Original ArticleThe Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders
Introduction
The report of Hagberg et al. in 1983 provided the first widely read English-language publication on Rett syndrome (RTT), resulting in the remarkable expansion of clinical studies to understand the specific features of this X-linked dominant disorder. The identification of mutations in methyl-CpG-binding protein 2 (MECP2) in 1999 allowed fundamental research to progress dramatically. However, increased recognition of the disorder, expansion of the scope of clinical assessments, and the active involvement of parents and other caregivers worldwide had begun to alter the extent of clinical involvement in the management of this unique neurodevelopmental disorder before 1999.1 Early longitudinal studies2 revealed that after the initial stagnation and regression of development, children reach a “steady state” in adolescence and adulthood. Neuropathological studies3 shifted the perception from “degenerative” to the current perspective of a neurodevelopmental disorder.4 With increasing recognition of the myriad clinical issues and the need for intense therapeutic approaches, longevity and overall quality of life improved.5 The predominant morbidity issues include growth,6 nutrition,7 scoliosis,8 seizures,9 aspiration risk, and gastrointestinal dysfunction (gastroesophageal reflux, delayed gastric emptying, and constipation).10 Clinical experience suggests that intense physical and occupational therapies reduced development of contractures and skeletal deformities and communication technologies improve engagement.
The initial report of deaths in RTT occurred before implementation of intense therapeutic approaches.11 Thus, of the reported deaths, half were attributed to frailty and debilitation with frequent aspiration and 25% were attributed to an unwitnessed event assumed to be related to seizures or aspiration. More than 10 years later, the first survival study, conducted among more than 1900 participants in the United States and Canada indicated 50% survival at 50 years.5 Shortly thereafter, an analysis of the original cohort seen by Rett indicated a much reduced survival rate.12 The same report, together with a recent study providing data from Australia,13 yield similar results to those from the United States and Canada.
In this report, we show that survival from the US RTT Natural History Study (RNHS) is somewhat better than the 2010 survival study.5 Using the detailed clinical data in the RNHS, we have analyzed the 52 deaths reported in this cohort; together, these represented 4.3% of those enrolled. In contrast to the 1997 study, only one of these was related to a debilitated condition. We sought to identify characteristics associated with greater likelihood of death.
Section snippets
Participants
Through the multicenter RNHS, individuals with clinical RTT were recruited from March 2006 until February 2015 and evaluated at one of eight United States sites every 6 to 12 months, as described previously.6, 9 The RNHS consortium is part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences. An RNHS neurologist or geneticist (J.L.N., W.E.K., D.G.G., S.A.S., and A.K.P.) confirmed the diagnosis
Results
Overall, 1205 individuals were enrolled in the RNHS. Diagnosis could not be verified on 14. Two with CDKL5 mutation and atypical RTT were excluded from further analysis; one of these died at age 6.9 years of age from presumed cardiac arrest. Fifty-one deaths occurred in the remaining cohort of 1189 participants; these were followed for up to 9.0 years (median 7.0 years), and included 925 with classic RTT (one male), 80 females with atypical mild RTT, 86 with atypical severe RTT (one male), 62
Discussion
Compared to the initial report of Kerr et al. in 1997, in which nearly 50% of deaths were attributed to a frail or debilitated state with recurrent aspiration and pneumonia, our study has revealed a striking difference in the general health of participants.11 Only one of the individuals in our cohort died as the result of a frail condition. Fifty of the fifty-seven reported causes of death in the 2014 Australian study of survival in RTT were similar to those reported here and specifically did
Conclusion
Longevity is a major concern of families after receiving the diagnosis of RTT. These data help with anticipatory guidance for families, which we believe should be addressed soon after the diagnosis is made to allay unspoken concerns. Because patients may outlive their caregivers, the issue of long-term planning needs to be addressed as children age. Additionally, the natural history data reveal associations with growth, epilepsy, and ambulation, all of which can be addressed with appropriate
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