or breath holding

  • Patients may also have seizures and vacant spells that resemble seizures

  • Sleep disorders, intermittent strabismus, and irritability may be noted

Typical stage III symptoms are as follows:

  • 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 patients have some degree of oral motor dysfunction

Typical stage IV symptoms are as follows:

  • No additional deterioration of cognitive skills, communication skills, or hand skills occurs; however, motor problems may increase, including hypertonia, dystonia, and parkinsonian symptoms (eg, bradykinesia, rigidity, and retropulsion)

  • Some patients stop walking

  • Seizure frequency may be reduced

Physical Examination

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

  • Patients may show gross motor development delay, loss of eye contact, deceleration in head growth (sometimes occurring by age 3 months), deceleration in weight growth (sometimes occurring by age 4 months), deceleration of height growth (sometimes occurring by age 16 months), hypotonia, and hand wringing

  • Infants may appear placid and calm in comparison with healthy infants

  • Cutaneous findings (eg, hypopigmented macules) are not observed on a Wood lamp examination

Typical findings in stage II include the following:

  • Patients may exhibit 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

Typical findings in stage III include the following:

  • Patients may have hand stereotypies, rigidity, hyperventilation, breath holding, bruxism, involuntary tongue movements, poor weight gain, and scoliosis

Typical findings in stage IV include the following:

  • Patients may have dystonia, rigidity, muscle wasting, quadriparesis, scoliosis or kyphoscoliosis, loss of ambulation, growth retardation, hyperventilation, and seizures.

  • Improvements may be observed in the 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

 

DDx

Diagnostic Considerations

Diagnosis of Rett syndrome (RS) is initially difficult; however, the observant pediatrician may note deceleration of head, weight, and height growth. Stereotypies involving separated or joined hands, mouthing, pill-rolling and twisting persist into adulthood and should therefore increase the index of suspicion of RS in adults with otherwise unclassified symptoms.[32]

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:

  • Stage I - Benign congenital hypotonia, cerebral palsy, Prader-Willi syndrome, Angelman syndrome, and metabolic disorders (eg, fetal alcohol syndrome and trisomy 13)

  • Stage II - Autism spectrum disorder, Angelman syndrome, encephalitis, hearing or visual disturbance, Landau-Kleffner syndrome, psychoses, slow virus panencephalopathy, tuberous sclerosis, metabolic disorders (eg, phenylketonuria and ornithine transcarbamoylase deficiency), and infantile neuronal ceroid lipofuscinosis

  • Stage III - Spastic ataxia, cerebral palsy, spinocerebellar degeneration, leukodystrophies, neuroaxonal dystrophy, Lennox-Gastaut syndrome, and Angelman syndrome (probably not Kabuki makeup syndrome, because patients would have macrocephaly)

  • Stage IV - Other degenerative disorders

Diagnostic criteria

Diagnosis of classic RS requires that patients meet certain necessary, supportive, and exclusionary characteristics. Because of the heterogeneity of the syndrome, atypical or variant instances of RS may occur; primary and supportive criteria for these have also been formulated.

Classic Rett syndrome

Necessary criteria for the diagnosis of classic RS are as follows:

  • 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 months to 3 years)

  • Loss of acquired skills (age, 3 months to 3 years), including learned purposeful hand skills, acquired babble 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, as well as jerky truncal ataxia, body dyspraxia, or both

  • Diagnosis is tentative until the individual is aged 2-5 years

Supportive criteria for the diagnosis of classic RS are as follows:

  • Breathing dysfunction, including periodic apnea during wakefulness, intermittent hyperventilation, breath-holding spells, and forced expulsion of air or saliva

  • Bloating or marked air swallowing

  • Electroencephalographic (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, or dystonic traits

  • Peripheral vasomotor disturbances

  • Neurogenic scoliosis

  • Hypotrophic small and cold feet

  • Growth retardation

Exclusion criteria for the diagnosis of classic RS are as follows:

  • Organomegaly or other signs of storage disease

  • Retinopathy or optic atrophy

  • Microcephaly at birth

  • Presence 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

Atypical or variant Rett syndrome

In a girl aged 10 years or older with intellectual disability of unexplained origin who does not demonstrate the exclusion criteria for classic RS (see above), atypical or variant RS can be diagnosed if at least 3 of the 6 primary criteria below are present, along with at least 5 of the 11 supportive criteria.

Primary criteria for the diagnosis of atypical or variant RS are as follows:

  • Partial or subtotal loss of acquired fine finger skills in late infancy or early childhood

  • Loss of acquired single words or phrases or nuanced babble

  • RS hand stereotypies, with hands together or apart

  • Early deviant communicative ability

  • Deceleration of head growth amounting to 2 standard deviations, even when the value is still within the reference range

  • RS disease profile (ie, a regression period [stage II] followed by some recovery of contact and communication [stage III], in contrast to slow neuromotor regression through school age and adolescence)

Supportive criteria for the diagnosis of atypical or variant RS are as follows:

  • Breathing irregularities (hyperventilation or breath holding)

  • Bloating or marked air swallowing

  • Characteristic RS teeth grinding

  • Gait dyspraxia

  • Neurogenic scoliosis or high kyphosis (in ambulant girls)

  • Development of abnormal lower limb neurology

  • Small blue or cold impaired feet, autonomic or trophic dysfunction

  • Characteristic RS findings on EEG

  • Unprompted sudden laughing or screaming spells

  • Impaired or delayed nociception

  • Intensive eye communication with eye pointing

Differentials

Acquired Epileptic Aphasia

Autism Spectrum Disorder

Cerebral Palsy

Encephalitis

Fetal Alcohol Syndrome

Hearing Impairment

Lennox-Gastaut Syndrome

Metachromatic Leukodystrophy

Neuronal Ceroid Lipofuscinosis

Ornithine Transcarbamoylase Deficiency

Patau Syndrome

Phenylketonuria

Prader-Willi Syndrome

Spastic Ataxia

Tuberous Sclerosis

 

Workup

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:

  • Serum lactate, ammonia, pyruvate, and amino acids

  • Urinary organic acids

  • Chromosomal studies, including specific tests for Angelman syndrome (chromosome 15)

  • Urinary tests for uroporphobilinogen to rule out intermittent porphyria (rarely helpful)

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

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.

Electrocardiography

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.

Electroencephalography

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

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:

  • 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

 

Treatment

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]

Diet

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]

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.

Consultations

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:

  • Agitation and screaming

  • Sleep disturbances

  • Constipation

  • Scoliosis

  • Osteopenia with possible fractures

  • Birth control

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

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]

Anticonvulsants, Other

Class Summary

AEDs are used to control seizure activity.

Carbamazepine (Tegretol, Epitol, Carbatrol)

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)

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)

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)

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.

Nutritional Supplements

Class Summary

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

Levocarnitine (Carnitor)

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.

Prokinetic agents

Class Summary

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

Metoclopramide (Reglan, Metozolv)

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

Sedative/Hypnotics

Class Summary

Sedative and hypnotic agents are used to induce sleep.

Zaleplon (Sonata)

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)

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