Areas of research

Current research being undertaken using AussieRett and InterRett

With the help of clinicians and families in Australia and world-wide who have children with Rett syndrome, our research aims to:

• improve our understanding of Rett syndrome;
• improve clinical care of those with Rett syndrome;
• contribute to the quest to discover cause and cure of Rett syndrome.

The Australian Rett Syndrome Database was established in 1993 and almost all Australian families with a child with Rett syndrome are participating. The population-base makes the research findings from this study very strong and we have established that Rett syndrome affects 1:9000 female births in Australia[1].

There are many types of specific individual mutations and in order to understand the clinical course and variability, we also collect information about Rett syndrome on much larger numbers of children and adults from all over the world in InterRett [2], our international project.

We are extremely grateful to all the doctors and families who have donated their time and energy to support this research which is leading the world in many areas. Thank you!

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Main areas of our research

Diagnosis of Rett syndrome

Our current research is investigating the systems for organising and funding genetic testing for Rett syndrome in Australia with the aim of streamlining the process and making it more efficient.

Further to the identification of the relationship between the MECP2 gene and Rett syndrome and following this the availability of genetic testing, the age at diagnosis of Rett syndrome has fallen over time both in Australia and internationally [3]. However we know that for some there is a delay in diagnosis. This prompted us to undertake research using Australian and international (InterRett) data to investigate the factors that might be associated with both early and late diagnoses. We found that factors related both to the child (e.g clinical symptoms and genetic mutation) and to the parents (e.g. socioeconomic status) were associated with how timely the diagnosis was [4].

Clinical patterns and course

Our Australian (AussieRett) and international (InterRett) databases contain information on many clinical features of Rett syndrome as well as the specific genetic mutation. We have conducted a large number of studies investigating how the different clinical patterns are influenced by the genotype. The genotype may relate to the specific mutation, to the effects of X inactivation or to the influence of other genetic modulators such as a certain polymorphism in the BDNF gene. Milder clinical presentations are often seen in those with a p.R133C, p.R294X, p.R306C or C terminal deletion whereas a p.R255X, p.R270X and large deletion mutations tends to be associated with more severe clinical features.

Clinical variants

It is important that we raise awareness amongst clinicians about the presentation of MECP2 abnormalities in baby boys.

Rett Syndrome in boys

Rett syndrome mostly affects girls but more rarely boys can be affected. Given that the MECP2 gene is on the X chromosome it was originally thought that boys would be severely affected by mutations in the gene and likely to die at a younger age. However, increasingly,  males with a range of MECP2 mutations and duplications of the gene are being reported in the literature. As with girls, these boys display a wide variety of symptoms and present with both mild and severe disabilities. Many symptoms closely resemble those of other more common disorders. This together with a lack of information and awareness of Rett syndrome in males likely contribute to under diagnosis or misdiagnosis of those affected.

Occurrence of Rett syndrome in boys

Early progressive encephalopathy in boys and MECP2 mutations

Mutations in the CDKL5 and FOXG1 genes give rise to clinical features that are similar to Rett syndrome.

The CDKL5 disorder

Individuals with a mutation in the CDKL5 gene may have some clinical features similar to Rett syndrome and may be clinically diagnosed as having atypical Rett syndrome. Some children with the CDKL5 disorder may be diagnosed with other disorders including West syndrome or infantile epileptic encephalopathy. We are currently conducting  a  CDKL5 disorder study to collect information on individuals with a mutation in this gene. This will allow us to develop a better understanding of the CDKL5 disorder phenotype and its clinical course, to assist in diagnosis and clinical management.

Learn more about our involvement with CDKL5

FOXG1

Individuals with a mutation in the FOXG1 gene have features in common with Rett syndrome including absence of language. Only a small number of cases have been reported to date and a recent review of 26 patients indicate that this might in fact be a new syndrome distinct from Rett syndrome. We continue to encourage families with mutations in this particular gene to participate in our InterRett and AussieRett studies. Information from these families will allow us to further identify the overlap in symptoms between those with a MECP2 mutation and those with a FOXG1 mutation and will be valuable to future research into the FOXG1 phenotype should it eventually be considered a separate syndrome.

