ANÁLISIS DE CURVAS DE PROPORCIÓN VERTICAL

4.2.1 Evaluation of existing RS literature

The review of the research on the behavioural and emotional features of RS led to the conclusion that there are a number of behaviours frequently associated with RS. These include hand stereotypies, breathing difficulties, sleeping problems, a number of autistic-like behaviours, grinding of teeth, self-injurious behaviour, and emotional features of anxiety and low mood. A number of methodological difficulties inherent in the existing research mean it is not possible to conclude whether the behaviours comprise an RS behavioural phenotype.

Very few of the studies reviewed in Chapter 2 used comparison groups. In most studies, the prevalence of the behaviours was assessed in individuals with RS only. Females with RS have been shown to suffer from severe to profound learning disabilities (e.g., Fontanesi & Haas, 1988; Garber & Veydt, 1990; Woodyatt & Ozanne, 1992a; Woodyatt & Ozanne, 1993; Woodyatt & Ozanne, 1994; Sparrow et al., 1984). Level of intellectual disability is known to be related to the extent of behavioural and emotional disturbance (e.g., Corbett, 1979; Einfeld & Tonge, 1996a; Einfeld & Tonge, 1996b; Rutter et al., 1970). Individuals with RS also suffer from physical disabilities, in particular gait abnormalities (e.g. FitzGerald et al., 1990a; Hennessy & Haas, 1988), and lack of hand skills (Budden, 1995; Coleman et al., 1988). Children with physical disabilities have been found to be at an increased risk of psychiatric disturbance (Breslau, 2000). Within a sample of children with severe learning disabilities, Chadwick, Piroth, Walker, Benard, and Taylor (2000) found those who were not ambulant showed a greater number of severe behaviour problems than those who were ambulant. Thus, the severe learning and physical disabilities associated with RS could be the cause of some of the behavioural and emotional features reported and so we do not know whether the behaviours described in the literature are specific to RS. It is important to note that this is the case for the hand stereotypies and breathing problems

associated with RS which are currently included in the diagnostic criteria for classic RS.

There are additional problems with the research conducted on the behaviours associated with RS to date. None of the studies used statistical tests to rule out chance as a possible explanation of the association between RS and the behaviours described. The sample sizes employed tended to be small, at the most around 30 cases. Using small samples is problematic since it unlikely that such samples are representative of individuals with RS in general. In addition, small sample sizes make it difficult to examine within- syndrome variability, an important part of delineating a behavioural phenotype (Dykens, 1995).

Two questionnaire surveys (Coleman et al, 1988; Sansom et al., 1993), which did use larger numbers of cases, failed to employ well-validated measurement tools, a drawback present in the majority of existing RS research. The consequence of this is that definitions for the behaviours described in the studies were not available. For example, Sansom et al. (1993) describe periods of low mood and anxiety associated with RS without stating what is meant by these terms. The results from the surveys may also have been unreliable, as the psychometric properties of the measurement tools were unknown.

In summary, the existing research on the behavioural and emotional features in RS does not meet any of the criteria suggested by Einfeld and Hall (1994) for the study of behavioural phenotypes. Research has yet to establish the degree and nature of the association between RS and the behavioural and emotional features currently described in the literature.

The current study aimed to determine whether there is a behavioural phenotype associated with RS. Careful delineation of the behavioural and emotional features specifically associated with RS will have a number of potential benefits. The validity of the existing diagnostic criteria describing

behavioural features will be investigated. Any specific behavioural features identified through the study may make useful additions to the diagnostic criteria. The knowledge acquired in the research can be passed onto parents and professionals, giving them more information for the prognosis of the disorder. The findings may also help therapists working with individuals with RS to consider how biological and behavioural factors might be related. I now turn to discuss methodological considerations for the empirical research conducted for this thesis.

4.2.2 Methodological considerations for study of RS phenotype

4.2.2.1 Control and comparison groups for RS

A case controlled study was required to rule out the severe learning and physical disabilities as potential causes for the behavioural and emotional features seen in RS. Three different options for control groups were available.

