A pediatrician was having a conversation with her high school son who said that in his English class they were about to start reading Shakespeare’s MacBeth. “Oh, that’s a great play,” she said. “Why do you think so?” he asked. “Well any play that starts out with witches is bound to be mysterious. Shakespeare wrote great characters who are terribly flawed,” she answered. “Plus, whenever I think about it, I think about the famous scene where Lady MacBeth washes her hands and that reminds me of a very nice family I took care of. Their daughter had a problem called Rett Syndrome. In Rett Syndrome the girls wring their hands and unfortunately also have other disabilities. Whenever I think of this play, I think of them and wonder how they are doing. It also usually inspires me to review a little bit about Rett Syndrome too,” she added.
Lady MacBeth and patients with Rett Syndrome (RS) are obviously not alike other than in making similar hand motions. In Shakespeare’s MacBeth (5.1.25-30), Lady MacBeth was driven into madness because of her murderous guilt and tries to wash the blood off her hands as she sleepwalks.
Doctor. What is it she does now? Look, how she rubs/ her hands.
Gentlewoman. It is an accustomed action with her, to seem thus/ washing her hands. I have known her continue in this/ a quarter of an hour.
In 1954, Dr. Andreas Rett observed 2 girls who were also making repetitive handwashing motions and later published a case series in 1966.
RS is a neurodevelopmental disorder caused by an X-linked dominant single gene deletion or mutation. The gene is the MECP2 gene which encodes for an epigenetic regulator protein called methyl-CpG protein 2 (MeCP2). Its complete function is still be elucidated but is involved in neurosynapse development and maintenance. The protein is found ubiquitously in the body but in higher concentrations in the brain. MeCP2 is found especially during early development but is also found in adults.
RS primarily affects females with an estimated prevalence of 1:10,000-15,000. Males with the mutation have a phenotype with severe neonatal encephalopathy and early death, but some males do survive. Classic RS patients are females who develop normally until ~6-18 months and then have developmental regression, deceleration of head growth and microcephaly, and stereotypical hand movements. There is marked differences in the phenotype for an individual but patients often have communication problems (both expressive and receptive language), cognitive deficits (can be severe), repetitive behaviors (particularly of the hands but also head, legs, feet, body and of sounds) and other problems including autonomic nervous system problems (irregular heart rate and breathing patterns), seizures (~70%) and spasticity, kyphoscoliosis, growth problems, gastrointestinal problems, small feet and gait abnormalities. Treatments are being worked on including genetic treatments and the use of medications such as IGF-1, GABA reuptake inhibitors and phentoin.
Other neurodevelopmental problems with epigenetic dysregulation include Fragile X syndrome, Prader-Willi syndrome, Angleman syndrome and Kabuki syndrome. A differential diagnosis of involuntary movement disorders can be found here.
RS is usually grouped with autism spectrum disorders (ASD) as ASD individuals have problems with communication, impaired social interaction and repetitive or stereotypical behaviors.
Hand stereotypies for patients with RS are much more common and marked than patients with ASD. One study of 40 patients with hand stereotypies found only patients with RS exhibited handwashing. A study of 83 patients with RS found that joined hand stereotypies occurred 80% of the time with washing behaviors occurring in 75.9% of patients. Mouthing occurred in 21.7% and clapping in 14.5%. Separated hand stereotypies occurred in 60.2% of patients with mouthing (36.1%), tapping (30.1%), hand gazing (14.5%) and hair pulling (10.8%) being the most common. Others included pill rolling, hand twirling, one hand behind neck, twisting 2-3 fingers, flapping, movements likes castanets or movements similar to Spanish dancers.
The stereotypies are often described as “…continuous, repetitive, compulsive automatisms…” that occur only during wakefulness and disappear during sleep.
Questions for Further Discussion
1. Compare and contrast Fragile X syndrome, Prader-Willi syndrome, Angleman syndrome and Kabuki syndrome.
2. What is epigenetics?
- Symptom/Presentation: Developmental Delay
- Age: Teenager
To Learn More
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Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol. 2002;6(5):293-7.
Temudo T, Oliveira P, Santos M, et. al.. Stereotypies in Rett syndrome: analysis of 83 patients with and without detected MECP2 mutations. Neurology. 2007 Apr 10;68(15):1183-7.
Goldman S, Temudo T. Hand stereotypies distinguish Rett syndrome from autism disorder. Mov Disord. 2012 Jul;27(8):1060-2.
Rangasamy S, D’Mello SR, Narayanan V. Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics. 2013 Oct;10(4):742-56
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Nissenkorn A, Levy-Drummer RS, Bondi O, et.al.. Epilepsy in Rett syndrome–lessons from the Rett networked database. Epilepsia. 2015 Apr;56(4):569-76.
International Rett Syndrome Foundation History of Rett Syndrome. Available from the Internet at: https://www.rettsyndrome.org/document.doc?id=159 (cited 10/13/15).
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital