Background
The neurological disorder Rett syndrome (OMIM 312750) was first described in the English literature in 1983 [
1] and later found to be associated with mutations in the methyl CpG binding protein 2 gene (
MECP2) [
2]. Females are mostly affected with an incidence of diagnosis of 1:9000 by the age of 32 years [
3]. Diagnosis depends on clinical presentation [
4] with or without a pathogenic
MECP2 mutation. Genetic testing occurs commonly in current diagnostic pathways but many older women may not have undergone genetic testing. The clinical characteristics of Rett syndrome first appear in early childhood. Gradual or sudden loss of speech and hand function, loss of acquired gross motor skills and the development of stereotypic hand movements mark a period of regression between the ages of 6 and 18 months. Gastrointestinal problems, respiratory dysfunction such as hyperventilation, breath holding and apnoea, sleep disturbance, spinal curvature and epilepsy are common comorbidities. Overall severity of symptoms is highly variable across individuals and studies have identified common mutations associated with either a milder phenotype (point mutations p.Arg133Cys, p.Arg294*, and p.Arg306Cys) or a more severe clinical presentation (point mutations p.Thr158Met, p.Arg168*, p.Arg255*, p.Arg270* and large deletions) [
5,
6]. Clinical presentation in adults with Rett syndrome is less well understood.
Emerging picture of health and wellbeing in adults with Rett syndrome
Thus far only two studies conducted in the Netherlands (2007: n = 53, 2012: n = 37) [
7] and Italy (n = 84) [
8] have specifically examined health in adults with Rett syndrome. Overall, general health was reported to be good. However epilepsy was found to be highly prevalent in both the Dutch (93%) and the Italian cohorts (82%), and while improvement in seizure activity with age was noted for some women [
8], some remained difficult to treat and the majority required medications for control of seizures. A post-adolescence decline in gross motor skills has been reported in some [
7,
9] but not all women with Rett syndrome [
7]. Gross motor capabilities are influenced by the type of mutation present in the
MECP2 gene and are generally poorer in those requiring surgical correction for scoliosis [
10]. Autonomic dysfunction which may manifest as hyperventilation or breath holding, or peripheral vasomotor disturbances is a well-recognised but poorly understood feature of Rett syndrome. Abnormal or disturbed sleep patterns and behavioural issues also appeared to persist [
7,
8]. Similarly, gastrointestinal issues such as constipation, reflux, and feeding difficulties remained prevalent [
7,
8] and may contribute to poor growth [
11]. However, there is a need for replication of these studies using larger sample sizes to improve our understanding of clinical presentations beyond the growth and development of childhood.
Survival
It is possible that those adults with Rett syndrome who survive into adulthood may represent a healthier group. The most recent Australian population-based estimate indicated that ~70% would be alive at 25 years with some evidence of improved survival over calendar time when comparing with the historical Austrian cohort [
12]. A study using data on 1,907 cases ascertained from a combined US and Canadian sample (n = 2,994) showed a similar result at age 25 years [
13]. A recent longitudinal study conducted in The Netherlands [
7] reported the death of 7 of 53 women aged between 21 and 43 years over a five-year period. However, it is difficult to measure survival accurately using small samples that are not population-based with only short follow-up time.
Our aims were to update our previous estimate of survival with now 20 years of follow-up in the Australian Rett Syndrome Database (ARSD) and to describe health status in individuals aged 18 years or older sourced from both the ARSD and the InterRett database.
Discussion
Using a population-based cohort we have shown that current survival to the age of 20 years is 77.6% with 59.8% surviving to early middle age. In women aged 18 years and older we found that epilepsy, breathing and sleep problems persisted, low weight and gastrointestinal issues were prevalent and although most have scoliosis loss of walking is not inevitable. The influence of genotype, while moderate, is in agreement with previous findings.
