Rett syndrome: A preliminary analysis of stereotypy, stress, and negative affect
Introduction
Rett syndrome (RTT) is a neurodevelopmental disorder primarily affecting females. The syndrome is typically characterized by a mutation in the methyl-CpG binding protein 2 (MECP2) gene with a prevalence rate of 1:10–15,000 female live births. From birth to 6–18 months, girls develop apparently normally, reaching age-appropriate milestones, such as the use of motor skills and some language. With the onset of the disorder, however, there is a loss of much of their adaptive functioning, such as purposeful hand movement, communicative abilities, and in many cases, locomotion. Subsequently, the behavioral characteristics upon which the diagnosis is based emerge including stereotypic hand movements, growth retardation, breathing abnormalities, seizures, gait abnormalities, scoliosis, and thermal dysregulation (Lotan and Ben-Zeev, 2006, Neul et al., 2011).
There is reason to believe that anxiety and related issues are also common among individuals with RTT. MECP2 deficient mice, which have been developed to recapitulate the core features of RTT, show significantly higher levels of anxiety-like behaviors (Adachi et al., 2009, Fyffe et al., 2008, Gemelli et al., 2006, McGill et al., 2006), and provide evidence of pathologically altered stress-response systems. It appears that MeCP2 modulates or otherwise regulates the expression of the corticotrophin-releasing hormone (Crh) gene, which is a part of a well-established pathway underlying anxiety (Fyffe et al., 2008, LeDoux, 2000, McGill et al., 2006). Although there has not been comparable work specific to anxiety among individuals with RTT, parents and other caregivers commonly report anxiety and stress-related issues. For example, in one study, 74% of caregivers reported that their daughters experienced fear or anxiety in unfamiliar situations (Mount, Charman, Hastings, Reilly, & Cass, 2002). In another, it was reported that 76% of individuals with RTT exhibited brief episodes of anxiety-like behavior, and these behaviors were reported to be precipitated by external events (Sansom, Krishnan, Corbett, & Kerr, 1993).
Although it is widely assumed that individuals with RTT have problems with anxiety (Lotan & Ben-Zeev, 2006), identifying if and when anxiety is being experienced is difficult, because of severe communicative impairments and therefore limited access to an emotional state (i.e., self-report is compromised; Didden et al., 2010). Most of the available information regarding emotional states among individuals with RTT is based on proxy reports such as rating scales or questionnaires, which is similar to, but not identical to, measuring symptoms. Another approach to examining anxiety among individual with RTT may be to use direct observation – which would be similar to measuring signs. To our knowledge, only two studies have utilized direct observation to assess behavioral or emotional states among individuals with RTT (Bergström-Isacsson et al., 2013, Woodyatt et al., 2004). The results of these studies indicate that, although it is possible for trained observers to identify facial expressions and other indications of emotional/behavioral regulation in this population, agreement regarding the meaning or intention of these behaviors is generally poor, and individualized operational definitions of behavioral indications are necessary.
Considering the current state of knowledge, it is possible that caregivers of individuals with RTT may be over- or under-identifying possible sign of anxiety. Additional research is clearly needed to identify the specific behavioral indications of stress or anxiety among individuals with RTT. One possible indicator is stereotyped hand movements. Although this type of movement is one of the defining characteristics of RTT, it has been suggested that hand stereotypies may increase or intensify in response to stress or arousal (Temudo et al., 2008). In fact, one study reported differences in the percent of time that individuals with RTT engaged in hand stereotypies across social and non-social activities, although the specific patterns differed across participants (Sigafoos, Woodyatt, Tucker, Roberts-Pennell, & Pittendreigh, 2000). Similarly, Hetzroni and Rubin (2006) reported that females with RTT exhibited increased hand stereotypy in response to interruptions of familiar activities like watching television or listening to music, and Stasolla and Caffo (2013) reported decreases in hand stereotypy, along with increases in indices of happiness, associated with structured activities and environmental stimulation. In all of these cases, the observed differences may have been due to changes in anxiety or arousal. Another possibility, however, is that hand stereotypies decrease when the individual is engaged with or oriented to an ongoing activity (Fabio, Giannatiempo, Antonietti, & Budden, 2009). Despite the clinical implications of the assumption that hand stereotypies are indicative of a state of anxiety among individuals with RTT, the relationship between stereotyped hand movements and stress has not been systematically studied in this population.
