Rett Syndrome

Original Editors - Sofie Bourdinon

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Definition/Description

Rett Syndrome is a rare progressive disorder of the nervous system, leading to impaired cognitive and physical development. The disorder results from a non-inherited genetic mutation, with almost all cases having no family history of the disorder.

Epidemiology

Rett syndrome occurs almost exclusively in girls, affecting approximately 1 in every 10,000-15,000 females. The incidence rate in males is unknown, partly due to males with the genetic mutation rarely surviving childbirth. In the rare circumstance where males with Rett syndrome survive, deficits are often more severe, as males do not have an additional X chromosome to compensate for the mutation. Children with Rett syndrome typically show normal development until 6 to 18 months after birth, later followed by regression of cogntive, language and motor function. On average, the life expectancy of females with Rett syndrome ranges between 40 to 50 years old, with death often occurring unexpectedly or due to secondary causes such as pneumonia.

Etiology

Most cases of Rett syndrome are caused by a non-inherited mutation on the dominant X chromosome, on the gene encoding methyl-CpG-binding protein-2 (MECP2). MECP2 is important for DNA methylation and mutations of this protein result in the inability to deactivate or repress specific genes. The ability to ‘turn-off’ certain genes is necessary for normal development and maintenance of the nervous system, with impairment in this function potentially leading to cognitive and motor deficits. The severity of Rett syndrome varies dramatically between individuals and depends on the type and location of the MECP2 mutation, as well as the process of random X chromosome inactivation. Approximately 5-10% of cases do not appear to have MECP2 mutations. Rather, a proportion of atypical cases result from mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, with seizures occurring before 6 months of age being characteristic of this mutation. Further research needs to be conducted in order to investigate how MECP2 gene mutations and other factors contribute to the development and severity of Rett syndrome.

Characteristics/Clinical Presentation

Rett syndrome is characterized by normal development during the first few months of life followed by regression of motor and communication skills, cognitive impairment, stereotypic hand movements, abnormal breathing, and gait abnormalities. In Rett syndrome, the central nervous system is primarily affected; however it often manifests as a multi-system disorder that impacts a child’s growth, pubertal development and overall health.

Comorbidities are common in Rett syndrome, including gastrointestinal problems, scoliosis, epilepsy, unusual breathing patterns, sleep disturbances and low bone density leading to increased risk of fractures. Scoliosis is the most prevalent orthopedic comorbidity, occurring by age 15 in approximately 75% of individuals with Rett syndrome. Altered sensitivity to pain is another characteristic that individuals with Rett syndrome may experience.

Signs and symptoms of Rett syndrome include:

Developmental and language skills
• Early developmental skills are usually acquired but many later than normal
• Significantly impaired communication and cognitive abilities
• Many children lose the ability to speak at around 12 to 18 months
• Gross motor and receptive language acquisition often superior to fine motor and expressive language skills
• Mathematics and reading skills are delayed or absent

Apraxia 
• Inability or impaired ability to perform tasks or movements
• Deficits in movements such as eye gaze and speech
• Complex motor skills such as managing stairs or riding a bike are delayed or absent

Hand movements
• Hang wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms are stereotypical in Rett syndrome
• Repeatedly moving the hands towards the mouth

Breathing Irregularities
• Apnea (breath holding)
• Hyperventilation
• Air swallowing

Other neurological symptoms
• Epilepsy
• Sleep disturbances
• Tremors
• Excess salivation
• Cognitive impairments

Symptoms affecting other parts of the body
• Scoliosis
• Microcephaly (small head size)
• Small hands and feet
• Gastrointestinal problems, including reflux and constipation
• Teeth grinding, issues with chewing and swallowing
• Heart rhythm abnormalities
• Low muscle tone
• Dystonia
• Toe walking

Diagnostic Procedures

A diagnosis of Rett Syndrome is made based on careful observation of a child’s growth and development, and the presence of certain core symptoms. A set of updated diagnostic criteria for Rett Syndrome was recently published. Rett Syndrome is often classified as either typical (classic) or atypical (variant) based on symptoms and severity (Figure 1). Although not a necessary diagnostic feature in the updated criteria, deceleration of postnatal head growth is often a sign that initially alerts medical professionals to Rett Syndrome as a potential diagnosis.

Table 1: Revised Diagnostic Criteria for Rett Syndrome (RS). Adapted from Neul et al. (2010)

Main Criteria	Required for Typical RS	Exclusion Criteria for Typical RS	Required for Atypical RS
• Partial or complete loss of acquired purposeful hand skills • Partial or complete loss of acquired spoken language • Gait abnormalities • Stereotypic hand movements	• Period of regression followed by recovery or stabilization • All main criteria and all exclusion criteria • Supportive criteria often present	• Brain injury secondary to trauma • Grossly abnormal psychomotor development in first 6 months of life	• A period of regression followed by recovery or stabilization • 2/4 of main criteria • 5/11 supportive criteria

Supportive Criteria for Atypical RS

• Breathing disturbances when awake • Teething grinding or jaw clenching • Impaired sleep pattern • Abnormal muscle tone • Peripheral vasomotor disturbances • Scoliosis • Slowed growth • Small, cold hands and feet • Inappropriate laughing • Diminished pain response • Intense eye communication

Genetic testing may be performed to screen for mutations in the MECP2 gene on chromosome Xq28. This mutation is apparent in approximately 95-97% of individuals with typical Rett Syndrome. However, the absence of a mutation on the MECP2 gene does not rule out Rett syndrome, and therefore diagnosis must be accompanied by the presence of distinct diagnostic criteria (Figure 1) and made on a case-by-case basis. Other neurodevelopmental conditions such as autism and non-specific intellectual disability can be associated with MECP2 mutations, and must first be ruled out before a confident diagnosis of Rett syndrome can be made.