A major strength of this study is the rich data sources available for analyses. Our population-based ARSD with follow-up of individuals up to 20 years was coupled with up-to-date death information has allowed us to make an accurate estimate of survival in Rett syndrome. Our cross-sectional analysis of a large multi-country study population, over half of whom have a confirmed mutation in the MECP2 gene has allowed us to more fully investigate the clinical profile, and influence of genotype, in ageing women. Limitations of this study include lack of representation of older women not living in the parental home in the international community since, unlike those who live in their parental home, their family members would be less likely to be active participants in online initiatives such as the InterRett database. Despite the survival analysis being undertaken on Australian population-based data collected over 20 years the capacity to detect differences in mortality risk across mutation groups was limited by the small number of deaths within specific mutation groups.
Importantly, we can now report survival in the ARSD cohort of slightly less than 60% at 38 years of age although the current estimate of survival to 25 years (71.5%) is lower compared to our 2006 analysis (77.8%) [
23]. Death was most commonly caused by respiratory illnesses. Increased ascertainment and follow-up of individuals in the more recent analyses likely explains the difference in the survival estimate over time. A higher estimate of survival to 25 years (~80%) was reported for a cohort of US and Canadian females (n = 1,907) [
13]. The authors of this study reported that many known individuals who had been identified through the family association were not included in their analysis due to failure to make contact (52%, n = 1,555) and it is likely that individuals who have not registered with the family association or clinics also exist within the US and Canadian populations. The survival estimate is likely over-estimated because it is quite plausible that the proportion of deceased compared to living cases would have been higher in the group whose families were not able to be contacted in comparison to the group whose families were able to be contacted and on whose data the analysis was based. As recommended by the authors of the study, a population-based national registry, similar to that in Australia, with links to national death registry and other pertinent data sources might be advantageous, as mortality in such cohort will yield more precise survival rates as case numbers and periods of follow-up increase over time.
Compared to those with the p.Arg133Cys mutation, the risk of death was high in those with a p.Arg270* mutation consistent with our previous findings [
24]. Our new findings indicate that survival in those with the p.Arg106Trp mutation or large deletion is similar to that of the p.Arg270* group and that those with p.Arg255* mutations demonstrate better survival. A proportion of those who were older had not been tested for a
MECP2 mutation because of its relative recent availability and some families do not now want to revisit diagnostic processes. Nevertheless, genetic testing for women with a clinical diagnosis of Rett syndrome has important roles to play. Some families do value more specific diagnostic information [
25] and the data contributes to greater accuracy in future estimations of the effects of genotype on phenotype including survival.
Our cross-sectional analyses used the largest sample size to date for investigating health and wellbeing in adulthood. Seizures are common in Rett syndrome and not surprisingly, almost two-thirds (263/411) of the women continued to take anti-epileptic medications at the time of data collection. Previous studies have reported stabilisation or improvement in epilepsy in older women [
7]. While some parents in the current study noted that the frequency or severity of seizures had diminished with age, the majority had active seizures, and of these, a third was considered to be refractory. An investigation of epilepsy in the InterRett study showed similar results for those aged 17 years or older [
18]. These findings indicate that management of epilepsy remains a serious challenge in ageing women and this picture was consistent across all mutation types.
Over half (60%) of the study cohort had some walking skills at the time of data collection. The proportions of women who could walk independently, with assistance, or not at all, were similar to that previously reported for an Italian cohort of women and adolescents aged 14 or more years [
8]. A longitudinal study of adult women with Rett syndrome conducted in the Netherlands [
7] indicated that age-related deterioration of gross motor function is slow. This observation concurs with findings from a video study which investigated general stability in gross motor function over a 3- to 4-year period: girls younger than 13 years with walking skills were more likely than teenagers and women to lose the more complex motor skills that enabled better negotiation of the environment [
26]. Together these findings add strength to the thesis that loss of walking is not inevitable as women with Rett syndrome age. It is likely, however, that these women represent the milder range of the severity spectrum and that those who could not walk from an early age, being more severely affected, may have died before reaching adolescence or adulthood. Those with spinal curvature were less likely to be ambulant and encouragingly, many were well following previous surgical management.