The purpose of this exploratory study was to build on the existing literature by testing the hypothesis that individualized behavioral indicators of negative affect (such as whining, and negative facial expressions) and the percent of time engaged in hand stereotypy would differ across controlled environmental conditions that were expected to be relatively stressful or non-stressful in a small consecutively enrolled clinical sample of females with classic RTT.
Section snippets
Participants
Five females (mean age = 17.8; range 4–47) with a clinical diagnosis of classical Rett Syndrome who met the core criteria defined by Neul et al. (2011), participated in the study. Participants were recruited through the Minnesota Rett Syndrome Research Association. The University of Minnesota Institutional Review Board approved the study and parents or legal guardians provided informed consent. Participants of all ages and levels of physical functioning were included in the study except those
Hand stereotypy
When the data were combined across all five participants (Fig. 1), the percent of intervals that hand stereotypy occurred did not differ statistically across the two conditions (low vs. high stress) (χ2 (1, N = 98) = 1.06, p = 30). Individual results are presented in Table 1. ML's hand stereotypy (hand clenching, hand clasping) was not significantly different across the two conditions (χ2 (1, N = 270) = .033, p = 85) (Fig. 2a); KP's hand stereotypy (hand tapping) was not significantly different across the
Discussion
The present study examined the hypothesis that behavioral indicators of negative affect and the occurrence of hand stereotypies would differ across putatively high- and low-stress environmental conditions in a small consecutively enrolled clinical sample of females with classic RTT. Despite the sense that hand stereotypy (a diagnostic feature of RTT) may be an indicator of increased anxiety or arousal associated with stress (Lotan & Ben-Zeev, 2006), there were no observed differences in hand
Acknowledgments
We are grateful to the families and their daughters for their willingness to participant in research. We would like to recognize Dr. Celia Gershenson and the late Dr. Herb Pick for their contributions to the REU program. Support for this work was provided, in part, by NSF Grant # SMA-1063006 at the University of Minnesota and NICHD Grant No. 44763.
References (24)
- et al.
How facial expressions in a Rett syndrome population are recognised and interpreted by those around them as conveying emotions
Research in Developmental Disabilities
(2013) - et al.
The role of stereotypies in overselectivity process in Rett syndrome
Research in Developmental Disabilities
(2009) - et al.
Deletion of Mecp2 in sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress
Neuron
(2008) - et al.
Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett Syndrome in mice
Biological Psychiatry
(2006) - et al.
Promoting adaptive behaviors by two girls with Rett syndrome through a microswitch-based program
Research in Autism Spectrum Disorders
(2013) - et al.
MeCP2-mediated transcription repression in the basolateral amygdala may underlie heightened anxiety in a mouse model of Rett syndrome
Journal of Neuroscience
(2009) - et al.
Communication in individuals with Rett Syndrome: an assessment of forms and functions
Journal of developmental and physical disabilities
(2010) - et al.
Facial action coding system
(2002) Single subject research methodology in behavioral sciences
(2010)- et al.
Identifying patterns of communicative behaviors in girls with Rett syndrome
Augmentative and Alternative Communication
(2006)
Toward a functional analysis of self-injury
Journal of Applied Behavior. Analysis
Emotion circuits in the brain
Annual Review of Neuroscience
Cited by (11)
Defining Hand Stereotypies in Rett Syndrome: A Movement Disorders Perspective
2017, Pediatric NeurologyCitation Excerpt :In the study with a completely blinded review, the focus was a comparison of HS between individuals with RTT and autism spectrum disorder. In addition, other studies have used categories without clearly defined terms18; only a recent study looking at anxiety and HS provided operational definitions of the abnormal movements.14 We endeavored to develop a protocol for the systematic characterization of HS.
Rett Syndrome: Clinical Aspects
2016, Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual DisabilityComparing social reciprocity in preserved speech variant and typical Rett syndrome during the early years of life
2015, Research in Developmental DisabilitiesApplying the ethoexperimental approach to neurodevelopmental syndrome research reveals exaggerated defensive behavior in Mecp2 mutant mice
2015, Physiology and BehaviorCitation Excerpt :Rett syndrome is associated with elevated anxiety [53,54] and panic-like behavior [55]. Since individuals diagnosed with Rett syndrome are largely non-verbal [56] this severely limits the ability to probe the psychological well being of an individual with the condition through self-report [57,58]. Therefore, careful investigation of emotion systems in animal models can help identify brain circuit alterations that manifest in adverse psychological symptoms.
Movement disorders in patients with Rett syndrome: A systematic review of evidence and associated clinical considerations
2021, Psychiatry and Clinical Neurosciences