Functional abilities

We are continuing to collect video data on girls and women in the Australian Database so that we can obtain a really good picture of the progress of Rett syndrome over time. This has never been done before.

Using Australian and international data we are also examining the range of communication being used by girls and women with Rett syndrome and the factors contributing to communication ability.

Functional abilities such as hand function, communication and gross motor skills are affected in Rett syndrome. We have used videos to understand more about the range of ways in which these skills are affected, how they may change over time and how they relate to genetic factors.  These studies are helping us identify where interventions are most likely to be effective.

Scoliosis

Using Australian data we are currently evaluating the benefits and costs of surgical for scoliosis in Rett syndrome. We are also monitoring the pattern of scoliosis curve progression in a total population of individuals with Rett syndrome.

Scoliosis is the most common orthopaedic condition in Rett syndrome. About 25% of girls are affected by the age of 6 years and about 75% affected by the age of 13 years. We have developed guidelines for the clinical management of scoliosis in Rett syndrome and have found that most of the girls and women retain or slightly improve their functional abilities after scoliosis surgery. However little is known about the pattern of curve progression over time and what factors affect this. There has been no research investigating the effect of different management regimes on the outcome of the scoliosis.

Epilepsy

We have ongoing work using Australian data investigating the different types of seizures occurring in Rett syndrome.

We are also using international data to examine the pattern and management of seizures.

Using Australian data we have found that seizures occur in the majority of girls with Rett syndrome. The average age of onset is four years and nearly 80% are affected by the age of ten years. Seizure rates are highest in the 7-12 year age group and least frequent in those aged over 17 years.

Bone health

We have arranged for a large number of girls and women to have bone density testing, some on two occasions and we are currently investigating how bone density  may change with age.

We are also developing clinical guidelines to help children and adults with Rett syndrome to achieve optimal bone health.

Osteoporosis occurs commonly in individuals with Rett syndrome and for many, fracture may also occur. In our Australian study we have examined the predictors of fracture and assessed the factors affecting bone density. We found that fractures may be associated with the type of genetic mutation, low levels of mobility and use of medications for epilepsy.

Growth and other gastro-intestinal disorders

With the involvement of an expert international panel we are currently developing clinical guidelines for the management of the commonly occurring gastro-intestinal problems.

We are also evaluating the outcomes of gastrostomy from the perspective of the person with Rett syndrome and their carers.

Poor growth is one of the characteristics of Rett syndrome, may be associated with difficulty feeding and is likely related to the type of genetic mutation. Reflux and constipation commonly occur.

Feeding experiences and growth status in a Rett syndrome population.

Health and well-being of families

We are currently examining the patterns of sleep problems in children with Rett syndrome and the factors associated with these, an important aspect of family health and well-being.

We have examined the factors that can influence maternal mental and physical health and found that family resources and social supports are important to well-being. However the child having a recent fracture would appear  to impact negatively on maternal health and well-being. We have also investigated the use of equipment and respite and it would appear that needs were not always being met.

Physical and mental health of mothers caring for a child with Rett syndrome.

Health services use

Rett syndrome is a complex disorder and care often involves the use of health services, respite services and other equipment needs. We found that although medical needs were likely to increase with age, use of services actually declined. We also undertook a study to measure use and cost of health sector and related services. We found that needs relating to health sector and related resources involved considerable costs and that many carers are likely to be facing undue financial pressures as a result. We have investigated these areas of care to better understand the impacts of Rett syndrome and to assist in advocacy for services to address family needs.

Use of equipment and respite services and caregiver health among Australian families living with Rett syndrome.

Measuring use and cost of health sector and related care in a population of girls and young women with Rett syndrome.