Perturbations in the development of infants with Rett disorder and the implications for early diagnosis

doi:10.1016/j.braindev.2005.03.013

Brain and Development

Volume 27, Supplement 1, November 2005, Pages S3-S7

https://doi.org/10.1016/j.braindev.2005.03.013 Get rights and content

Abstract

The gene discovery in Rett disorder has opened the way for the development of clinical intervention. Initial recognition of affected infants will depend on observation by clinicians and the development of key diagnostic criteria is of crucial importance. Perturbations in the development of very young infants are emerging in studies of home videos. Observations from experienced health practitioners and home video transcriptions are presented which indicate the nature of early clues to the disorder and their fluctuating nature. Early diagnosis is likely to be available before the development of effective treatment. Most children are not diagnosed before regression and, currently, no therapies are equipped to offer support to pre-regression infants and their families. When earlier diagnosis becomes available, parents of the newly-diagnosed infant will be aware of their infant's difficult future before her problems are fully apparent. Practitioners in regular contact with families will have the sensitive task of supporting infants in early infancy and into regression.

Introduction

The discovery of the affected gene in Rett disorder [1] has opened the way for development of early clinical intervention and diagnosis in early infancy is now of crucial importance. Clinical observation will have the key role in the initial recognition of affected infants and will require clearly defined criteria that can be reliably observed and which are distinct from those observed in infants with other developmental disorders. In Rett disorder, there is slowly growing evidence of perturbed development in early infancy from parental reports and observational studies of home videos [2], [3], [4], [5], [6] and it is likely that diagnosis before regression will become possible in advance of effective intervention. There is some evidence that early clues are fluctuating and sporadic [2] and diagnostic procedures will need to accommodate this variability. Comprehensive descriptions of the infant's interactions with people and her surroundings and her responses to opportunities for learning and new experiences offer a good foundation from which to begin.

This paper presents observations from an ongoing study of family home videos from (a) video reviews by experienced health practitioners and (b) transcriptions of infants' activity.

Section snippets

Video reviews by health practitioners

This section focuses on the nature of the behaviours observed by practitioners in individual children (see [2] for a full account of methodology and group findings).

Twenty-six health visitors and 10 midwives each reviewed short video clips from home videos of infants with Rett (RD group) and with normal development (ND group). In the UK, these practitioners are closely involved in the care and development of very young infants and have built up a wealth of knowledge about normal development

Descriptive analysis

Comprehensive description of how infants are behaving and responding will form a sound foundation for the development of observation schedules designed to address these needs. With this objective, the home videos of 70 infants (50 RD and 20 ND, aged from birth to 12 months) are being transcribed, noting the numbers of adults and other children present, a description of the surroundings (for example, whether toys are within reach; freedom to move around) and what the infant is doing. This allows

Discussion

Early clues that development is not proceeding normally in RD infants are variable. They are inconsistent between infants and erratic within individuals. However, some similarities in facial appearance and hand postures have been noted. Many RD infants pass routine screening, but this focuses on achievements expected at a certain age. It might be more productive to look at the way in which infants acquire, consolidate and exploit new developments. Clues may also lie in the infant's emotional

Acknowledgements

This research was supported by the Economic and Social Research Council. I express my gratitude to Dr Alison Kerr, University of Glasgow, and Dr Hamish Macleod, University of Edinburgh, for their generous co-operation and support, to the health visitors and midwives for their time and valuable insights, and to the universities of Glasgow and Edinburgh. I owe special thanks to the families who donated videos and to the Rett Syndrome Association Scotland for funding further research.

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Nurse recognition of early deviation in development in home videos of infants with Rett disorder
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There are more references available in the full text version of this article.

