eMedicine Specialties > Pediatrics: Developmental and Behavioral > Medical Topics

Pervasive Developmental Disorder: Rett Syndrome

Author: Bettina E Bernstein, DO, Assistant Professor, Department of Psychiatry, Philadelphia College of Osteopathic Medicine; Private Practice at the Wynnewood House, Consultant to Child Guidance Resource Centers, Early Elementary Education Program
Coauthor(s): Joseph H Schneider, MD, Clinical Assistant Professor of Pediatrics, Section of Neonatology, Univ. Texas Southwestern at Dallas and Childrens Medical Center; Daniel G Glaze, MD, Medical Director, Blue Bird Circle Rett Center; Associate Professor, Departments of Pediatrics and Neurology, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Mar 13, 2008

Introduction

Background

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

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

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

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

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

Pathophysiology

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

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

Frequency

United States

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

International

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

Mortality/Morbidity

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

Race

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

Sex

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

Age

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

Clinical

History

History varies by clinical stage as follows:

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

Physical

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

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

Causes

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

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