Resourceful and creative methods are necessary to research rare disorders


SIR–In his commentary, Dr Angus Clarke discussed the methodology and findings from our recent investigation of epilepsy in Rett syndrome[1, 2] and we welcome this opportunity to respond. Our investigation used the infrastructure of InterRett, established in 2002 with dual aims of encouraging international collaboration and ascertaining the large case numbers required for statistically meaningful research in Rett syndrome. InterRett was ahead of its time in its global approach to rare disease research including the use of the internet for data collection. The database is continuing to grow and now includes data from 54 different countries. With its large sample size, InterRett has provided valuable opportunities to explore the relationships between genotype and phenotype[3] in now replicated studies,[4] mainly limited to eight common and two groups of mutations, large deletions and C terminal deletions. However, there are many less common but not rare mutations (e.g. p.R106W, p.P255R, p.R133H) with specific phenotypes in need of investigation. InterRett will therefore have a continued important role to play.

Information on genotype-phenotype relationships already provides guidance to clinical practice, for example concerning management of scoliosis and growth, although we acknowledge the role of X inactivation, as demonstrated in our previous work with Dr Clarke.[5] However, this research has not been replicated and, although assumed, it has not been possible to demonstrate that the pattern of X inactivation in the brain is related to the clinical phenotype in humans. We acknowledge InterRett's limitations but the need to translate genetic information into useful clinical knowledge is a worthy challenge. Are we also to assume that additional information provided by new genetic techniques such as next generation sequencing will have little prognostic value or do we dare to be adaptive and innovative and ask ourselves: how might we harness clinically useful knowledge from the latest data rich diagnostic tools?

For this current study,[2] our large sample size allowed for powerful analyses of relationships between aspects of epilepsy and genotype. We do not believe that the InterRett database is biased towards the exclusion of cases with a more severe phenotype. In fact, cases with mild mutations like p.R133C or p.R294X are more likely to be excluded because of later diagnosis. Socioeconomic bias is a weakness of any database or clinical study which is not population-based or actively ascertaining cases. InterRett is not alone in this shortcoming while the Australian database is uniquely population-based.[6] In our epilepsy investigation, we used a number of statistical techniques including time-to-event analysis to account for the age distribution when determining rates. Also, our large sample provides the clearest findings to date on how genotype influences both the development of epilepsy and its severity. Epilepsy is a serious comorbidity and our data has set the scene for further investigation of how best to manage epilepsy in Rett syndrome. For example, families far too often request information about the optimal epilepsy management regime for their child and are frustrated when management does not achieve good control of seizures. Thus we believe that between-country variation in ‘prescription habits’ should not be dismissed but considered as a potential avenue for investigation without the need for a clinical trial. We also acknowledge that the CDKL5 disorder is characterized by early onset epilepsy and has some common features with Rett syndrome. However, all cases in our study had a pathogenic MECP2 mutation.

In addition to genotype-phenotype studies,[3] the InterRett dataset has already been used for a wide range of investigative topics ranging from barriers to diagnosis of Rett syndrome in China,[7] to investigation of pain insensitivity and factors influencing diagnosis in the developed world. InterRett was not designed as a source of recruitment for clinical trials as stated by Dr Clarke. However, high ascertainment is needed to provide adequate patients for clinical trials. Here we would cite the case of China where we estimate 1000 cases of Rett syndrome per birth year.[7] In China we do not find families ‘living close to a research site’ or cases ‘receiving regular assessments’. What we find is a high prevalence of eligible cases living in close proximity. InterRett has opened the door to collaborations with Chinese families[7] who are keen to participate in research and possibly clinical trials.

How much further can large international databases take Rett syndrome research? This depends on the research question but on the whole, much further than fragmented data collections, often not representative of a single national population.[6] An international approach involving standardization of data collection methods for both phenotype and genetic information is increasingly recognized to be pivotal in rare and complex disease research, and InterRett will have a role to play. For example, autism researchers are using the latest data federation technology to analyse harmonized data from multiple countries. The InterRett project also gives a voice to families worldwide. At a recent InterRett family teleconference the difficulty of distinguishing between paroxysmal events of epileptic and non-epileptic origin was again highlighted and we were alerted to the existence of a parent-developed smart phone app for monitoring seizure activity. We therefore believe that a further important question for the Rett syndrome research community is: how do we work collaboratively with families to develop innovative approaches to improved understanding and management in Rett syndrome?