Exploring autism symptoms in an Australian cohort of patients with Prader-Willi and Angelman syndromes

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders associated with deficits in intellectual functioning. Both disorders are caused by opposing effects of copy number or DNA methylation changes at the same locus on chromosome 15 [1]. PWS results from the loss of function of paternal genes from chromosome 15q11.2-q13 while AS from the absence of function of the maternal genes in the same region [2]. In PWS, three primary mechanisms result in the lack of expression of key genes and thus the resulting condition: (i) a deletion from the paternally contributed chromosome 15 (65–75% of cases); (ii) maternal uniparental disomy (matUPD; 20–30% of cases) and (iii) an imprinting centre defect (ICD; 1–3% of cases). Similarly, deletions from the maternally contributed chromosome 15 are the most common cause of AS (~ 75% of cases). Paternal UPD (patUPD) occurs in approximately 1–2% of AS cases and ICD in approximately 1–3% of cases [2]. Approximately 5–10% of AS cases result from a mutation in the ubiquitin-protein ligase E3A gene (UBE3A) [2]. In these cases, no deletion, UPD or methylation abnormality is observed and can be familial [2]. The remaining ~ 10% of cases have the disorder as a result of an as-yet unidentified genetic mechanism that is not detected by standard diagnostic testing [3].

General intellectual functioning in PWS ranges from average abilities to moderate intellectual disability (ID), with the majority of individuals with PWS falling in the mild ID range (IQ between 55 and 70) [4]. AS is commonly associated with severe intellectual impairment: most individuals with AS are non-verbal, though some individuals may have a few single words and in very rare cases some individuals are able to use phrase speech [5]. However, receptive language abilities are significantly better developed than expressive language abilities [6]. Individuals with AS are reported to plateau at a developmental level usually attained by typically developing infants of approximately 24–30 months [7]. Thus, the use of standardised, age-appropriate, assessments is difficult, and valid IQ scores are rarely obtained.

Children with PWS are frequently reported to have social difficulties that lie along the same continuum of autism spectrum disorder (ASD), though the severity is reported not to be as great as those diagnosed with ASD [8]. In contrast, individuals with AS are usually eager to communicate and engage socially with others [9]. However, repetitive and restricted behaviours (RRBs) are commonly reported in both those with PWS and AS [10]. In particular, those with PWS are reported to order and arrange objects and have insistence on routines, as well as repetitive speech [11], while hand and body mannerisms (e.g. hand flapping) are reported in nearly all cases of those with AS [12].

Overexpression of maternally expressed genes in the 15q11-13 region, including UBE3A, has been proposed to be a susceptibility factor for ASD [13]. Thus, higher rates of ASD might be expected in those PWS patients with the matUPD subtype compared to deletion cases and those with AS [14]. The most comprehensive PWS study to date assessed the prevalence of ASD in 146 children and adolescents aged 4–21 years [15]. Using the ADOS-2, 21.9% of the samples were classified as having ASD. Those individuals meeting criteria for ASD on the ADOS-2 were subsequently reviewed by an expert clinical team, which reduced the rate of ASD to 12.3% (18 children and adolescents). Individuals with the matUPD sub-type were more likely to meet criteria for ASD compared to the other sub-types (14 matUPD versus 2 ICD and 2 deletions). Interestingly, 46% of individuals with PWS had difficulties with social reciprocity items on the ADOS-2 (e.g. amount of reciprocal communication, quality of social overtures, social response and rapport) despite being below the autism-spectrum threshold. ADOS-2 overall and social affect (SA) calibrated severity scores (CSS) were negatively correlated with verbal, non-verbal and composite IQ scores derived from the Kaufman Brief Intelligence Test-2nd Edition (KBIT-2) [16].

