By Dr. J Singh, MSc, PhD
‘My lungs felt if they were on fire and I could not breathe Daddy.’ This is what my daughter told me one day as she was playing tag in the park during a cold winter’s day. Breathing is fundamental to all life processes; however, in Rett Syndrome breathing is impaired. But how, you may ask?
Like a puzzle, Rett Syndrome is part of molecular jigsaw that has many unique parts. This brings us to perhaps the most unique part - 'dysautonomia.' For each one of us, the autonomic nervous system represents a physiological see-saw, when it is stable it is vital for physiological process such as regulating blood pressure and breathing - all of which it does automatically.
On one side of the see-saw sits the ‘sympathetic,’ and on the other side sits the ‘parasympathetic’ component. Dysautonomia refers to an imbalance in the sympathetic and parasympathetic parts of the autonomic nervous system. Several medical conditions can present with this imbalance. In Rett Syndrome, mutations in the gene encoding the methyl CpG binding protein 2 (MECP2) cause developmental brain stem immaturity (1,2) and the resulting brain stem dysfunction (indicated by red circle) can imbalance the physiological see-saw (see diagram). The knock on effect of brain stem immaturity is the underdevelopment of nascent neurotransmission pathways (3,4,) which is a major underlying component of the dysautonomia seen in children with Rett.
Dysautonomia can cause a variety of problems in children with Rett such as palpitations, panic attacks and excessive sweating but perhaps the most distressing consequences of dysautonomia to the child and their family are breathing problems.
Current indications suggest that these breathing problems usually appear when the child is about 4.5 year old (5) and clinically seems to be a largely undervalued factor in children with Rett. Breathing problems can have a significant burden on the quality of life not only for children with Rett but also their families.
Research has begun to explore the respiratory signatures in children with Rett with an aim to allow better management of respiratory problems (6). There is however, a long road ahead of us before we make good headway. Not all children with Rett have breathing problems and as the emotional state such as anxiety is a significant driver in the breathing cycle, treatment may not be as straightforward as it seems.
So I end with 'what’s breathing got to do with it….?' Well, in Rett, a lot actually! Given the impact it has on longevity, the quality of life of the individual with Rett and the impact this has on their family, it is one clinical feature of Rett that can no longer be ignored. (7)
Dr J Singh MSc, PhD is a member of the Reverse Rett Professional Advisory Board. He works as an Independent Medical Writing Consultant and Scientific Advisor for a range of clients including those in the pharmaceutical and charity sector. You can read more about J here
1. Julu PO, Kerr AM, Hansen S et al. (1997). Functional evidence of brain stem immaturity in Rett syndrome. Eur. Child Adolesc. Psychiatry. 6 Suppl 1: 47-54.
2. Julu PO & Witt Engerstrom I. (2005). Assessment of the maturity-related brainstem functions reveals the heterogeneous phenotypes and facilitates clinical management of Rett syndrome. Brain & Development. 27 (Suppl. 1): S43–S53.
3. Guideri F, Acampa M, Blardi P. et al. (2004). Cardiac dysautonomia and serotonin plasma levels in Rett syndrome. Neuropediatrics. 35: 36-8.
4. Paterson DS, Thompson EG, Belliveau RA. et al. (2005). Serotonin transporter abnormality in the dorsal motor nucleus of the vagus in Rett syndrome: potential implications for clinical autonomic dysfunction. J. Neuropathol. Exp. Neurol. 11: 1018-27.
5. Zoghbi HY (2016). Rett Syndrome and the Ongoing Legacy of Close Clinical Observation. Cell. 167: 293-297.
6. Halbach N, Smeets EE, Julu P, et al. (2016). Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study. Am. J. Med. Genet. A. 170: 2301-9.
7. Twenty years of surveillance in Rett syndrome: what does this tell us?, Orphanet Journal of Rare Diseases 2014, 9:87