Course:MEDG550/Student Activities/Rett Syndrome

From UBC Wiki

Rett Syndrome is a genetic disorder affecting brain development. Children with Rett Syndrome lose their developmental milestones as they age.  Rett Syndrome primarily affects girls.

Clinical Characteristics

Rett Syndrome causes a range of cognitive and physical disabilities.

Babies with Rett Syndrome develop normally for the first 6-18 months. Over time, girls with Rett Syndrome  lose developmental skills such as the ability to speak, walk, and control their hands. Many individuals with Rett Syndrome make repetitive hand movements, such as wringing, tapping, or rubbing. Girls with Rett Syndrome are often small for their age from toddlerhood on. Their height, weight, and head size may all be smaller than other girls their age.[1]

The clinical presentation of Rett Syndrome is separated into four stages:[2]

Progression of a girl with Rett Syndrome: This patient shows a blank gaze at 9 months old, use of a ventilator to help with nighttime breathing at 3 years old, and use of physical supports at 5 years old. [1]

Stage 1

  • Begins at 6 to 18 months of age (development is normal for the first months of life)
  • Development stalls, girls do not reach their expected developmental milestones

Stage 2

  • 1 to 4 years of age
  • Development moves backwards. Developmental skills including language, socialization, gross motor, and fine motor skills are lost to varying degrees
  • Repetitive hand movements may start
  • Head growth may slow down

Stage 3

  • May begin as early as 2 years old
  • Development stabilizes, and some of the skills lost in stage II may be re-learned
  • May develop an intense eye gaze
  • Become more socially aware

Stage 4

  • May begin as early as 10 years old
  • The longest stage, lasting for years or decades
  • Motor skills deteriorate. Girls experience reduced mobility, muscle weakness, and spasticity.
  • Girls may develop hand and foot deformities and lose muscle control over time

Not all people with Rett syndrome show identical symptoms. The severity and progression of the condition varies from person to person.

People with Rett Syndrome are at an increased risk for a range of other medical complications. The majority of girls with Rett Syndrome experience seizures. Many girls with Rett Syndrome experience digestive problems like reflux or chronic constipation, and may have trouble eating. This can lead to nutrient deficiencies and low weight gain. Most girls with Rett Syndrome experience osteoporosis, which may lead to scoliosis (bent spine). Rett Syndrome can also cause breathing disturbances.[2]

Diagnosis

Rett Syndrome is diagnosed if a person shows these symptoms:[3]

  • Normal development for the first 6 months of their life
  • Developmental skills are lost, and then later on development stabilizes or skills are re-learned
  • Partially or completely lose the ability to make purposeful hand movements
  • Partially or completely lose learned speech
  • Abnormal walking or inability to walk
  • Repetitive hand movements like wringing, tapping, or rubbing

Rett syndrome can not be diagnosed if a person has had a severe brain injury or an infection affecting the brain.

Management

Treatment of Rett Syndrome is based on managing a person’s symptoms. There is no cure for Rett syndrome.

  • Medications[4]
    • Multiple different drugs can be used to avoid seizures
    • Magnesium can be used to hep regulate breathing
    • Melatonin may be given to help with sleep
  • Physical Therapy[4]
    • Help develop gross motor skills, like walking
    • Manage mild scoliosis (severe scoliosis may require surgery)
  • Occupational Therapy
    • Help with fine motor skills, especially involving hand control[4]
  • Speech Therapy
    • Work on language skills or alternative communication
  • Other support[5]
    • Special equipment, such as wheelchairs, walkers, braces, or communication devices
    • Supportive education, such as an educational aide at school or placement in attending a school program for students with disabilities

Because of the multiple health complications associated with the condition, a person with Rett Syndrome may be taken care of by multiple specialist teams (e.g. a psychologist for behavioural concerns, a skeletal team for scoliosis, and a gastrointestinal team for nutrition and feeding).

Genetics

Human Chromosomes. Males have one X and one Y chromosome, while females have two X chromosomes. The first 22 pairs of chromosomes are the same in both sexes.

Rett Syndrome is caused by a change in the MECP2 gene. The MECP2 gene produces a protein needed to organize brain development.

The MECP2 gene is located on the X chromosome. Women and girls have two X chromosomes, while men and boys have one X and one Y chromosome.

In Males

Because boys only have one X chromosome, a boy with a changed copy of the MECP2 gene has no “back up” healthy copy. Boys with an MECP2 gene change do not show the same features as girls with Rett Syndrome. Boys with an MECP2 gene change are born with brain damage and usually pass away before they are 1 year old.[6] Having an MECP2 change in a boy often prevents the pregnancy from surviving to term, so very few boys are born with an MECP2 change.[7]

In Females

Girls have two X chromosomes, but only one is active in each cell. In a girl with Rett Syndrome, the X chromosome with the MECP2 change may be active in some cells, while in other cells, the X chromosome with a healthy MECP2 copy may be active. Cells with the healthy MECP2 copy active will make normal amounts of the protein, while cells with the changed copy active will not.

