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What is Rett syndrome?

What is Rett syndrome?

Rett syndrome (RTT) is a severe progressive neurological disorder that mainly affects females and was first reported by Andreas Rett in 1966. It interferes in the normal brain development from early childhood. Most individuals with RTT have a random ‘mistake’ (mutation) in the Methyl CpG Binding Protein 2 (MECP2) gene located on an X chromosome. 

How many children does it affect? 

The worldwide incidence of RTT range between one in 10,000 to 23,000 live female births. An Australian-epidemiological study suggested that one in 8500 females in Australia are diagnosed with RTT by the age of 15 years, making it the second most common cause of severe intellectual disability in females after Down Syndrome. In Australia it is likely that there are now over 400 affected individuals nationally.

What are the symptoms of RTT and how is it diagnosed?

Before establishing the genetic cause, affected individuals are often first clinically classified using diagnostic criteria established for RTT3. Classic (or typical) RTT individuals exhibit an apparently normal development until six to 18 months of age after which developmental regression occurs, followed by recovery or stabilization in their condition. The most common features observed in affected females are: 

  • loss of acquired purposeful hand skills (such as grasping, holding or self-feeding)
  • loss of acquired spoken language (speech)
  • repetitive hand movements (wringing, squeezing, washing, clapping, tapping or rubbing)
  • difficulty walking or loss of the ability to walk

In addition, other features that are often seen in RTT individuals include slower growth, a smaller head size, breathing difficulties, abnormal muscle tone, teeth clenching, small and cold hands and feet, inappropriate laughing or crying spells, intense eye communication, impaired sleep and sideways curvature of the spine.

Variant (or atypical) RTT individuals have many features of classic RTT but do not meet all the specific diagnostic criteria. Children with variant RTT might exhibit milder or more severe features than classic RTT.

How is it caused?

Errors in the MECP2 gene are the main cause of RTT in females. This type of random mutation is not inherited from either parent but instead occurs spontaneously. 

This error results in a faulty MeCP2 protein, which is critical for regulating the production of other key proteins needed for proper functioning of the brain and body. 

Only one X chromosome needs to develop a fault in the MECP2 gene to cause the features seen in of RTT.

There are also other genes that can also cause this devastating condition which we are learning more about.

What RTT research is taking place at Murdoch Children's Research Institute (MCRI)?

In collaboration with the experts in the field, we are using cutting-edge genetic sequencing technologies to discover new genes associated with RTT. In addition, we are using stem cell technologies to allow us to better study the consequences of mutations identified in these genes, providing specific models for high-throughput screening of potential therapeutics.

The identification of the underlying genetic cause for an individual’s clinical condition gives families a precise diagnosis. We are also understanding the biological mechanisms of these gene mutations to define their cause and the disease pathways involved. This will allow us to expedite the identification of new treatments for children with RTT and related disorders.

Author: 

Dr. Simranpreet Kaur is a Research Fellow based in the Brain and Mitochondrial Research Group at MCRI. Dr Kaur is currently focusing on understanding the genetic and molecular basics of RTT and other related rare neurological disorders. She is passionate about bridging the gap between knowledge gain and translational drug discoveries for various neurological disorders. 

References: 

1. Fehr, S, Bebbington, A, Nassar, N, Downs, J, Ronen, GM, N, DEK, & Leonard, H. Trends in the diagnosis of Rett syndrome in Australia. Pediatr. Res. 2011:  70 (3); 313-319. doi:10.1203/PDR.0b013e3182242461.

2. Armstrong, AH, Hangauer, J, Agazzi, H, Nunez, A, & Gieron-Korthals, M. (2010). Individuals with intellectual and developmental disabilities. In Handbook of Pediatric Neuropsychology (pp. 537-550). New York: Springer.

3. Neul, JL, Kaufmann, WE, Glaze, DG, Christodoulou, J, Clarke, AJ, Bahi-Buisson, N, Leonard, H, Bailey, ME, Schanen, NC, Zappella, M, Renieri, A, Huppke, P, Percy, AK, & RettSearch, C. Rett syndrome: revised diagnostic criteria and nomenclature. Ann. Neurol. 2010:  68 (6); 944-950. doi:10.1002/ana.22124.

4. Kaur, S, & Christodoulou, J. (1993). MECP2 Disorders. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews((R)). Seattle (WA).

5. Kaur, S, Van Bergen, NJ, Ben Zeev, B, Leonardi, E, Tan, TY, Coman, D, Kamien, B, White, SM, St John, M, Phelan, D, Rigbye, K, Chern Lim, S, Torres, MC, Marty, M, Savva, E, Zhao, T, Massey, S, Murgia, A, Gold, WA, & Christodoulou, J. Expanding the genetic landscape of Rett syndrome to include Lysine (K) acetyltransferase 6A (KAT6A). Journal of Genetics and Genomics. 2020. 

6. Kaur, S, Van Bergen, NJ, Gold, WA, Eggers, S, Lunke, S, White, SM, Ellaway, C, & Christodoulou, J. Whole exome sequencing reveals a de novo missense variant in EEF1A2 in a Rett syndrome-like patient. Clin. Case Rep. 2019:  7 (12); 2476-2482. doi:10.1002/ccr3.2511.

7. Kaur, S, Van Bergen, NJ, Verhey, KJ, Nowell, CJ, Budaitis, B, Yue, Y, Ellaway, C, Brunetti-Pierri, N, Cappuccio, G, Bruno, I, Boyle, L, Nigro, V, Torella, A, Roscioli, T, Cowley, MJ, Massey, S, Sonawane, R, Burton, MD, Schonewolf-Greulich, B, Tumer, Z, Chung, WK, Gold, WA, & Christodoulou, J. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). Hum. Mutat. 2020a:  41 (10); Cover image. doi:10.1002/humu.24115.

8. Kaur, S, Van Bergen, NJ, Verhey, KJ, Nowell, CJ, Budaitis, B, Yue, Y, Ellaway, C, Brunetti-Pierri, N, Cappuccio, G, Bruno, I, Boyle, L, Nigro, V, Torella, A, Roscioli, T, Cowley, MJ, Massey, S, Sonawane, R, Burton, MD, Schonewolf-Greulich, B, Tumer, Z, Chung, WK, Gold, WA, & Christodoulou, J. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). Hum. Mutat. 2020b:  41 (10); 1761-1774. doi:10.1002/humu.24079.

9. Schonewolf-Greulich, B, Bisgaard, AM, Duno, M, Jespersgaard, C, Rokkjaer, M, Hansen, LK, Tsoutsou, E, Sofokleous, C, Topcu, M, Kaur, S, Van Bergen, NJ, Brondum-Nielsen, K, Larsen, MJ, Sorensen, KP, Christodoulou, J, Fagerberg, CR, & Tumer, Z. Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements. Clin. Genet. 2019:  95 (3); 403-408. doi:10.1111/cge.13473.

10. Schonewolf-Greulich, B, Bisgaard, AM, Moller, RS, Duno, M, Brondum-Nielsen, K, Kaur, S, Van Bergen, NJ, Lunke, S, Eggers, S, Jespersgaard, C, Christodoulou, J, & Tumer, Z. Clinician's guide to genes associated with Rett-like phenotypes-Investigation of a Danish cohort and review of the literature. Clin. Genet. 2019:  95 (2); 221-230. doi:10.1111/cge.13153.