Original articleMeaningful word acquisition is associated with walking ability over 10 years in Rett syndrome
Introduction
Rett syndrome (RTT) (OMIM #312750) is a neurodevelopmental disorder primarily affecting females. Most cases of RTT are caused by de novo mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) [1]. Approximately 90%–95% of typical RTT cases exhibit loss-of-function mutations in the MECP2 gene of the X-chromosome [2].
Clinical manifestations include microcephaly, loss of psychomotor abilities, intellectual disability (ID), autistic behaviors, and hand stereotypies. Recent large cross-sectional studies revealed substantial clinical variability in MECP2 mutations [2]. It has been reported that girls and women with the mutations p.Arg270* (R270X) or p.Arg255* (R255X) present with more severe motor disability, whereas those with mutations p.Arg306Cys*, p.Arg133Cys*, and p.Arg294* (R306C, R133C, R294X, respectively), and C-terminal deletions exhibit a milder phenotype, and, in most cases, acquire the ability to walk [3], [4], [5], [6], [7]. However, it is difficult to estimate genotype-phenotype correlations because of the role of X inactivation. In the present study, we utilized the Japanese Rett syndrome database (JRSD), which was established in October 2012 and contains clinical data from over 102 RTT patients. Walking ability is important for family counselling and planning for the provision of care for young children with RTT. In the current study, we investigated factors related to ambulation ability in young children over 10 years of age with or without genetic effects, based on the JRSD.
Section snippets
Japanese Rett syndrome database and subjects
The JRSD is operated by management officers consisting of child neurologists and RTT family associations, and is supported by the Japanese government. The registration document is completed with a combination of parents’ questionnaire responses and doctor’s examination data after children’s diagnosis with RTT with clinical criteria and/or genetic abnormality [2]. A total of 102 female patients with RTT were registered from October 2012 to December 2015. For the current study, we obtained
Results
Two patients were excluded from the study because of incomplete data for RTT diagnosis, according to recent clinical diagnostic criteria [2]. We analyzed registered data from 86 typical and 14 atypical RTT patients. All patients were female, and ages ranged from 1 year to 43 years of age (mean ± SD; 14.5 ± 11.2 years of age; median; 11.4 years of age). Table 1 shows the age distribution and frequency of symptoms and signs. Of 100 RTT patients, 92 (92%) underwent genetic examination by Southern
Discussion
RTT, a neurodevelopmental disorder predominantly affecting females, has been characterized by apparently normal initial development followed by frank regression of fine motor and communication skills, typically between 6 and 18 months of age [13]. Our univariate analysis revealed that walking ability was correlated with crawling, meaningful word acquisition, microcephaly, MECP2 mutation type, and BMI. Multivariate analysis revealed that only meaningful word acquisition was robustly related to
Limitations of this study
Several limitations of this study may should be considered in interpreting the results. The principal limitation was the relatively small sample size of the study, limiting the generalizability of the results. Our study also used a cross-sectional design. However, our study also had several unique features, including collaborative study of parents or caregivers, and direct examination by a pediatric neurologist. In most previous studies, data were derived from questionnaires without direct
Author contributions
All authors have been involved in drafting or revising the manuscript, have given final approval, and agree to be accountable for all aspects of the work involved. Each author’s individual participation is outlined below. TS, Shin N, ST, TM, and MI did the conceptualization and design of the study and acquisition, analysis, and interpretation of the data. MK and TK did the statistical analysis of the data. Tetsu T, KY, SN, TT, YY, YK, and CH performed the follow-up examinations and
Sources of funding
This work was partially supported by a Grant-in-Aid for Research from the Japan Agency for Medical Research and Development (AMED) and a grant for research on Rare and Intractable Disease from the Ministry of Health, Labour and Welfare, Japan.
This work was partly supported by Grants-in-Aid for Scientific Research (No. 18K07893 to TM) from the Ministry of Education, Culture, Sports, Science and Technology, MEXT, and also partly supported by JSPS KAKENHI Grant Number 16H01880 to TM).
Conflict of interest
None of the authors have conflicts of interest to declare.
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