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Rett syndrome is a rare neurodevelopmental disorder caused by a mutation in the MECP2 gene and associated with severe functional impairments and medical comorbidities. Since first described in 1966, there has been striking progress in understanding biological and clinical aspects. With the phenotype of the affected child in mind, this chapter describes the genetic cause and adverse biological effects of reduced MeCP2 production. We illustrate the clinical presentation of functional abilities and the health challenges of comorbidities, each of which can be associated with adverse effects on quality of life. We discuss the more recent field of epigenetics in relation to Rett syndrome and highlight possible therapeutic avenues that would aim to reduce adverse neighborhood effects on biological functioning and thereafter phenotype. Finally, we consider how these three fields of investigation can each contribute to insightful epidemiological datasets to accelerate the pipeline of discovery.
Comparing social reciprocity in preserved speech variant and typical Rett syndrome during the early years of life
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This study compared early markers of social reciprocity in children with typical Rett syndrome (RTT) and in those with the preserved speech variant (PSV) of RTT. Retrospective video analysis of 10 toddlers with typical RTT and five with PSV investigated participants’ orientation to their name being called between the ages of 5 and 24 months, prior to their diagnosis. From analysis of the recordings two distinct profiles were apparent. Although response rate was higher in girls with typical RTT than PSV at 5 to 8 months this noticeably reversed from 9 to 12 months onwards. By two years of age there was a markedly higher rate and range of responses from girls with PSV. This study contributes to the delineation of different profiles for the variants of RTT.
Early socio-communicative forms and functions in typical Rett syndrome
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Nevertheless, this is the first study to examine the early communicative forms and functions in children with RTT in their pre-regression period. Our data advance the understanding of the early developmental impairments associated with MECP2 mutations (Burford, 2005; Burford et al., 2003; Marschik et al., 2012a, 2012b, 2012c, 2012d, 2013; Tams-Little & Holdgrafer, 1996). Even though there is the need to assess early socio-communicative functions in a larger group of individuals with RTT across a wider age range and if the database is comprehensive enough also in terms of type-token-ratio (i.e., how many of each function benchmarked over time), these findings are useful as a preliminary description of the developing socio-communicative domain in typical RTT.
Rett syndrome (RTT) is a severe neurological disorder characterized by a developmental regression in motor and speech-language domains. There is, however, limited research on socio-communicative development of affected children before the onset of regression. We analyzed audio–video recordings made by parents of six 9- to 12-month old girls later diagnosed with typical RTT, applying the Inventory of Potential Communicative Acts (IPCA) to identify early communicative forms and functions. Each girl used at least one communicative form (e.g., body movement, eye gaze, or vocalizations) to gain attention and answer, but none were observed to make choices or request information. Varying numbers of children were observed to perform other communicative functions according to the IPCA including social convention, rejecting or requesting an object. Non-verbal forms (e.g., reaching, moving closer, eye contact, smiling) were more common than non-linguistic verbal forms (e.g., unspecified vocalizations, pleasure vocalizations, crying). (Pre-)linguistic verbal forms (e.g., canonical or variegated babbling, proto-words) were not used for communicative purposes. These data suggest that atypical developmental patterns in the socio-communicative domain are evident prior to regression in young individuals later diagnosed with RTT.
Peculiarities in the gestural repertoire: An early marker for Rett syndrome?
2012, Research in Developmental Disabilities
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Regression is defined by a loss of previously acquired skills, specifically spoken language and purposeful hand use. The general development before regression was initially believed to be asymptomatic, but recent research has provided mounting evidence of subtle abnormalities in the motor, speech-language and communicative repertoires during the first year of life (e.g. Burford, 2005; Einspieler, Kerr, & Prechtl, 2005a,b; Kerr et al., 2006; Leonard & Bower, 1998; Marschik, Einspieler, Oberle, Laccone, & Prechtl, 2009; Marschik, Einspieler, & Sigafoos, 2012; Marschik, Kaufmann, et al., in press; Marschik, Pini, et al., 2012; Tams-Little & Holdgrafer, 1996). The recent description of early peculiarities in the speech-language and motor domain have contributed to a better understanding of how MECP2 deficiencies influence early (functional) brain development, and consistent additions to this body of knowledge might lead to a more timely diagnosis.
We studied the gestures used by children with classic Rett syndrome (RTT) to provide evidence as to how this essential aspect of communicative functions develops. Seven participants with RTT were longitudinally observed between 9 and 18 months of life. The gestures used by these participants were transcribed and coded from a retrospective analysis of a video footage. Gestures were classified as deictic gestures, play schemes, and representational gestures. Results of the analysis showed that the majority of gestures observed were of deictic character. There were no gestures that could be classified as play schemes and only two (e.g., head nodding and waving bye bye) that were coded as representational or symbolic gestures. The overall repertoire of gestures, even though not necessarily delayed in it's onset, was characterized by little variability and a restricted pragmatic functionality. We conclude that the gestural abilities in girls with RTT appear to remain limited and do not constitute a compensatory mechanism for the verbal language modality.
Solving the puzzle: Case examples of array comparative genomic hybridization as a tool to end the diagnostic odyssey
2012, Current Problems in Pediatric and Adolescent Health Care
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Rett syndrome is a complex genetic disorder primarily affecting females. Infants typically develop normally until about 6-18 months of age, after which they may show signs of developmental regression.5 Additional abnormalities often include acquired microcephaly and stereotypic hand movements (ie, hand “wringing”).
We review 3 cases where array comparative genomic hybridization made a difference in the medical management of the patient, ended the diagnostic odyssey, predicted prognosis for the patient, and/or provided closure to the family. Comparative genomic hybridization is a useful tool for testing individuals with clinical examinations suggestive of a genetic syndrome but in which a specific syndrome may be difficult to pinpoint. The cost is similar to that of a standard karyotype but there is a higher yield in children and adults with clinical signs of a genetic syndrome.
Contributing to the early detection of Rett syndrome: The potential role of auditory Gestalt perception
2012, Research in Developmental Disabilities
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Notwithstanding the different age group and another vocalization type observed, our findings are in line with this study, which was also based on retrospective sound files from home-movies, stating that a significant qualitative difference is observable by naive listeners. For girls with Rett syndrome, it has previously been shown that professionals and experienced parents could detect peculiarities in early development (Burford et al., 2003; Burford, 2005; Leonard & Bower, 1998). In a study conducted by Burford et al. (2003), Burford (2005) health professionals without prior knowledge of Rett syndrome were asked to note (any) peculiarities in early development documented by home videos of infants with RTT.
To assess whether there are qualitatively deviant characteristics in the early vocalizations of children with Rett syndrome, we had 400 native Austrian–German speakers listen to audio recordings of vocalizations from typically developing girls and girls with Rett syndrome. The audio recordings were rated as (a) inconspicuous, (b) conspicuous or (c) not able to decide between (a) and (b). The results showed that participants were accurate in differentiating the vocalizations of typically developing children compared to children with Rett syndrome. However, the accuracy for rating verbal behaviors was dependent on the type of vocalization with greater accuracy for canonical babbling compared to cooing vocalizations. The results suggest a potential role for the use of rating child vocalizations for early detection of Rett syndrome. This is important because clinical criteria related to speech and language development remain important for early identification of Rett syndrome.

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Original articlePerturbations in the development of infants with Rett disorder and the implications for early diagnosis

Abstract

Introduction

Section snippets

Video reviews by health practitioners

Descriptive analysis

Discussion

Acknowledgements

Brain Dev

Brain Dev

Rett Syndrome is caused by mutations in X linked MECP2, encoding methyl-CpG- binding protein 2

Nat Genet

Nurse recognition of early deviation in development in home videos of infants with Rett disorder

J Intellect Disabil Res

Original article
Perturbations in the development of infants with Rett disorder and the implications for early diagnosis