Definition/Description[edit | edit source]
Rett syndrome is a rare progressive neurodevelopmental disorder , leading to impaired cognitive and physical development. The disorder results from a non-inherited genetic mutation, with almost all cases having no family history.
Epidemiology[edit | edit source]
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 cognitive, 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[edit | edit source]
Nowadays, RTT is considered as a part of a spectrum of disease related to mutation of the methyl CpG binding protein 2 (MECP2) gene, which is located on the long arm (q) of the X chromosome (Xq28).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. Infants often experiencing seizures before 6 months of age were often diagnosed as having Rett syndrome were described as atypical cases resulting from mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, however CDKL5 has now been classified as a separate disorder. 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[edit | edit source]
Clinical feature of RTT patients is highly variable. 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.
Co-morbidities 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 co-morbidity, 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[edit | edit source]
- Early developmental skills are usually acquired but many later than normal time required
- 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 [edit | edit source]
- 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[edit | edit source]
- Hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms are stereotypical in Rett syndrome
- Repeatedly moving the hands towards the mouth
Breathing Irregularities[edit | edit source]
- Apnea (breath holding)
- Air swallowing
Other neurological symptoms[edit | edit source]
Symptoms affecting other parts of the body[edit | edit source]
- 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
- Toe walking
Diagnostic Procedures[edit | edit source]
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|
|Supportive Criteria for Atypical RS|
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[edit | edit source]
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 with 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:
- 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[edit | edit source]
There is a diminished ability to move in persons with Rett syndrome. The Rett Syndrome Gross Motor Scale was created and is used to assess and monitor the progression of symptoms along with the improvement in the ability of the patient to perform important every day gross motor skills. There are standardized, detailed instructions and definitions of each item available to the health care provider administering the test. The items include motor tasks in sitting, standing, walking and running. Each of the items is scored from 0-4; 0 being the highest assistance needed and 4 being no assistance needed. The maximum value that can be scored overall is 45, corresponding to the highest level of functioning. The minimum value that can be scored is 0, corresponding to the lowest level of functioning. There are also 3 subscales that can help break down and distinguish where the patient is having the most difficulties including sitting, standing and walking, and challenge.
Downs et al. (2016) stated that the outcome measure has great repeatability (intraclass correlation coefficient for total score 0.99, 95% CI 0.93–0.98). They also stated that a 4-point change in the 45-point scale would be a significant change.
Please refer to Supporting Information(S1) Appendix in the Rett Syndrome Gross Motor Scale for the full outcome measure with instructions.
Medical Management[edit | edit source]
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 for motor dysfunction in Rett syndrome.
In addition to pharmacologic treatments, orthopaedic approaches may be required for the management of contractures or scoliosis in efforts to optimize gait or skeletal alignment. Specifically, surgery should be considered when lateral curvatures exceed 45 degrees. Similarly, persons with Rett syndrome who have feeding disorders may have a gastrostomy 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 for 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
Physiotherapy Management[edit | edit source]
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 the 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. Physiotherapy 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 are 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
- In the 2001 case report by Yasuhara et al., thirty-minute private sessions of active music therapy were used to treat three children with RTT. At the end of the treatment, patients showed (1) some degree of mental and physical development, (2) improvement of purposive hand use, and (3) development of language comprehension
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 time-frame to begin physiotherapy (the earlier the better)
Systematic review infers a multimodal individualized physical therapy program should be prescribed to patients with Rett syndrome to preserve autonomy and improve quality of life. However, further high-quality studies should be carried out to confirm the findings. 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.
Resources[edit | edit source]
We have kindly been given permission to share this video of Esme on Physiopedia. Learn about Esme's journey, a 4 year old girl with Rett syndrome. For more information about Rett's Syndrome in the UK you can visit Rett UK
'RETT: There is Hope' is a movie focusing on families affected by Rett syndrome, treatments of the disorder, and emerging research in the field.
References[edit | edit source]
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