The first option was to employ the use of two comparison groups, one to control for level of learning disability and one to control for level of physical ability. For example, to control for level of learning disability individuals with RS could be compared to individuals with Angleman syndrome. This is another genetic syndrome with similar associated severe to profound learning disabilities (Summers & Feldman, 1999). To control for physical ability, individuals with RS could be compared to individuals with Cerebral Palsy. The difficulty with this design would be that the behaviours seen in RS would be compared to just two other disorders. It might be that other disorders with associated with severe to profound learning disabilities or physical disabilities are more or less similar to RS than Angleman syndrome or Cerebral Palsy. These kinds of comparisons are useful for identifying partial or total specificity effects for an already established behavioural phenotype (as suggested by Hodapp, 1997) but probably not useful for identifying candidate behaviours for a behavioural phenotype in the first place.

The second option for a comparison group was a group of individuals with learning disabilities of mixed aetiologies matched to the RS individuals on level of cognitive and physical impairment. This would have been a difficult sample to obtain because of the severity and the nature of the physical impairment in RS (e.g., it is common to see females with RS who are able to walk but have little hand skill (Kerr, 1995)). It would prove difficult to obtain a group of individuals with the same physical problems to compare to RS. The third option for a control group, which would overcoming this difficulty, was a statistical control procedure. For example, RS individuals could be compared with a group individuals with a similar level of learning disability. Physical impairment could be measured in both groups and then controlled for in between-group comparison analyses. Based on the literature on the cognitive abilities in RS (see section 1.2.5.1), a similar level of learning disability to RS would comprise individuals with severe to profound learning disabilities.

Age may have a direct influence of the behavioural and emtional features (e.g., Tonge et al., 1996) and so the range in age of the comparison group should be similar to that in the RS to rule out the potential age effects. RS is only seen in females. Studies of children in the general population have discovered that males are more prone to psychiatric disorders than females (Rutter et al., 1970). However, once individuals are grouped according to ability level (mild, moderate, severe and profound learning disability) the gender effects on behavioural and emotional disturbance tend to disappear (Chadwick et al., 2000; Einfeld & Tonge, 1996b; Flint & Yule, 1994). However, there remains the possibility that gender effects could be present in a comparison group of individuals with severe to profound learning disabilities and so to eliminate the possible effects of gender, females with RS could be compared to females only with severe to profound learning disabilities.

The difficulty with using a comparison group of females with mixed aetiologies would be that it would contain small numbers of individuals with

particular identified genetic syndromes. Even those who have not been diagnosed as having a particular syndrome, may have a syndrome which has yet to be discovered. Each of these different syndromes may have their own associated behavioural phenotype which might bias the sample toward one particular behavioural profile. Therefore, it is important to describe the comparison group sample and replicate the results with a different, independent sample.

4.2.2.2 What to measure in RS?

It was stated in section 4.2.2.1 that level of learning disability needed to be ruled out as a potential cause of the behavioural and emotional features seen in RS. Level of intellectual ability could be directly assessed in the RS and comparison groups. This might be problematic as many standardised IQ assessments are known to be unreliable for individuals with IQs under 50 (moderate to severe and profound range). Assessing IQ or general level of functioning is further compromised in the RS population due to their lack of hand skills. Many measures of cognitive ability require a certain amount of hand skill to perform the necessary tasks. It is not clear what meaning well- validated measures of cognitive ability would have in this population. Thus, directly measuring level of functioning may not be the best way to rule out the effects of level of learning disability on the behaviours seen in RS. Comparing the behaviour seen in individuals with RS to that seen in individuals with severe to profound learning disabilities would provide an indication as to the behaviours seen in RS unrelated to their level of learning disability.

It would be necessary to assess physical ability in order to rule it out as a cause for the behavioural features seen in RS since it would be difficult to recruit a comparison group with similar difficulties (see section 4.2.2.1). Physical ability would be far easier to measure in RS than level of learning disability. Based on the RS literature, the important aspects of physical ability to measure would be ability to walk (Fitzgerald et al, 1990) and level of hand skills (Budden, 1995; Coleman et al. 1988).

