Rett Syndrome

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Updated: Jul 15, 2015
  • Author: Bettina E Bernstein, DO; Chief Editor: Caroly Pataki, MD  more...
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.

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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.

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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]

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Epidemiology

United States and international statistics

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

Wide variations in incidence have been reported in various countries; rates as high as 1 per 10,000 live female births have been reported. [24] One study in Japan found an incidence of 1 per 45,000 girls aged 6-14 years. [25] 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, [26] 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. [27]

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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. [28] 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. For example, 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.

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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.

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