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Aim Rett syndrome is a severe neurodevelopmental disorder that typically affects females. Little is known about the natural history and survival time of these females.
Method We compared the survival of all Austrian female participants from Rett’s historical cohort (1966) with that of affected females registered in the Australian Rett Syndrome Database. The analysis included both Kaplan–Meier analysis and a log-rank test for equality of survivor functions.
Results Of females in the original Austrian group, three are still alive. The median age at death was 13 years 4.8 months. The probability of survival up to the age of 25 years was 21%, compared with 71% in the Australian cohort (p<0.001). We found no practical or statistically significant differences in survival between the various birth year groups within the Australian cohort.
Interpretation Our data indicate that survival of females with Rett syndrome has improved since the late 1960s but that there has been shown no change in survival over the last 30 years, possibly because the follow-up time has been too short.
Rett syndrome (OMIM 312750) is a severe neurodevelopmental disorder originally described by Andreas Rett.1 In the ensuing years consensus diagnostic criteria have been established for both classical and atypical Rett syndrome.2,3 In 1999, Amir et al.4 identified mutations in the transcription repressor gene MECP2 as the underlying cause of Rett syndrome. The diagnostic incidence of Rett syndrome in females by the age of 15 years is estimated to be 1:8500.5
Despite increasing interest in the ageing process in individuals with intellectual disabilities,6 to our knowledge few publications have described the natural history of neuropaediatric conditions.7,8 Little is known about the longevity and everyday life of females with Rett syndrome. In their series from 1971 to 1999, Berg and Hagberg9 reported a mortality rate of 18% (median age at death 24y) in a cohort of 54 females (age range 5–60y; median 20y). Among individuals registered on the Australian Rett Syndrome Database (ARSD), the oldest of whom is 28 years, the reported mortality was 2% at 10 years and 22% at 25 years.5
The aims of this study were (1) to explore the lifespan of females with Rett syndrome by comparing survivor information from Andreas Rett’s original publication1 with more recent information from the ARSD10 (we hypothesized a gradual improvement in survival from 1966–2008) and (2) to evaluate the functioning of the known survivors first studied in Dr Rett’s 1966 publication.
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Rett syndrome is a neurodevelopmental disorder with regressive and static stages (stages I–IV17) and severe functional impairment. Reduced survival time of affected individuals has been reported.5 It has been reported that in Western Sweden most of the deaths are sudden and unexpected and occur during the night, or at the onset of acute infections,18 whereas in Australia most deaths are reportedly linked to pneumonia.5 Other causes of death in individuals with Rett syndrome include sudden unexpected death in epilepsy (SUDEP), brainstem autonomic failure with or without cardiac arrhythmias, pneumonia/aspiration, acute gastric dilatation and rupture, inflicted injury, and medication-related problems.19 Among the seven individuals from the original cohort for whom a registered cause of death was available, pneumonia, heart failure, gastric ulcer, and status epilepticus were similar to the more commonly listed causes of death in the Australian cohort.
Information on mortality in females with Rett syndrome is limited because of the relatively young age of those registered.5,20 This study compares the large Australian cohort that includes individuals born since 1976 with the smaller Austrian cohort that included individuals born before 1965. This report explores the prospect of increasing survival time over the last four decades. There is a significant difference between the Austrian group and each of the three Australian birth year groups, but there is little difference between the three Australian birth year groups. Quality of care and placement issues may account for the difference between the cohorts.21 However, we could not identify any improvement in average life expectancy over the last three decades. The follow-up period for the ARSD (since 1976) has not been sufficiently long to establish information on life expectancy after 32 years. Moreover, to date, insufficient deaths have accrued in the ARSD to evaluate any potential improvement in survival of subgroups with specific levels of impairment, as has been reported for populations with cerebral palsy.8 The surviving individuals in the Austrian cohort, particularly the one meeting all the necessary criteria for typical Rett syndrome, demonstrate levels of functioning at an older age similar to those published by Hagberg.22,23
These results may also affect clinical care and counselling of the parents. Physicians should be aware of the prolonged survival in Rett syndrome and should offer families the latest information, especially about up-to-date antiepileptic treatment and available surgical interventions (e.g. scoliosis surgery, gastrostomy tube insertion) possibly affecting their quality of life and survival.
In summary, we present survival data, accounting for delayed entry, for the earliest published cohort of females with Rett syndrome. The longer survival reported from Australia may reflect improvements in the symptomatic quality of care of females with Rett syndrome.