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Abstract

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgement
  7. What this paper adds
  8. References

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.

List of Abbreviation
ARSD

Australian Rett Syndrome Database

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.

Method

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgement
  7. What this paper adds
  8. References

Austrian (historical) cohort (n=22)

We obtained the date of death of individuals in this cohort by searching local obituary columns using demographic information obtained from the original and subsequent publications (initials, date of birth, and place of birth). We were able to ascertain the cause of death in six individuals from the Austrian Statistical Office (Statistik Austria) and in one from the original publication.1 Contact with two of the three survivors was established through regular publications in the newsletter of the Austrian Rett Syndrome Society. We were not able to contact the third known living female. Published diagnostic criteria were used to classify and scoring the phenotype of the these two females.3

Australian (current) cohort (n=332)

The Australian cohort was obtained from the ARSD, a population-based study of individuals in Australia with Rett syndrome born since 1976.5 Since the end of 2004,5 61 participants have been added and 19 deaths have occurred. For the present study, all records were updated with date of death or date last known to be alive as of December 2008. The last date at which participants were known to be alive was estimated from their last contact with their family or clinician.10–12 We excluded individuals with only a single contact (n=6) and those for whom only posthumous information was available (n=2). We ascertained the cause of death, where available, from the Australian National Death Index (n=19) and otherwise from the family or clinician (n=13).

Consent

The study was conducted with approval from the Ethics Committees of the Medical University of Vienna (No. 786/08) and the Princess Margaret Hospital for Children, Western Australia. Informed consent was given by the parents for the use of data on the living individuals, their early development, actual functioning, and genetic testing (within clinical routine management).

Statistical analysis

Survival analysis was undertaken using Stata version 9 (StataCorp LP, College Station Texas, TX, USA). For all individuals, age at entry was taken as the age at the first contact (either with the ARSD, or the earliest date obtainable from the Austrian records), and age at exit was taken either as the age at death (if the individual was deceased) or the age last known to be alive (for most censored individuals, the age at December 2008). We defined time at risk as ‘age at exit’ minus ‘age at entry’. In this way we created a survival dataset such that the individuals come under observation at the age of entry (although they became at risk at birth), and remain in the study at risk until the age at exit. In this ‘delayed entry’ scenario, survival time as an outcome of survival analysis does not measure survival to time t but, rather, survival to time t conditional on survival up to the minimum age at entry.13 Failure was set as 1 if the individual was deceased and 0 if the individual was known to be alive. The Stata survival analysis package provides a suite of commands to create Kaplan–Meier survival graphs, to compare the equality of survivor curves using the log-rank test, and to carry out regression using the Cox proportional hazards model, all corrected for the delayed entry of individuals to the observed dataset.

Birth years were grouped as follows: before 1965 (n=22), 1976 to 1985 (n=86), 1986 to 1995 (n=136), and 1996 or after (n=110). We performed Kaplan–Meier analysis using age at entry to the study (rather than birth, to account for individuals dying before the beginning of the study period and thus never coming under observation) to either age at censoring (date last known to be alive) or age at death (whichever occurred first). Survival was estimated using the Kaplan–Meier survivor function, conditional on survival to the minimum age at entry to the study (10mo) in this delayed entry situation. We used the log-rank test to assess equality of survivor functions and Cox proportional hazards regression to estimate hazard ratios, which can be interpreted as relative risks (with age as the analysis time). As age is used as the analysis time variable (rather than time on study), through the use of the survival analysis set-up described above, it is appropriate for the x-axis of the Kaplan–Meier survival curve graphs (Figs 1 and 2) to be labelled ‘age’, and this age at exit is also the outcome variable for the reported Cox regression analysis. Time at risk remains the same as if the conventional analysis time (age at exit minus age at entry) was used.

image

Figure 1.  Survival curve of the Austrian (historical) and the Australian (current) group from the Australian Rett Syndrome Database.

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image

Figure 2.  Survival curve by birth year group in the Austrian (historical) and Australian (current) cohorts.

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Results

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgement
  7. What this paper adds
  8. References

Austrian (historical) cohort

We were able to identify information on survival on all 22 (100%) of Rett’s original participants. Three females were still alive, two aged 48 and one aged 49, leaving 19 dates of death to identify. We found the date of death of 12 individuals in the local obituary columns. The approximate age at death for an additional three individuals (numbers 07, 08, and 15 from the original publication) was deduced from information in the original paper1 by Dr Rett and his later review.14 Dates of death for four individuals (participants 04, 05, 18, and 20 from the original publication) were obtained from a neuropathological study on Rett syndrome.15

All the originally described females were born between 1954 and 1964 in Austria. The original publication from Andreas Rett1 documents the date of first electroencephalogram, which closely corresponded to the date of first contact; the mean age at the time of the first electroencephalogram (n=21; except for number 22) was 3 years 9.6 months the mean age at publication in 1966 was 6 years 4.8 months. Age at entry to the study ranged from 10 months to 9 years 3.6 months, and age at censoring or death ranged from 2 years 1.2 months to 49 years 3.6 months. A total of 19 females had died at a median age of 13 years 4.8 months (range 2–32y; mean 15y 6mo). The cause of death was listed as pneumonia in two; heart failure in two; and gastric ulcer, status epilepticus, and death in the context of a chronic disease in one each.