Data collected on post-regression behavioural and emotional features would be more reliable than that collected on pre-regression features. Individuals with RS are not diagnosed until regression has occurred (Hagberg, 1993). Only through retrospective report or early videos is it possible to investigate pre-regression behavioural and emotional features.

So little is currently known as to which behaviours described in the literature are specific to RS. Studies have already started to describe, in detail, particular behaviours associated with RS (hand stereotypies, autistic behaviours, sleep and breathing difficulties). These studies are premature until research has determined which behaviours are RS-specific. Therefore, an assessment of post-regression general behaviour disorder would provide the most appropriate first stage in the investigation of the RS behavioural phenotype.

An important aspect of characterising a behavioural phenotype is the investigation of within-syndrome variability in the behaviours, and the consideration of some factors which may contribute to this variability (Dykens, 1995). For the current study of RS, important factors to consider include level of learning disability, level of physical ability, developmental effects, epilepsy, early difficulties, and diagnosis.

There is evidence to suggest that some RS features change over development. Physical abilities, mental age and visual processing have been found to decline with age in individuals with RS (Hagberg, 1993; Perry et al., 1991; von Tetzchner et al., 1996). Daily living skills and communication abilities have been found to improve slightly with age (Perry et al., 1991; Woodyatt & Ozanne, 1993). It is also suggsted that Individuals with RS go through four developmental stages (developmental stagnation, regression, pseudo-stationary phase and late motor deterioration; Engerstrom, 1990). It would therefore be important to consider the role played by developmental factors in any within-RS variability in behavioural and emotional features.

Developmental trends could be assessed in several ways in RS including chronological age, mental age, and RS stage. In a questionnaire survey, chronological age may be the most reliable assessment of development.

Presence of seizures also may have an influence on the behavioural and emotional features within RS. Between 70-80% of RS individuals are reported to experience seizures (Coleman et al., 1988; Naidu et al., 1986; Nomura et al., 1984) The effect of epilepsy on behavioural and emotional features is unclear. Some studies conducted on individuals with learning disabilities have found no influence of epilepsy on behavioural disturbance (Jones & Cull, 1998; Chadwick et al., 2000; Matson, Bamburg, Mayville, & Khan, 1999). Wheras other studies conducted on general populations have found those with epilepsy show increased levels of psychiatric disorder (Gillberg et al. 1986). Presence of seizures is a factor worth measuring in the current study in order to assess its possible association with the presentation of behavioural and emotional features.

Early developmental and medical factors may influence behavioural and emotional features in RS. Although individuals with RS appear to develop within the normal range for the first few months of life, there is evidence to suggest that subtle abnormalities are present during this time (Engerstrom, 1992; Tams Little & Holdgrafer, 1996; Nomura & Segawa, 1990, see section 1.2.3.4). Increased presence of early difficulties and an earlier onset of obvious symptoms may be indicative of a more severe disease process in RS. In individuals with learning disabilities, increased obstetric complications including difficulties during pregnancy and delivery and low birth weight, have been found to be risk factors for increased behavioural problems later in life (e.g., Cocchi, Felici, Tonni, Venanzi, 1984; Fortin & Bigras, 1997; Goldberg, Corter, Lojkasek, & Minde, 1991; Ohyama, Kikuchi, Hatayama, & Maeda, 1976). Early feeding difficulties have also been linked to a higher incidence of behavioural problems later in life (Newton, 1951). Better prognosis, in terms of increased IQ and fewer behavioural problems, has been found in children with autism who experience a late onset (>30 months) rather than an earlier

onset (<30 months) (Dahl, Cohen, & Provence, 1986; Short & Schopler, 1988). Correlational analysis have revealed associations between the age at regression had later cognitive and communicative abilities in RS (Fontanesi & Haas, 1988; Woodyatt & Ozanne, 1992a; von Tetzchner et al., 1996). Those with a later onset of regression had increase motor and daily living skills later in life (Fontanesi & Haas, 1988; Woodyatt & Ozanne, 1992a). In summary, obstetric complications, early feeding difficulties, length of time for which development is normal, and the age of onset of regression could be associated with the presentation of behavioural and emotional features in RS later in life. Therefore, these factors would be worth measuring in the current study in order to assess their association with the behavioural and emotional features.