Peters and colleagues [12] assessed 19 children with AS using the Autism Diagnostic Observation Schedule-Generic (ADOS-G) [17] in addition to independent evaluation of autistic symptoms by a team of clinicians using DSM-IV [18] criteria. Based on the DSM-IV, 42% of the sample met criteria for ASD and all these children also met criteria for ASD on the ADOS-G. Those AS children who did not receive an ASD diagnosis nonetheless exhibited characteristics of ASD, primarily stereotyped hand and body mannerisms. In describing the AS individuals who met criteria for ASD, the authors noted that they rarely directed vocalisations, were not responsive to their name being called and did not exhibit shared enjoyment in interactions with others. Generally, these children were more focused on objects and the repetitive use of these objects and made few social overtures to others. In addition, those children meeting criteria for ASD had significantly lower mental scores on the Bayley Scales of Infant Development [19] compared to their non-ASD counterparts.

Overall autism symptoms appear to be highly prevalent in individuals with PWS and AS. Until recently, the majority of research had used autism screeners rather than objective assessment to determine prevalence rates of ASD in these conditions. In addition, there is limited research comparing the overlap of symptoms between those with PWS and AS. Considering that both disorders are caused by opposing effects on imprinting resulting in abnormal expression of the same gene cluster on chromosome 15, exploring the similarities and differences in these two groups, has the potential to shed light on the genetic susceptibility factors associated with ASD more generally and, more specifically, to improve understanding of the natural history of both PWS and AS. Further evidence supporting an association between the PWS/AS locus and autism comes from the observation that autism is common in individuals who have a duplication on the maternally inherited copy of 15q11-13 [20]. In particular, increased gene dosage of UBE3A has been shown to result in defective social interaction and communication and increased repetitive behaviours in mice [21]. Moreover, identifying specific symptoms associated with the presence of ASD in these populations can assist diagnosticians in identifying ASD in these patients. By detecting ASD in these cases, autism-specific interventions can be employed to assist in the treatment of ASD symptoms that may exacerbate core symptoms of the genetic diagnosis.

This study aimed to explore, using objective assessment, symptoms associated with ASD in well-characterised cohorts of Australian individuals with PWS and AS, and to compare symptom profiles between the two disorders. It was hypothesised that those with PWS would have significantly greater number and severity of symptoms associated with ASD compared to individuals with AS.

To our knowledge, this is the first study to investigate and compare autism symptoms and intellectual functioning in well-characterised cohorts of individuals with PWS and AS using objective assessments. PWS participants had significantly higher overall and SA CSS compared to participants with AS. Individuals with AS are typically reported to be motivated to engage socially with others [31], while those with PWS are more frequently described to have social communication difficulties [32]. Although no significant group differences were observed for key diagnostic social affect items, medium effect sizes were observed for shared enjoyment and pointing. A greater proportion of individuals with PWS presented with reduced shared enjoyment with the researcher, while AS cases presented with more atypical pointing. It is likely that those with PWS present with more global social communication difficulties, increasing SA scores overall, while those with AS may present with difficulties on particular items due to other comorbidities associated with AS. In particular, motor deficits associated with AS may impair the individual’s ability to point, gesture and show items to others. Moreover, for the items pointing and showing, these need to be paired with eye contact to obtain a ‘typical’ score. The coordination of these behaviours may be difficult in those with AS, leading to a more atypical presentation. Nonetheless, these findings are similar to those of Trillinsgaard and Ostergaard [6] in which 10 children with AS + ASD (by ADOS-G) and eight children with ASD only were shown to have significant deficits on tasks requiring triadic exchanges (e.g. pointing and showing). The authors stated that such behaviours were practically non-existent in the two groups.

It has been suggested that during childhood, other developmental difficulties and behaviours associated with PWS may overshadow ASD symptoms, which may not become fully apparent until the child is older [33]. Indeed, internalising symptoms such as anxiety, low self-worth and sadness have been shown to increase with age in patients with PWS [34]. As previously reported by Molloy and colleagues [35], other developmental and behavioural problems may inflate ADOS scores, which may be the case in the participants observed here; mental health issues may be inflating scores on the ADOS in PWS patients, particularly SA scores in adolescents and adults.

