Rett syndrome is a multisystem disorder that primarily affects girls. Only in rare cases are boys affected (who may experience more severe symptoms). Multiple loss-of-function mutations to the MECP2 gene are the cause of Rett syndrome.

It is a progressive, neurodevelopmental disorder, but infants with Rett syndrome generally develop normally for about 6 to 18 months after birth. After this period, these children experience development regression, and motor control anomalies (e.g., ataxia, uncontrolled hand movements) begin to emerge. With a heterogenous presentation, recognition of Rett syndrome can be challenging.

Beyond development issues, patient physical disability may range from mild to severe, but the following serious complications may become evident:

  • Autism-like behaviors
  • Seizures
  • Cardiac conduction abnormalities
  • Endocrine and growth abnormalities
  • Abnormal movement
  • Sleep disturbances
  • Scoliosis and other skeletal issues
  • Breathing problems
  • Swallowing issues and gastrointestinal complications

Although there’s no cure for Rett syndrome, potential treatments are being studied. Patients with Rett syndrome often survive to middle age. Current treatment focuses on the signs and symptoms presented by the individual patient, including improving movement and communication, and treating seizures and disease complications. Additionally, management must include providing long-term support for caregivers and the families of children and adults with Rett syndrome.

 

INTRODUCTION

First described in the 1960s,[1,2] Rett syndrome is a rare, neurodevelopmental disorder that is generally caused by one of more than 300  loss-of-function mutations in the MECP2 gene, located on the X chromosome.[3] The mutations responsible for Rett syndrome are not inherited; they seem to appear spontaneously.[1]

MECP2 plays a key role in multiple stages of brain development.[4] It is part of a spectrum of disorders related by MECP2 gene dysfunction (e.g., PPM-X syndrome, MECP2-related severe neonatal encephalopathy).[3]

However, Rett syndrome is not considered a neurodegenerative condition but a progressive disorder that affects multisystem evolution over time.[1,2]

Rett syndrome is most common in girls, and it is one of the most common genetic causes of developmental and intellectual impairment in girls.[3] The disorder may occasionally be seen in boys, in whom the symptoms and dysfunction seem to be more severe. [5]

Infants with Rett syndrome generally develop normally for about 6 to 18 months after birth. [6] At this point, they lose previously acquired skills (i.e., developmental regression), such as purposeful hand movements and the ability to communicate. [7] A large percentage of patients with Rett syndrome meet the diagnostic criteria for autism spectrum disorder, although it is not identified as a separate subtype of the disorder. [8]

This article reviews what is currently known about the etiology, prevalence, progression, and management of this disabling genetic disorder.

 

PATHOGENESIS

The X-linked gene MECP2 encodes for the production of MeCP2, [4] a transcription regulator that plays a crucial role in regulating the production of methyl-CPG binding protein-2, which is essential for all stages of brain and neurodevelopment.[3,4] The brain appears to be globally affected by MeCP2-deficiency,[1] likely as a result of deficits in synaptic maturation throughout the brain.[8]

Ninety-five percent of all Rett syndrome cases are caused by MECP2 mutations. Patients are heterozygous for the disorder (one mutated copy and one working copy of the gene).[2] De novo or spontaneous mutations are responsible for 99.5% of cases.[2]

Among the 300 mutations that have been associated with MECP2; R168X, R106W, R255X, R270X, R133C, R294X, R306C, and T158M are among the most common.[1,3,8,9] Severity of disease may be linked to some specific mutations affecting MeCP2 production and function.[8] According to some reports, up to 25% of “variant” Rett syndrome patients have no known MECP2 mutations.[10,11]

The effects of MeCP2 deficiency on both excitation and inhibition can be found on at least three different levels: (1) anatomical (an increase in perisomatic GABAergic terminals), (2) synaptic level (potency of excitatory synapses), and (3) the synaptic efficacy.[8] Researchers have argued that Rett syndrome might be more appropriately categorized as a disorder of synaptic function or plasticity.[8]

PREVALENCE

Worldwide, the prevalence of Rett syndrome is 1 in 20,000 to 40,000 people,[1] affecting up to 1 in 10,000 girls aged 12 years or younger.[1] One estimate specific to the United States calculated approximately 6,000 to 9,000 children and adults living with Rett syndrome.[12]

Rett syndrome has been classified into two categories: (1) classical or typical and (2) variant or atypical. This may help describe the different symptomatology of individual patients (see Diagnosis, below). There are no specific data on the prevalence of typical versus atypical Rett syndrome.