Diagnosis may also be associated with the presentation of behavioural and emotional features. It is difficult to hypothesise whether the classic or atypical cases would show a more severe profile of disturbance since some atypical cases have a milder form or the disorder than classic cases and some have a more severe form (see section 1.2.7). To investigate the influence of diagnosis, extensive diagnostic information would be needed to establish exactly why each individual had been given an atypical diagnosis, this might not be possible in a parental questionnaire study.

4.2.2.3 Sample recruitment for RS phenotype study

Different methods of recruitment for behavioural phenotype research were discussed in Chapter 3. These methods included recruitment of individuals with a genetic syndrome via parent support groups, from clinic services or genetic registries, and from epidemiological samples. RS is a rare syndrome and so recruitment via an epidemiological sample would not feasible. In 1997, when the current study was started, RS had yet to be proven to be a genetic disorder. Therefore, no cases would be included on genetic registries. There were a number of specialist clinical services for individuals with RS. However, these services were likely to attract more severe cases.

biasing any samples recruited this way and it would be unlikely that large number of cases could be recruited in this way.

Recruitment via a parent support group would allow for large numbers of cases to be recruited and the sample would include classic as well as atypical cases, adults and children, i.e., it would include the whole spectrum of RS cases. However, recruitment via this route would have potential difficulties. First, the sample may not be representative of the entire UK RS population but the only way of ensuring a truly representative sample would be to recruit using a epidemiological sample. Second, the diagnosis may not be confirmed and may not be valid. The Rett Syndrome Association UK (RSAUK), are careful to only grant membership to those parents who have a daughter, or carers who are looking after a female with a confirmed diagnosis of RS. Through twice yearly diagnostic clinics organised by the RSAUK, the diagnosis of new members is confirmed by one of the leading RS specialists. In the past, this has been Dr. Alison Kerr. When recruiting a sample from the UK Rett Syndrome Association it would be sensible to ask parents if their child’s diagnosis had been confirmed by Dr. Kerr.

The third potential difficulty with recruiting from the parental association is that parents may be influenced by the Association’s literature to over-report certain behavioural features that are not present in their child. The vast majority of RS publications are concerned with describing medical problems rather than behavioural difficulties and so it would be unlikely that parents would have read much literature on the behavioural features associated with RS.

A comparison group of females with severe to profound learning disabilities could be recruited in several ways. An epidemiological study would be too costly in terms of time and resources. Parent groups for individuals with learning disabilities could be contacted, e.g., MENCAP. However, parents may have joined such associations because of particular difficulties they were experiencing and so recruitment in this way might lead to a sample of

more severe cases. Recruiting via clinics for individuals with learning disabilities might also lead to a sample with more severe difficulties. Recruiting via schools for children with learning disabilities would be a good compromise.

In the UK, there are separate schools for children with mild, moderate, severe, and profound and multiple disabilities. This does not mean that all of the individuals attending, for example, a school for children with moderate learning disabilities, will be at that ability level. Children may attend a particular school due to a number of reasons other than their level of ability, such as location or particular facilities in that school. However, the majority of the children attending the school will have abilities appropriate for the facilities in that school. In order to recruit a comparison group of females with severe to profound learning disabilities, schools for children with severe learning disabilities and schools for children with profound and multiple disabilities could be approached.

Recruiting via schools would mean that only children would be acquired for the comparison group (individuals aged up to 18 years). Recruiting the RS group via the UKRSA would mean that children and adults with RS would be recruited. It could be possible to recruit a comparison group of adults, but