Author: Shayan Mackie

Editor: Leah Farquharson

Overview

Rett syndrome (RTT) is a rare (1:10,000) genetic neurological disorder (Cianfaglione et al., 2015). As a developmental disorder affecting the brain, RTT has the potential to change many different aspects of a child’s life (Cianfaglione et al., 2015). It has been shown that RTT can slow normal development, cause problems with movements and walking, slow down brain growth and cause intellectual disabilities (Marschik et al., 2017). This condition was first identified by Dr. Andreas Rett Hagberg in 1966 (Schönewolf-Greulich et al., 2016). Rett Syndrome predominantly affects women (Amoako & Hare, 2019).

Etiology

It is known that the most common cause of RTT is the de novo mutation of methyl-CpG-binding protein 2 (MECP2) gene located on the X chromosome at Xq28 (Cianfaglione et al., 2015). The MeCP2 protein is a biochemical signal that influences gene expression in the brain (Wang et al., 2020). This mutation can cause a wide range of neurological and developmental impairments in patients depending on location and severity (Wang et al., 2020).

Symptoms

RTT is a neurodevelopmental illness with a highly variable set of symptoms (Marschik et al., 2017). Although not exhaustive, below is a list of common symptoms seen among individuals with RTT: Slowed growth, cognitive (and potentially intellectual) disabilities, loss of communicative abilities (including loss of speech) (Marschik et al., 2017), loss of normal movements (repetitive and purposeless hand movements such as a squeezing, tapping, rubbing, etc. are very typical), motor disabilities (Larsson et al., 2018), sleep problems (including apnea), breathing problems, seizures, heart problems, muscle loss and scoliosis (Ehrhart et al., 2016).

Risk factors

RTT predominantly occurs in females and is caused by a de novo mutation which occurs randomly, therefore no major risk factors have been identified (Cianfaglione et al., 2015). However, males have only 1X chromosome, therefore any defective copy of the MECP2 gene can cause RTT (Ehrhart et al., 2016). Females have two X chromosomes and may present with milder symptoms compared to hemizygous males (Ehrhart et al., 2016). The risk of mutation is increased in sperm with higher age and increased exposure to environmental toxins (Clarke &Abdala Sheikh, 2018).

Diagnosis

It has been found that in most cases, infants do not display any signs or symptoms of RTT until they are 6 to 18 months old (Ehrhart et al., 2016). At this point, doctors and other healthcare professionals can monitor the child for the presence of symptoms and regression of abilities (Brunetti &Lumsden, 2020).

Additionally, genetic testing can be used to investigate the presence of MECP2 mutation in the genome (Wang et al., 2020).

Due to its well-established genetic basis, RTT was removed from DSM-5 (it was previously considered a subtype of Autism spectrum disorder) (Association, 2013). Other potential misdiagnoses are other underlying causes such as cerebral palsy, degenerative disorders, head trauma, metabolic disorder, and other genetic disorders that could explain the symptoms (Association, 2013).

Treatment

Due to the randomness associated with RTT’s underlying genetic mutation, there are no preventative measures identified (Cianfaglione et al., 2015). Currently, with gene therapy and medical gene editing being at their infancy stage, there is no cure for RTT, and most interventions aim to relieve the effects of the symptoms in multi-faceted and palliative care (Clarke & Abdala Sheikh, 2018). 

• Glatiramer acetate has also been shown to improve cognition, gait velocity, abnormal respiration, and epileptiform discharges in girls 10-years and older (Naguy & Bedour, 2017). 
• Mecasermin, a recombinant human insulin-like growth factor 1 (IGF-1), has been shown to positively impact mood symptoms associated with RTT, anxiety, and sleep apnea (Naguy & Bedour, 2017). 
• Phytocannabinoid cannabidivarin (CBDV) has been found to be an effective treatment for seizures (Gomathi et al., 2020). 
• Sarizotan is being investigated for its potentially beneficial influence on breathing abnormalities associated with RTT (Gomathi et al., 2020). Likewise, serotonin-based therapies are under study for their role in improving behavioral symptoms and nighttime respiratory problems (Naguy & Bedour, 2017).

Non-pharmaceutical treatments include occupational therapy, physical therapy, braces, and other assistive technologies, nutritional intervention, special needs education, speech therapy, and behavioral interventions among others, as dictated by the specific needs of an individual with RTT (Amoako & Hare, 2019).

An important part of the treatment plan for a child with RTT must focus on the parents or caregivers responsible for the child (Lane et al., 2017). This condition does not display itself at birth and is due to the regression of previously acquired skills (Pari et al., 2020). In addition to the many and diverse complications that RTT causes for the child, there are many complications that parents and caregivers will face as well (Lane et al., 2017).

Parents and caregivers must quickly come to terms with the condition of their child and may undergo an unexpected but lengthy psychological tension (Pari et al., 2020). The highly demanding and challenging expectations of caring for children with RTT may hinder a parent or caregiver’s ability to cope and care for themselves (Pari et al., 2020).