The most commonly reported symptoms associated with ASD in both PWS and AS are captured by the RRB domain, which likely explains the lack of significant differences between the two groups on the RRB CSS. Nonetheless, differences emerged on the specific behaviours that are associated with this domain. In particular, PWS participants were more likely to engage in sensory-seeking behaviours compared to AS participants, while AS patients were more likely to be observed to use hand mannerisms. Hand flapping is a characteristic of individuals with AS; thus, it is not surprising that the groups differed on this item; however, sensory exploration of objects is not commonly reported for individuals with PWS. The most frequent sensory-seeking behaviours observed during the assessments included feeling textural elements of objects (n = 7), followed by smelling items (n = 5). Four children with PWS were also observed to visually inspect objects. In regard to the code of unusually repetitive interests or stereotyped behaviours, the two groups did not differ in the proportion of individuals who coded as atypical. Ten children in the AS group and eight children in the PWS group engaged in repetitive play with objects. One adult with PWS became fixated on the miniature chocolate bar during the Joint Interactive Play task. This same adult and another child engaged in repetitive food-seeking behaviour during the assessment. Seven PWS participants also discussed highly specific topics of interest. Of these seven, one participant repeatedly brought up the topic of food. Thus, some of the behaviours observed in individuals with PWS may be attributed to their PWS diagnosis, specifically food-seeking behaviour, rather than the presence of ASD.

Consistent with previous literature [15], there were significant correlations between VIQ and each of the ADOS CSS in the PWS group, whereby poorer verbal skills were associated with higher ADOS scores. Similarly, lower FSIQ scores were associated with greater overall and social affect CSS in the PWS group. However, no significant associations between ADOS CSS and intellectual functioning scores were observed in the AS group. Thus, poorer cognitive ability, particularly verbal ability, appears to be associated with symptoms of ASD in individuals with PWS.

According to Barbaro and Dissanayake [36] ‘red flags’ for ASD in young children include a lack of eye contact, interest and pleasure in others, emotional expression, directed vocalisations, joint attention skills (e.g. pointing to share interest, following other’s pointing and monitoring of others’ gaze), requesting behaviours and gestures. While in adolescents and adults, ASD may be suspected when there are persistent difficulties with social interaction, social communication and/or the presence of stereotypic behaviours. These should be accompanied by difficulties in obtaining and sustaining education or employment, difficulties in initiating and maintaining social relationships and/or previous contact with mental health or learning disability services [37]. More than 50% of individuals in each group had inconsistent eye contact and a limited range in facial expressions; however, joint attention skills (initiation and response) generally had low atypical rates in both the PWS and AS groups. Approximately 50% of individuals in each group used gestures to facilitate their communication. Thus, while some ‘red flag’ behaviours associated with ASD appear to be present in the majority of individuals with these conditions, other behaviours tend to present more typically. Thus, it is likely that behaviours such as poor eye contact and a reduction in the range of emotional expression are associated with the genetic conditions themselves, or the comorbidities associated with the conditions. However, when deficits with joint attention skills and gesturing are also observed, further assessment for ASD may be warranted.

This is the first study to explore and compare objective assessments of ASD symptoms and intellectual functioning in patients with PWS and AS. Despite small sample size being a limitation, this is one of the largest studies to date of its kind in these rare disorders. While particular behaviours that are associated with an ASD diagnosis (e.g. poor eye contact, limited range of emotional expression, poor quality social overtures) were particularly prevalent in both PWS and AS individuals, joint attention skills were less commonly deficient. Differential diagnosis of ASD versus other mental health issues in PWS is particularly pertinent, as this will have implications for treatments and interventions. In addition, consideration of the common comorbidities associated with each of the conditions (e.g. motor impairments) should be taken into consideration when assessing for the presence of ASD.