The presentation is heterogenous, at least partly because of the number of potential point mutations and their locations involved, as well as the randomness of X-chromosome inactivation.[13]

DIAGNOSIS

Confidently diagnosing Rett syndrome in patients younger than 2 years of age may be challenging[1]; again, the symptom profile is highly variable.[3] The average age of patients with typical Rett syndrome at the time of diagnosis is 2.5 years; however, as genetic testing becomes more prevalent, earlier diagnostic confirmation may be possible in the future.[3] The average age of diagnosis for patients with atypical Rett syndrome is 3.8 years.[8]

Since the mutations are not inherited, family history does not play a role in diagnosis. Rather, it is based almost solely on presentation and recognition of the symptomatic pattern. The first sign is the loss of previously acquired skills (also referred to as developmental regression), followed by recovery or stabilization for a time: the absence of purposeful hand movements, motor skills, and the ability to communicate.[7] The other regression of clinical earliest signs are loss of acquired speech and motor skills, repetitive hand movements, breathing irregularities, and seizures.[1,2,9]

Table 1 describes the criteria for diagnosis, in addition to the developmental regression and recovery patterns, based on consensus clinical guidelines.[14]

Table 1. Diagnostic Criteria for Typical and Atypical Rett Syndrome[14]
Required for Typical Rett Syndrome Required for Atypical Rett Syndrome
All main criteria and all exclusion criteria ≥ 2 of the 4 main criteria
Supportive criteria not required, although often present ≥ 5 of the 11 supportive criteria
Main Criteria
·       Partial or complete loss of acquired purposeful hand skills
·       Partial or complete loss of acquired spoken language
·      Gait abnormalities (impaired or absence of ability)
·       Stereotypic hand movements (hand wringing, squeezing, clapping/tapping, mouthing, washing/rubbing automatisms
Supportive Criteria
·       Breathing disturbances while awake
·       Bruxism while awake
·       Abnormal muscle tone
·       Peripheral vasomotor disturbances
·       Scoliosis/kyphosis
·       Growth retardation
·       Small, cold hands and feet
·       Impaired sleep pattern
·       Inappropriate laughing or screaming
·       Diminished response to pain
·       “Eye pointing”/intense eye communication

Two specific criteria can exclude a diagnosis of Rett syndrome (typical or atypical): (1) brain injury secondary to trauma (peri-or postnatally), neurometabolic disease, or severe infection causing neurologic problems and (2) grossly abnormal psychomotor development in the first 6 months of life.

The differential diagnosis includes Angelman syndrome, a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities, ataxia, and absence or near absence of speech.[15] In some rare cases, boys with neurodevelopment disorders are found upon testing to have MECP2 mutations. These cases of “male RTT encephalopathy” have symptoms distinct from typical or atypical Rett syndrome and may also be linked to other distinct disorders, such as MECP2 duplication syndrome (characterized by developmental disability, poor muscle tone, poor or absent speech),[3,16] CDKL5 deficiency disorder (causing seizures, inability to speak, motor dysfunction),[3,15] or FOXG1 syndrome (which has sufficient clinical similarities to have previously been classified as a “congenital variant” of Rett syndrome).[3,17]

Diagnosing Rett Syndrome
Laura Mamounas PhD, Program Director at the National Institute of Neurological Disorder and Stroke (NINDS) at the NIH, discusses the challenges of diagnosing Rett syndrome.

Rett Syndrome Needs a Team of Specialists
Jeffrey L. Neul, MD, PhD, at the Vanderbilt University Medical Center, discusses the need for a multidisciplinary approach to care for Rett syndrome.

NATURAL HISTORY

Although Rett syndrome is heterogenous in the timing of symptoms and the symptoms themselves, patients typically go through four distinct clinical stages throughout their lives.[2]

  1. As mentioned above, affected infants continue to attain developmental milestones until approximately 6 to 18 months, when developmental progression ceases or continues at a significantly delayed rate (e.g., an infant may learn to sit upright, but not to crawl).
  2. Rapid Regression. Children with Rett syndrome begin to lose their communication and motor skills and may begin to develop seizures and other impairments. This stage lasts from age 1 to 4 years.
  3. These children may actually recover some of their lost developmental skills, but purposeful hand and body movements remain severely diminished. This may begin at 2 years of age; some patients may remain in this stage their entire lives.
  4. Motor Deterioration. From 10 years of age, patients with Rett syndrome may experience severe deterioration and complete loss of ambulation. This stage is not experienced universally by the patient population.

Patients with Rett syndrome often survive into their fifth decade3 and require lifelong, intensive care. As a result, the health (physical, mental, and financial) of caregivers must be a consideration.

MANAGEMENT

Over the course of the patient’s life, patients’ physical disability may range from mild to severe, and several clinical features may be evident. For example, patients often will develop hypotonia, and microcephaly is also a common feature.[3] Beyond the motor, neurological, and behavioral issues already mentioned, patients may also experience any of these abnormalities[3]:

  • Endocrine and growth abnormalities
  • Sleep disturbances
  • Scoliosis and other skeletal issues
  • Breathing problems
  • Swallowing issues and gastrointestinal complications

Overall, the clinical status of patients with Rett syndrome tends to stabilize as patients enter young adulthood[3]; for example, the incidence of scoliosis in patients with Rett syndrome generally lessens after the onset of puberty.[3] However, these patients are at higher risk than the general population for osteopenia and contractures, and consensus guidelines recommend surveillance for these musculoskeletal issues.[3]

The following longer-term issues should also be noted: The guidelines also recommend monitoring for potential urinary retention.[3] Motor function deficits may result in the inability or refusal to eat or drink, and a gastrostomy tube may be needed (in up to one-third of patients).[9] The cause of death in those with Rett syndrome is often related to respiratory infection and aspiration/asphyxiation.[9]

Current medical management is focused on the treatment of the patient’s signs and symptoms, and requires the collaboration of several medical specialties.[1] Table 2 outlines several considerations and recommendations.