Survival rate at the age of 20 years was 31.1% (95% CI 12.0–52.6), at the age of 25 years was 20.7% (95% CI 6.8–39.7), and at 32 years was 10.4% (95% CI 2.3–25.7).

Australian cohort (updated 2008)

The Australian cohort includes 332 confirmed females with Rett syndrome, born from 1976 onwards. Age at entry ranged from 11 months to 24 years 7.2 months, and age at censoring or death ranged from 1 year 10.8 months to 32 years 10.8 months. Forty individuals had died (mean age at death 16y 7.2mo; median 16y 9.6mo; range 3y 10.8mo–28y 2.4mo). Of these, eight had been able to walk and 32 had never walked. The causes of death were categorized as aspiration in 11 (27.5%), respiratory infection in 10 (25%), respiratory failure in three (7.5%), and related to seizures in three (7.5%). Other reported single causes included haemorrhagic stroke, cardiogenic shock, feeding disorder, asphyxiation, and in the course of palliative care. Survival rate at 20 years of age was 78.3% (95% CI 70.6–84.3), at 25 years of age was 70.7% (95% CI 61.5–78.0), and at 32 years of age (the oldest age in the study) was 64.9% (95% CI 52.9–74.5).

Kaplan-Meier survival curves of the Austrian (historic) patient group and the Australian (current) cohort from the ARSD (Fig. 1) showed significantly better survival in the later cohort (log-rank test χ2 [df=1] 29.91, p<0.005).

We found no practical or statistically significant differences in survival between the various birth year groups within the Australian cohort (log-rank test χ2 3.28 [df=2]; p=0.194). These groups are shown as the three broken lines in Fig. 2. Comparing the mortality of the birth year groups 1976 to 1985, 1986 to 1995, and 1996 and after with the Austrian cohort gave relative risks of 0.21 (95% CI 0.104–0.41; p<0.001), 0.27 (95% CI 0.14–0.53; p<0.001), and 0.26 (95% CI 0.064–1.03; p=0.055). Adjusting for age at entry to the study in the analysis for birth year group did not result in a significant improvement to the model (likelihood ratio test χ2 6.19 [df=4]; p=0.186).

Functioning of the two known survivors of the historical participant group

We have no additional information on the functioning of one (number 22) of the three living females from Rett’s original cohort. One surviving female (number 02) was born in 1959 and seen by Andreas Rett in Vienna for the first time in 1963; she showed typical early features concordant with the diagnostic criteria.3 She currently lives at home with her parents. She eats puréed meals, is provided with a brace for her scoliosis, and, in 1998, underwent a nephrectomy after pyelonephritis and was diagnosed with dermatofibrosarcoma. Mutation screening and deletion analysis of the MECP2 coding region by sequencing and multiplex ligation-dependent probe amplification identified a single nucleotide deletion in exon 4 codon 237 (c.710delG), a previously published frameshift mutation that causes a sure stop codon after amino acid 246.16 Such small-scale deletions account for approximately 17% of all MECP2 mutations.17 A second surviving female (number 12) was born in 1960, with an uneventful delivery, and presented with impaired motor milestones and spasticity. She displayed typical early features consistent with the diagnostic criteria3 and is living at home with her mother. She is able to speak in single words and two-word phrases and is walking independently, despite severe scoliosis. She takes carbamazepine for her well-controlled epilepsy and has neither respiratory problems nor autonomic dysfunction of her feet. We did not find any sequence alteration.16

Re-evaluating both participants’ early development revealed that participant 02 with the mutation met all the main and six of the eight supportive criteria necessary for establishing the diagnosis of classical Rett syndrome. Participant 12, without mutation, would not qualify as having classical Rett syndrome but meets the inclusion criteria (4/6 main and 6/11 supportive criteria) for variant Rett syndrome.3

Discussion

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgement
  7. What this paper adds
  8. References

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.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgement
  7. What this paper adds
  8. References

The authors are indebted to the families for their continued support throughout the study. H Leonard and GM Ronen contributed equally to this work.

What this paper adds

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgement
  7. What this paper adds
  8. References
  •  We provide information on the survival time of females with Rett syndrome over the past 50 years.
  •  The registered causes of death in Austrian and Australian cohorts of females with Rett syndrome are reported.
  •  We provide additional details on the historical cohort of Dr Andreas Rett.

References

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgement
  7. What this paper adds
  8. References
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