The proportion of those who could walk in the p.Arg133Cys mutation baseline group (76%) was similar to those with a p.Arg294* mutation (81%) and significantly better than those with large deletions (27%). Improved gross motor skills for those with a p.Arg133Cys and p.Arg294* has been previously observed in a video study of 99 girls and women from the ARSD registry, 29 of whom were 19 years or older, possibly reflecting some survival bias [
10]. A 2008 study (n = 272) found that the overall phenotype of those with p.Arg133Cys and p.Arg294* mutations is mild [
5] and Cuddapah et al [
6] found significant differences in ambulation, not adjusted for age, between those with p.Arg133Cys and nine other mutation groups (p.Thr158Met, p.Arg168*, p.Arg255*, p.Arg270*, Deletions, Insertions, Large Deletions, Splice Sites and No mutations). These consistent findings across and within age groups help to provide a clearer clinical picture of mobility outcomes in those affected by these common mutations.
We found, as had others, that sleep disturbance [
7,
8] and gastrointestinal problems [
7] were highly prevalent in older women. We recently found the rate of gall bladder disease in a Rett syndrome population-based study to be 2.3 per 1000 person years (ie. two new cases if 100 individuals are followed for 10 years) [
27]. Available population-based data on typical paediatric populations suggested a lower prevalence than this [
28,
29]. Although gall bladder disease was identified in 5% of adults in our current study it is unclear how this compares with the general population. We suggest that gall bladder disease should be considered in the differential diagnosis of abdominal pain in Rett syndrome.
Unusual breathing patterns including hyperventilation and breath holding were highly prevalent yet there has been a paucity of research in this area. Women with a p.Arg255* mutation were least likely to hyperventilate and also had a lower mortality. The influence of breathing irregularities on overall health and survival is not well understood and further research in this area is warranted. Similarly, the frequency of respiratory type infections indicates that these health issues may also need to be closely monitored, including attention to upright postures during daytime activities and a low threshold to the prescription of antibiotics.
Fortunately, behavioural difficulties and anxiety only appeared to affect a relatively small proportion of women although these issues would likely have a major impact on the daily quality of life of those with Rett syndrome and their carers. Small increases in the mood and anxiety scores were observed for those aged 26-30 years in comparison to the older and younger age groups. In the Dutch cohort, behaviour was assessed using the Observational Questionnaire Elderly Residents with Intellectual Disabilities (OOB). Based on this instrument, two thirds of Dutch women showed anxiety and during the five year study period improvements were mainly seen in those age 30 years or more (2007-2012) [
7]. It might be expected that those with a milder phenotype can better communicate their feelings, however, we observed higher predicted scores for mood and anxiety in mutations associated with both mild and severe phenotypes.
The change in composite health status by mutation type over time was outside the scope of the current study. However, a previous study of health trajectories over time in our Australian cohort [
30] found that for most mutations, including p.Arg133Cys where health status at a younger age was better, health status deteriorated over time. For a few others, which tended to be severe mutations, health status either remained unchanged (pArg106Trp) or improved slightly (p.Arg255* and p.Arg168*) with age [
30]. The authors of the US longitudinal study [
6] reported that severity of symptoms increased by age for most mutation types in both cross-sectional analysis across five age groups and longitudinal analysis within individuals. The severity score for an individual was determined by a protocol developed by the authors who acknowledged that the inclusion of some items, which cannot change with time, may have led to an underestimation of age-related changes in their longitudinal analyses. Given that there is considerable variance in clinical outcomes within mutation types, consistent ongoing follow-up of existing cohorts is required to obtain a clearer picture of mutation-specific severity in women with Rett syndrome.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
The study was conceptualised by HL and JD both of whom participated in the organisation and execution of the study including drafting and critique of the manuscript. AA participated in the study design, organisation and statistical analysis and wrote the first draft of the manuscript. KW and PJ designed and executed statistical analysis and all authors contributed to the drafting and critique of the manuscript. All authors read and approved the final manuscript.