Table 2. Current Approaches to Medical Treatment of Rett Syndrome[3]
Anticonvulsants for the treatment of seizures
Individualized treatment for GI issues (e.g., constipation and gastroesophageal reflux, treated with laxatives, and H2 inhibitors or proton pump inhibitors, respectively)
Supplementation for poor nutritional/vitamin intake
Medication suppress menses in patients exhibiting early signs of puberty
Orthopedics/rehabilitation for scoliosis, contractures, osteopenia/fractures
Behavioral health and psychological issues

Several other problems associated with Rett syndrome are very important but are underaddressed; they do not have pharmaceutical remedies.[3] These wide-ranging issues include breathing abnormalities like hyperventilation or breath-holding, nighttime behaviors (e.g., screaming, laughing), stereotypic hand movements, nonverbal communication, inattention and anxiety, and orthopedic and mobility issues. A multidisciplinary team of physicians, specialists, and specialized therapists is needed to help manage this wide range of symptoms and to afford the opportunity for comprehensive care.[3]

Treatments are not yet available to address the underlying genetic anomaly or to supplement the deficient protein caused by the MECP2 mutation.[3] Nor is there any approved medications to delay the progression of patients’ disability.

CLINICAL TRIALS INVOLVING RETT SYNDROME

For a list and descriptions of active clinical trials involving Rett syndrome, please click on the link to ClinicalTrials.gov.

RESOURCES

National Organization for Rare Disorders (NORD)
Provides a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.

Rett Syndrome Research Trust
RSRT is singularly focused on accelerating a genetic cure for Rett syndrome and is home to the cure community for parents, family, and caregivers. Since its founding in 2008, RSRT has awarded more money than any other Rett organization in the world to leading scientists pursuing targeted research on Rett.

REFERENCES
  1. Ivy AS, Standridge SM. Rett Syndrome: A timely review from recognition to current clinical approaches and clinical study updates. Semin Pediatr Neurol. 2021;37:100881. doi: 10.1016/j.spen.2021.100881.
  2. Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018;8(2):1-17.
  3. Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open. 2020;4(1):e000717.
  4. Tillotson R, Bird A. The molecular basis of MeCP2 function in the brain. J Mol Biol. 2019;S0022-2836(19)30595-9.
  5. Neul JL, Benke TA, Marsh ED, et al. The array of clinical phenotypes of males with mutations in Methyl-Cpg binding protein 2. Am J Med Genet B Neuropsychiatr Genet. 2019;180:55-67.
  6. Percy A. Rett syndrome: coming to terms with treatment. Adv Neurosci. 2014;2014:345270.
  7. Gogliotti RG, Niswender CM. A coordinated attack: Rett syndrome therapeutic development. Trends Pharmacol Sci. 2019;40:233-236.
  8. Banerjee A, Miller MT, Li K, et al. Towards a better diagnosis and treatment of Rett syndrome: a model synaptic disorder. Brain. 2019;142:239-248.
  9. Anderson A, Wong K, Jacoby P, et al. Twenty years of surveillance in Rett syndrome: what does this tell us? Orphanet J Rare Dis. 2014;9:87.
  10. Neul JL, Lane JB, Lee H-S, Geerts S, Barrish JO, Annese F, et al. Developmental delay in Rett syndrome: data from the natural history study. J Neurodev Disord. 2014;6:20.
  11. Gold WA, Krishnarajy R, Ellaway C, et al. Rett syndrome: A genetic update and clinical review focusing on comorbidities. ACS Chem Neurosci. 2018;9:167-176.
  12. Rett syndrome US prevalence. Acadia Pharmaceuticals Inc. Data on file (unpublished). March 2022.
  13. Archer H, Evans J, Leonard H, et al. Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MeCP2 mutation, and the direction and degree of skewing of X-chromosome inactivation. J Med Genet. 2007;44:148–52.
  14. Neul JL, Kaufmann WE, Glaze DG, et al for the RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68:944-950.
  15. Rett syndrome. National Organization for Rare Diseases. December 17, 2019. https://rarediseases.org/rare-diseases/rett-syndrome/?filter=ovr-ds-resources. Accessed October 10, 2022.
  16. Rett syndrome. MedlinePlus October 1, 2018. https://medlineplus.gov/genetics/condition/rett-syndrome/. Accessed August 17, 2022.
  17. Akol I, Gather F, Vogel T. Paving therapeutic avenues for FOXG1 syndrome: Untangling genotypes and phenotypes from a molecular perspective. Int J Mol Sci. 2022;23:954. https://doi.org/

Managing Rett Syndrome
Jana von Hehn, PhD, Chief Scientific Officer of the Rett Syndrome Research Trust, discusses current strategies for managing Rett syndrome.

Rett Syndrome Related Disorders
Jeffrey L. Neul, MD, PhD, at the Vanderbilt University Medical Center, discusses disorders related to Rett syndrome.

 

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