Realizing the importance of the role of parents and caregivers in the non-pharmaceutical treatments for children with RTT (Lane et al., 2017). Multiple models have been used to determine the type and degree of burden that parents of children with RTT experience to create a caregiver inventory for RTT, which can be used to assess and care for the physical and psychological needs of parents and caregivers (Lane et al., 2017).

 

Articles on misdiagnosis

Buccino, M. A., & Weddell, J. A. (1989). Rett syndrome–a rare and often misdiagnosed syndrome: case report. Pediatric dentistry, 11(2), 151–157.

Casanova, M. F., Buxhoeveden, D., Switala, A., & Roy, E. (2003). Rett syndrome as a minicolumnopathy. Clinical neuropathology, 22(4), 163–168.

D’ Orsi, G., Demaio, V., & Minervini, M. G. (2009). Myoclonic status misdiagnosed as movement disorders in Rett syndrome: A video-polygraphic study. Epilepsy & Behavior, 15(2), 260–262. doi:10.1016/j.yebeh.2009.03.033 

Young, D. J., Bebbington, A., Anderson, A., Ravine, D., Ellaway, C., Kulkarni, A., de Klerk, N., Kaufmann, W. E., & Leonard, H. (2008). The diagnosis of autism in a female: could it be Rett syndrome?. European journal of pediatrics, 167(6), 661–669. https://doi.org/10.1007/s00431-007-0569-x

 

References

Amoako, A. N., Hare, D.J. (2020). Non‐medical interventions for individuals with Rett syndrome: A systematic review. J Appl Res Intellect Disabil, 33: 808-827. doi: 10.1111/jar.12694

 

Association, A.P. Diagnostic and statistical manual of mental disorders (DSM-5). 2013: American Psychiatric Pub. Brunetti, S., &Lumsden, D. E. (2020). Rett Syndrome as a movement and motor disorder – A narrative review. European Journal of Paediatric Neurology, 28, 29-37.

 

Cianfaglione, R., Clarke, A., Kerr, M., Hastings, R.  P., Oliver, C., and Felce, D. (2016) Ageing in Rett syndrome. Journal of Intellectual Disability Research, 60: 182– 190. doi: 10.1111/jir.12228.

 

Clarke, A.J., Abdala Sheikh, A.P. A perspective on “cure” for Rett syndrome (2018). Orphanet J Rare Dis, 13, 44. doi:10.1186/s13023-018-0786-6

 

Ehrhart, F., Coort, S.L.M., Cirillo, E. et al. Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes. Orphanet J Rare Dis 11, 158 (2016). doi: 10.1186/s13023-016-0545-5

 

Gomathi, M., Padmapriya, S. & Balachandar, V. (2020). Drug Studies on Rett Syndrome: From Bench to Bedside. J Autism Dev Disord 50, 2740–2764. doi: 10.1007/s10803-020-04381-y

 

Lane, J. B., Salter, A. R., Jones, N. E., et.al. (2017). Assessment of caregiver inventory for Rett syndrome. Journal of Autism and Developmental Disorders, 47(4), 1102-1112. doi:10.1007/s10803-017-3034-3

 

Larsson, G., Peter O.O. Julu, Ingegerd Witt Engerström, et.al. (2016). Walking on treadmill with Rett syndrome—Effects on the autonomic nervous system, Research in Developmental Disabilities, 83, 99-107. doi: 10.1016/j.ridd.2018.08.010.

 

Marschik, P.B. Sanne Lemcke, Christa Einspieler, et.al. (2018) Early development in Rett syndrome – the benefits and difficulties of a birth cohort approach, Developmental Neurorehabilitation, 21:1, 68-72, doi: 10.1080/17518423.2017.1323970

 

Naguy, A., &Bedour, Y. (2017). Rett Syndrome – Current status and future directions. Pediatric Neurology, 70, e5-e6. 

 

Pari, E, Cozzi, F, Rodocanachi Roidi, ML, Grange, F, Toshimori, K, Ripamonti, E. (2020). Parenting girls with Rett syndrome: An investigation on self‐perceived levels of stress. J Appl Res Intellect Disabil, 33: 1348-1356.  doi: 10.1111/jar.12755

 

Schönewolf-Greulich, B., Stahlhut, M., Larsen, J. L., Syhler, B., &Bisgaard, (2017) Functional abilities in aging women with Rett syndrome – the Danish cohort, Disability and Rehabilitation, 39(9), 911-918, doi: 10.3109/09638288.2016.1170896

 

Wang, L., Hu, M., Zuo, MQ. et al. (2020). Rett syndrome-causing mutations compromise MeCP2-mediated liquid–liquid phase separation of chromatin. Cell Res 30, 393–407. doi: 10.1038/s41422-020-0288-7