Differential Diagnosis

Infantile autism is the most common incorrect diagnosis made for children with Rett syndrome. Autism spectrum disorders (ASDs) and Rett Syndrome have common symptomology including impaired social interaction and communication, as well as unusual behaviour or movements. Boston Children’s Hospital encourages clinicians to think of Rett Syndrome as a distinct disorder that has autism- like characteristics.

Other disorders with similar symptoms to Rett Syndrome must be ruled out before a diagnosis can be made.
Some of these conditions include:
• Autism
• Cerebral palsy
• Other genetic disorders
• Hearing or vision problems
• Degenerative disorders that cause the body or brain to break down
• Brain disorders caused by trauma or infection
• Prenatal brain damage

Outcome Measures

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Medical Management

The medical care and management for Rett Syndrome is symptomatic and varies among each individual. For example, persons with Rett Syndrome may take antiepileptic drugs for seizures and antidepressant drugs for anxiety  Currently, there is no effective treatment available; however, there are several potential avenues under investigation. Research on MeCP2 deficient mice suggests that the effects of dopamine agonists (levodopa) may be a potential treatment on motor dysfunction in Rett Syndrome.

In addition to pharmacologic treatments, orthopaedic approaches may be required for the management contractures or scoliosis in efforts to optimize gait or skeletal alignment. Specifically, surgery should be considered when lateral curvatures exceed 45 degrees. Similarly, feeding disorders among persons with Rett Syndrome may have a gastrotomy tube inserted to prevent aspiration during feeding . Furthermore, maintaining good bone health is also an area of management for persons with Rett Syndrome. Both pharmacological and non-pharmacological methods to improving bone density and reducing fractures are shown to be effective. In particular, Rett Syndrome  guidelines emphasize vitamin D supplementation and increasing levels of physical activity.

Other health care professionals also play a crucial role in the treatment of persons with Rett Syndrome. Some may include:

• Speech-language pathologists – treatments targeted towards developing communication skills including non-verbal forms of communication (eye gaze, symbol boards), speech and language development
• Occupational therapists – therapy focused on achieving independence with activities of daily living and control over movements
  

Physical Therapy Management

Rett Syndrome is characterized by neuromuscular limitations that require active therapeutic intervention. Moreover, physical therapy is an important part of the management of the disorder as it aims to maximize and maintain function of persons with Rett Syndome. Target areas of treatment in persons with Rett Syndrome include low cardiovascular capacity, uncoordinated movements (ataxia), bony deformities (spine, peripheral extremities) and spatial disorientation. Physical therapy aims to improve or maintain mobility and balance, prevent or reduce bony deformities, and ultimately improve independence. Given the large variability among persons with Rett Syndrome, some physiotherapy goals that may be appropriate for a majority of this population include (but not limited to):

• Improve mobility and posture and reducing tone (improves feeding abilities)
• Reducing apraxia through repetitive functional movements/activities
• Increase cardiovascular fitness
• Stimulate hand use (hand splints, fine motor activities)
• Enhance coordination and balance through practice in various situations and environments
• Improve body awareness through proprioceptive training
• Other therapies including hydrotherapy and hippotherapy

Some considerations with treatment:

• Individuals with Rett Syndrome experience daily fluctuations in mood and function. Therefore, the intervention plan should be flexible and constantly adjusted to the patient’s state . Therapists should practice good follow-up routines regarding the client’s status and adjust interventions as needed.
• Therapy goals (intensity and pace of treatments) should be adjusted according to reaction of patient
• Foster elements of independence by enabling the patient to have control and choice in activities
• There is no optimal timeframe to begin physiotherapy (the earlier the better)

Overall, the literature suggests that preventative approaches undergoing functional therapy with a multidisciplinary team should be adopted to maintain and maximize the abilities of persons with Rett Syndrome. 

Key Research

Haberg, B.'s (1995) review was one of the first studies to attempt to develop an understanding of the typical phenotype as well as other clinical signs. This research was pivital in recognizing and diagnosing RS patients as genetic loci for RS had not yet been identified. A summary of the paper's findings can be found below. 

Abstract

Rett syndrome, a peculiar neurodevelopmental deficiency affecting females, which starts in early childhood, is reviewed based on a Swedish series of 170 females, 2-52 years of age (to December 1994). To date, the well recognized classical phenotype was found in 75% of cases. Atypical variant forms, mainly more mildly affected mentally retarded girls and adolescent women, were still in a minority, but constitute, with increasing experience, an expanding cohort. The biology and genetics of the condition seem puzzling. Traditional neurodegenerative pathology has been excluded. An age-limited neurodevelopmental, as yet unknown, brain growth deficiency, is at present indicated. The syndrome is most probably genetically determined, but the mode of transmission is not convincingly compatible with any known pattern.

Introduction

In a review of 170 Swedish female cases of Rett syndrome, the recognized classical phenotype was present in 75% of the cases. Supportive clinical peculiarities are also presented.

Case Presentation

The Swedish case series are comprised of 170 females, diagnosed over 35 years. 127 are classified as classic Rett syndrome cases and 43 are considered variant forms of Rett syndrome.

Discussion

Diagnostic efforts in brain research, genetics and molecular biology may lead to identification of chemical or genetic markers for Rett syndrome. Although the genetic basis for Rett syndrome is indisputable, genetic investigations have not identified a specific locus responsible for the syndrome. Similarly, urine, blood and cerebrospinal fluid analysis has yet to reveal a diagnostic marker for Rett syndrome. Rett syndrome is thought to be a neurodevelopmental disorder but the biological parameters have not yet been determined.

References

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