Which X chromosome is active is assigned randomly before a girl is born. This randomness results in some of the variability in symptoms and severity between Rett Syndrome patients. Not all girls with an MECP2 gene change will have the same symptoms. One person may be more or less severely affected than another, show different features, or develop symptoms at different times.

Random selection of an active X chromosome in cells in the embryo (top) results in either the healthy or changed copy of MECP2 being active in body cells (bottom)

Prevalence and Population Frequencies

Rett Syndrome affects approximately 1/10,000 females.[3] All ethnic and cultural groups can be affected by Rett syndrome.

Rett Syndrome is extremely rare in males.[8]

Inheritance

Rett Syndrome is inherited in an X-linked dominant inheritance pattern. This means one changed copy of MECP2 is sufficient to cause the condition.

Rett Syndrome is not passed through families. Women with Rett Syndrome are fertile but due to multiple medical and developmental challenges, they do not have children.[9] Nearly all (99.5%) cases of Rett Syndrome result from a new change in the MECP2 gene in the affected child that was not inherited from either parent.[7]

Some people may have an MECP2 change in their body cells, but may have changed MECP2 in some of their eggs or sperm. This can be difficult to test for. These individuals are not affected by Rett Syndrome as most cells in their body do not have an MECP2 genetic change. In these rare cases, a family would be at an increased chance of having multiple children with Rett Syndrome.

Genetic Testing

Diagnosis of Rett Syndrome can be confirmed by genetic testing of the MECP2 gene.

If a family has had a daughter affected by Rett Syndrome, they can choose to have prenatal testing of the MECP2 gene in future pregnancies. Because almost all cases of Rett Syndrome are due to a brand new genetic change, the risk of a family having a second child with Rett Syndrome is very low.[7]

Genetic Counselling Issues

Psychosocial Considerations

Because 99% of Rett Syndrome cases are the only case in a family, family members have likely never heard of the condition before and might know nothing or very little about it. A diagnosis of Rett Syndrome is often an unexpected surprise.

Because each person with Rett Syndrome may show different symptoms, a diagnosis of Rett Syndrome can leave a family with a lot of uncertainty in what to expect for their child. Connecting with other families affected by Rett Syndrome can be a source of support, but can also create anxiety by comparing differences in symptoms and severity between children.

Many girls with Rett Syndrome have a limited ability to speak or are not able to talk at all.[1] It can be stressful for families to try and understand their child’s needs and wishes without speech. Using other communication methods like signing, pictures, and special technology can help girls with Rett Syndrome to share their feelings and needs.[10]

Patient Resources

RettSyndrome.org: https://www.rettsyndrome.org/

Rett Syndrome Research Trust: https://reverserett.org/

Girl Power 2 Cure: https://www.girlpower2cure.org/

To locate a genetics clinic near you, speak to your primary health care provider or visit www.cagc-accg.ca (Canada) or www.nsgc.org (United States).

References

  1. ↑ 1.0 1.1 1.2 Smeets, E.E.J.; Pelc, K.; Dan, B. (2012). "Rett Syndrome". Molecular Syndromology. 2: 113–127.
  2. ↑ 2.0 2.1 Gold, W.A.; et al. (2018). "Rett Syndrome: A genetic update and clinical review focusing on comorbidities". ACS Chemical Neuroscience. 9: 167–176. Explicit use of et al. in: |last2= (help)
  3. ↑ 3.0 3.1 Neul, Jeffrey L; et al. "Rett Syndrome: revised diagnostic criteria and nomenclature". Annals of Neurology. 68 (6): 167–176. Explicit use of et al. in: |last2= (help)
  4. ↑ 4.0 4.1 4.2 Weaving, L. S.; Ellaway, C.J.; Gécz, J.; Christodoulou, J. (2004). "Rett syndrome: clinical review and genetic update". Journal of Medical Genetics. 41 (1): 1–7.
  5. ↑ "For Families: Living with Rett". Rettsyndrome.org. 2020.
  6. ↑ Schüle, B.; Armstrong, D.D.; Vogel, H.; Oviedo, A.; Francke, U. (2008). "Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure". Clinical Genetics. 74 (2): 116–126.
  7. ↑ 7.0 7.1 7.2 Trappe, R.; et al. (2001). "MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin". American Journal of Human Genetics. 68: 1093–1101. Explicit use of et al. in: |last2= (help)
  8. ↑ Reichow, B.; et al. (2015). "Brief Report: Systematic Review of Rett Syndrome in Males". Journal of Autism and Developmental Disorders. 45 (10): 3377–3383. Explicit use of et al. in: |last2= (help)
  9. ↑ Comings, D. E.; Opitz, J. M.; Reynolds, J. F. (1986). "The genetics of rett syndrome: The consequences of a disorder where every case is a new mutation". American Journal of Medical Genetics. 25 (51).
  10. ↑ "Communication". Rettsyndrome.org. 2020.
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