Investigators: Daniel Ta, Helen Leonard, Jenny Downs, Peter Giudice-Nairn
Project description
We have collected clinical and genetic information on children newly diagnosed with the MECP2 duplication syndrome throughout Australia. We have confirmed that this is a very rare disorder affecting approximately 1:150,000 children in Australia and that there is need for development of an international database to better understand the clinical features and natural history.
Mutations in the MECP2 gene were first identified in 1999 as the major cause of Rett syndrome. Six years later micro-duplications involving the MECP2 gene were reported to be a cause of severe intellectual disability in males. Subsequent studies have now established MECP2 Duplication as a specific syndrome that might account for approximately 1% of unexplained X-linked intellectual disability in males. To date most publications have been based on small case series with no studies describing prevalence or epidemiology such that the natural history of MECP2 Duplication syndrome remains unclear.
In 2016 we published data on 57 cases (49 males and 8 females) with MECP2 Duplication syndrome which had been provided to our International Rett syndrome (InterRett) database. The median age at ascertainment of our cases was 7.4 years (range 1.2-37.6 years) and at diagnosis 3.0 years (range 3 weeks-37 years). Less than a third had learned to walk. Speech deterioration was reported in over a third and only one if five used word approximations or better at ascertainment. Over half of the individuals had been hospitalised for respiratory infections in the first two years of life. Just under half had seizures, occurring daily in nearly half of this group. The majority had gastrointestinal problems and a third had a gastrostomy.
We are currently using the Australian Paediatric Surveillance Unit to collect information on newly diagnosed cases of MECP2 Duplication Syndrome in Australia. Our specific study aims are to: use the information collected to generate population-based estimates of incidence and prevalence of this syndrome, and describe the core clinical features of MECP2 duplication syndrome. Over 54 months of surveillance we have had 20 cases (16 males and four females) reported to the study.
During 2018 we analysed these Australian data provided by clinicians, supplemented by data on Australian cases of MECP2 Duplication syndrome ascertained in InterRett. We found that the birth prevalence was 0.65/100 000 for all live births and 1/100 000 for males. Diagnostic incidence was 0.07/100 000 person-years overall and 0.12/100 000 person-years for males. The median age at diagnosis was 23.5 months (range 0 months–13 years). A history of pneumonia was documented in three quarters of the clinical cases, half of whom had more than nine episodes. Cardiovascular abnormalities were reported in three cases and one child died due to severe idiopathic pulmonary hypertension.
Establishing an early diagnosis and understanding the natural history of the disorder is vital to the design of future therapeutic strategies and monitoring of outcomes. We propose the development of an international registry specific to MECP2 Duplication syndrome to facilitate future studies. It would also allow for better depiction of phenotypic variability, developmental trajectories and disease progression.
During 2019 we have worked towards the development of this registry which will be launched in 2020.
Partners
- APSU