Definition/Description
Rett syndrome is a rare progressive disorder of the nervous system, leading to impaired cognitive and physical development[1][2]. The disorder results from a non-inherited genetic mutation, with almost all cases having no family history[1].
Epidemiology
Rett syndrome occurs almost exclusively in girls, affecting approximately 1 in every 10,000-15,000 females[3]. The incidence rate in males is unknown, partly due to males with the genetic mutation rarely surviving childbirth[1]. 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[1][2]. 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[4][1]. 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[2][5].
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)[5][6]. MECP2 is important for DNA methylation and mutations of this protein result in the inability to deactivate or repress specific genes[5]. 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[4][6]. 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[6]. Approximately 5-10% of cases do not appear to have MECP2 mutations[7]. 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[3][7]. 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[8]. 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[8].
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[9]. Scoliosis is the most prevalent orthopedic comorbidity, occurring by age 15 in approximately 75% of individuals with Rett syndrome[10]. Altered sensitivity to pain is another characteristic that individuals with Rett syndrome may experience[11].
Signs and symptoms of Rett syndrome include:
Developmental and language skills
• Early developmental skills are usually acquired but many later than normal[8]
• Significantly impaired communication and cognitive abilities[12]
• Many children lose the ability to speak at around 12 to 18 months[12]
• Gross motor and receptive language acquisition often superior to fine motor and expressive language skills[8]
• Mathematics and reading skills are delayed or absent[8]
Apraxia
• Inability or impaired ability to perform tasks or movements[12]
• Deficits in movements such as eye gaze and speech[12]
• Complex motor skills such as managing stairs or riding a bike are delayed or absent[8]
Hand movements
• Hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms are stereotypical in Rett syndrome[13]
• Repeatedly moving the hands towards the mouth[12]
Breathing Irregularities[12]
• Apnea (breath holding)
• Hyperventilation
• Air swallowing
Other neurological symptoms[12]
• Epilepsy
• Sleep disturbances
• Tremors
• Excess salivation
• Cognitive impairments
Symptoms affecting other parts of the body[12]
• 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[13]. Rett syndrome is often classified as either typical (classic) or atypical (variant) based on symptoms and severity (Figure 1)[13]. 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[13][14].
Table 1: Revised Diagnostic Criteria for Rett Syndrome (RS). Adapted from Neul et al. (2010)[13]
| 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[15]. 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[13]. 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[16].
Differential Diagnosis
Infantile autism is the most common incorrect diagnosis made for children with Rett syndrome[17]. 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[12].
Other disorders with similar symptoms to Rett syndrome must be ruled out before a diagnosis can be made. Some of these conditions include[14]: 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 everyday gross motor skills[18]. 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 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[18]. 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[18]. Please refer to Supporting Information(S1) Appendix in the 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 [19] 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[20].
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[21]. Similarly, persons with Rett syndrome who have feeding disorders may have a gastrotomy tube inserted to prevent aspiration during feeding [9]. 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[22].
Other health care professionals also play a crucial role in the treatment of persons with Rett syndrome. Some may include:
Rett syndrome is characterized by neuromuscular limitations that require active therapeutic intervention[25]. 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[24]. Target areas of treatment in persons with Rett syndrome include low cardiovascular capacity, uncoordinated movements (ataxia), bony deformities (spine, peripheral extremities) and spatial disorientation[25]. Physical therapy aims to improve or maintain mobility and balance, prevent or reduce bony deformities, and ultimately improve independence[26]. 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)[25]:
Some considerations with treatment:
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. Film of Esme, a 4 year old girl with Rett syndrome. ‘RETT: There is Hope’ is a movie focusing on families affected by Rett syndrome, treatments of the disorder, and emerging research in the field. Haberg, B.’s (1995) case review was one of the first studies to attempt to develop an understanding of the typical phenotype as well as other clinical signs.[30] This research was pivital in recognizing and diagnosing Rett syndrome patients as genetic loci for Rett symdrome had not yet been identified. A summary of the paper’s findings can be found below. Abstract
This review of a series of Swedish females with Rett syndrome examined their signs and symptoms and found that 75% of cases shared the characteristics which were recognized as the classic phenotype. Atypical forms of Rett syndrome were found to be a minority in the cases reviewed. The study successfully confirmed the classic Rett syndrome phenotype and suggested that Rett syndrome is a neurodevelopmental deficiency, but was unable to determine a genetic determinant.
Introduction
In a review of 170 Swedish female (2 to 52 years of age) cases of Rett syndrome, the recognized classical phenotype was present in 75% of the cases. Supportive clinical peculiarities were also presented. The females in the study were diagnosed over 35 years, 127 were considered to have the classic Rett syndrome and 43 were considered variant forms of Rett syndrome.
Case Presentation
Haberg identified six obligate manifestations in the diagnosis of Rett syndrome. They included: Infant apparently normal during first six months, head circumference stagnation, hand skill loss, psychomotor regression, stereotypic hand movments and gait/posture dyspraxia. Discussion
Haberg suggested that diagnostic efforts in brain research, genetics and molecular biology may one day lead to identification of chemical or genetic markers for Rett syndrome. Although the genetic basis for Rett syndrome was indisputable at the time, genetic investigations had not identified a specific locus responsible for the syndrome. Similarly, urine, blood and cerebrospinal fluid analysis could not reveal a diagnostic marker for Rett syndrome. Rett syndrome was thought to be a neurodevelopmental disorder but the biological parameters had not yet been determined at the time of this study.
• Autism
• Outcome Measures
Physical Therapy Management
Resources
Key Research
References
