RES: Dr Singh, congratulations on the recent publication of the team’s paper on movement disorders in Rett Syndrome, entitled ‘Movement disorders in patients with Rett Syndrome: A systematic review of evidence and associated clinical considerations.’(1) This paper, published in the Journal of Psychiatry and Clinical Neurosciences (PCN), continues the theme of clinical translational outputs from the CIPP Rett Centre in the first two years of operations.
Moving forward, what are your hopes for future research outputs in the CIPP Rett Centre?
JS: The CIPP Rett Centre has contributed to a deeper understanding of Rett Syndrome. Not only has it provided helpful guidance for families, but it has also kept people with Rett as safe as possible during the ongoing pandemic. As we emerge out of the pandemic, we hope that the centre can continue to address the gap in knowledge and make this information easily accessible for the wider Rett community, especially as patients prepare for the first gene therapy trials in the next few years.
RES: Why did the team choose to do a review of movement disorders in Rett Syndrome?
JS: We chose to do a comprehensive systematic review of movement disorders in Rett Syndrome because movement problems such as dystonia, stereotypies etc., are often debilitating symptoms in patients. The purpose of the paper was to see if the team could better understand (I) the clinical impact of movement disorders in Rett patients and,
(II) whether the information obtained would be clinically relevant and valuable when assisting in managing movement disorders in patients.
RES: Which symptoms of Rett Syndrome are considered to be movement disorders?
JS: The team focused on all movement disorders. We reasoned that because nearly all patients with Rett have stereotypies that co-occur alongside other abnormal movement disorders, we would be able to detect most of the studies of abnormal movements in Rett patients. To extend this, we also searched for other specific movement disorders in patients with Rett: dystonia, Parkinson, bruxism, spasticity, tremor and ataxia.
RES: What were the main findings of the paper?
JS: The main findings from the paper can be summarised as (I) further understanding and learning of the clinical features of movement disorders in Rett patients, (II) genotype-phenotype relationships of movement disorders in Rett, (III) recognition of symptoms and stressors that impact movement disorders, (IV) deeper insight into the possible underlying neurobiological mechanisms, (V) how the quality of life of Rett patients can be affected by movement disorders and (VI) treatment implications for managing movement disorders in Rett patients.
RES: To what extent do particular genetic mutations correlate with the severity of movement disorders in Rett Syndrome, and why would it be useful for treating clinicians?
JS: There is some information on this in the Rett literature. By synthesising all this information, the team could get a better clinical overview of the genotype-phenotype relationships of movement disorders in Rett patients. We were able to recognise that (a) the phenotype of movement disorders is different between patients with typical and atypical Rett, (b) patients with truncating mutations or large deletions had worse clinical symptoms and outcomes and (c) patients with C-terminal deletions were less severe. This information is helpful because, as many specialist clinicians are involved in Rett patients’ care, they might not be completely aware of the relationship between the specific mutation and the severity of the movement disorder.
RES: What is environmental enrichment?
JS: There is some evidence indicating that environmental stimulation can positively impact patient quality of life and reduce the care-giver burden. It has been suggested that positive environmental stimulation leads to changes in levels of some specific proteins that promote neuronal health. Our paper suggests that environmental enrichment offers an attractive non-drug based strategy that could help manage some aspects of movement disorders in Rett patients. We feel that even minor improvements would improve the well-being of patients.
RES: What are the specific recommendations to clinicians managing patients with Rett to come out of the systematic review?
JS: Our paper includes detailed information on movement disorders in Rett Syndrome, and to make this information more accessible, we summarised treatment information in a summary table (see Table 3). While limited data is supporting different treatments in movement disorders, we were able to place the information in context for Rett patients. This would enable clinicians who manage patients to have the necessary information readily to hand. Some points to take note of are:
- Trihexyphenidyl has been used to target dystonia. The most common side effects include a reduction in concentration and memory, but this might not be easily detected in Rett patients. Peripheral side effects can include dry mouth, urinary retention, constipation and blurred vision.
- Oral baclofen to manage specificity and dystonia can cause dose-dependent side effects, including sedation, hypoventilation and increased seizures. This can potentially worsen pre-existing breathing problems and epilepsy.
- Benzodiazepines can be prescribed to target spasticity and dystonia; however, their use should be avoided in Rett patients because (I) they might induce respiratory depression for which Rett patients already have a vulnerability, (II) benzodiazepines such as clonazepam can cause excess drooling, that could increase the risk of aspiration pneumonia.
- Botox can be used to help in the management of focal and segmental dystonia/spasticity. Reinjection is necessary at 12-14 weeks. The procedure is minimally invasive for superficial muscles but can require sedation, which has additional complications for Rett patients.
- Gabapentin can improve muscle tone in children with refractory dystonia; however, its effectiveness in Rett patients is unknown. Given the lack of available data on Rett Syndrome and the potential for multi-system side effects, the use of gabapentin for managing movement disorders in Rett must be done with caution.
RES: Dr Singh, congratulations to you and all the team at the CIPP Rett Centre on the publication of this, your sixth published paper since Reverse Rett started to core fund the Centre in September 2019. Thank you to you all for all your continued work for patients with Rett Syndrome and to you personally, for taking the time to provide this further information to clinicians and families.
(1) Singh J, Lanzarini E, Nardocci N, Santosh P. Movement disorders in patients with Rett syndrome: A systematic review of evidence and associated clinical considerations. Psychiatry Clin Neurosci. 2021 Sep 2. doi: 10.1111/pcn.13299. Epub ahead of print. PMID: 34472659.