Understanding Rett syndrome

A multisystem disorder with a multitude of symptoms to address

Rett syndrome (RTT) is a rare neurodevelopmental disorder.1 Within the US alone, there are approximately 6,000 to 9,000 individuals living with RTT.2 It is a complex, progressive, and multisystem disorder that primarily affects girls.1 In rarer cases, RTT can also affect males, with oftentimes more severe symptoms.3

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Causes of RTT

RTT is almost always caused by loss-of-function mutations in the MECP2 gene, located on the X chromosome.1

MeCP2 is an essential transcriptional regulator and plays a key role in all stages of brain development4

  • There are more than 200 different mutations on the MECP2 gene that interfere with generation of the normal gene product5
  • Based on animal models, downstream effects of loss of functional MeCP2 is thought to result in deficits in synaptic maturation in the brain6

Diagnosing RTT

RTT requires a clinical diagnosis. And while underlying mutations in genes like MECP2 are not required for diagnosis, mutational analysis can help predict severity and, as a result, help caregivers prepare for the needs of individuals with RTT.7,8

RTT leads to loss of expressive language and purposeful hand use, impaired ambulation, and stereotypical hand movements. Individuals with RTT also show signs of microcephaly, can develop seizures, and experience severe motor deficits.1,7 Autonomic, gastrointestinal, and other systemic symptoms may also be present.1

A diagnosis of RTT should be considered when postnatal deceleration of head growth is observed.7

RTT includes both typical and atypical presentations7

Typical and atypical RTT diagnostic criteria 2010

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In most cases, children with RTT develop normally during their first months of life. Symptoms of RTT tend to present between 6 and 18 months of age, marked by developmental regressions and functional impairments.9

RTT is a heterogeneous condition; the timing and occurrence of symptoms varies widely between children.10,11 Clinical diagnostic features can progress throughout 4 stages.9

Timing of RTT Stages and Symptom Onset9

Stage 1

Stagnation
(6-18 months)

Children stop meeting developmental milestones like sitting, crawling, or vocalizing

Stage 2

Rapid regression
(1-4 years)

Children begin to lose already developed motor and communication skills and can develop seizures and other impairments

Stage 3

Plateau period
(2 years to life)

Children may show mild cognitive interest recovery, but purposeful hand and body movements remain severely diminished

Stage 4

Motor deterioration
(10 years to life)

Severe deterioration and complete loss of ambulation occur, though this stage is not experienced by every individual with Rett syndrome

Physical and behavioral manifestations of RTT

In addition to the symptoms that are part of the main diagnostic criteria for typical RTT, individuals can experience a range of physical and behavioral manifestations, many of which can significantly impact the ability to function.7,12,13

Physical manifestations can include13:

brain icon – head
  • Seizures
Talking/mouth icon – mouth
  • Swallowing dysfunction
  • Irregular breathing pattern, eg, hyperventilation, breath-holding
Legs/movement icon – calf
  • Abnormal movement
Sleep/nighttime icon – head
  • Sleep disturbances
Spine icon – upper chest
  • Skeletal abnormalities, eg, scoliosis
Icon depicting a heart
  • Cardiac conduction abnormalities
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  • Growth abnormalities
  • Endocrine abnormalities
Stomach/intestine icon – lower abdomen
  • Gastrointestinal issues or complications
Stylized list of the physical and behavioral manifestations of Rett syndrome

Behavioral manifestations can include13:

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  • Anxiety
  • Mood disturbances

The majority of individuals with RTT live to middle age.1 However, these functional and behavioral manifestations cause lifelong dependence,1 placing immense responsibility on the caregivers of these individuals.

“If she had better control of her hands and could stop constantly flapping them and just relax, it might make her happier—and give us some relief, too.”

– Caregiver and mother to 5-year-old with RTT

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With heterogeneous presentation and no FDA-approved treatment, management of RTT can be challenging.

FDA=Food and Drug Administration.

References:

1. Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open. 2020;4(1):e000717. 2. Acadia Pharmaceuticals Inc. Data on file. RTT US Prevalence. March 2022. 3. 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(1):55-67. 4. Tillotson R, Bird A. The molecular basis of MeCP2 function in the brain. J Mol Biol. 2019;S0022-2836(19)30595-9. 5. Williamson SL, Christodoulou J. Rett syndrome: new clinical and molecular insights. Eur J Hum Genet. 2006;14(8):896-903. 6. Tropea D, Giacometti E, Wilson N, et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. PNAS. 2009;106(6):2029-2034. 7. Neul JL, Kaufmann WE, Glaze DG, et al for the RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-950. 8. Cuddapah VA, Pillai RB, Shekar KV, et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 2014;51(3):152-158. 9. Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018;8(2):1-17 10. Percy A. Rett syndrome: coming to terms with treatment. Adv Neurosci. 2014;2014:345270. 11. Tarquinio DC, Motil KJ, Hou W, et al. Growth failure and outcome in Rett syndrome: specific growth references. Neurology. 2012;79(16):1653-1661. 12. 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. 13. Fu C, Armstrong D, Marsh E, et al. Multisystem comorbidities in classic Rett syndrome: a scoping review. BMJ Paediatr Open. 2020;4:e000731.