Three descriptive case studies were identified. Of the four cases that these three studies described, there was one female study participant, with a translocation between chromosomes 5 and 15 and a partial deletion from 15pter to the Angelman region, who was found to have ASD (Arrieta et al., 1994). Two male participants were diagnosed with PDD-NOS (Not otherwise specified) (Demb and Papola, 1995; Eikelenboom and Berckelaer-Onnes, 2000) and one further female participant was reported not to have ASD (Eikelenboom and Berckelaer-Onnes, 2000).
The six case-series reports identified were of varying relevance in fulfilling the aims of this review (see Table 2a). Akefeldt and Gillberg's (1999) study intended to determine whether children with PWS had behaviors that were not specifically related to mental retardation or obesity, whether these behaviors were age-related, and whether treated and untreated PWS cases differed with respect to behavior. They ascertained PWS cases from a variety of sources and included a comparison group of individuals matched group-wise on the basis of age, IQ, body mass index, and appetite. Forty of the 44 participants underwent molecular genetic screening, though apart from two cases, they were not systematically examined for UPD or DEL status. One 10-year-old boy with a deletion (probably a mosaic form) was diagnosed by a neuropediatrician as having DSM-IV autistic disorder (Akefeldt, 12 August 2003; personal communication).
Excluding the descriptive case reports, a total of 348 (including 10 new cases as yet unpublished, see Table 2b) patients with PWS were described in the six selected case-series investigations (see Tables 2a and 2b). The rates of ASD found within PWS patients were calculated using five of the six case-series reports concerning PWS (diagnostic information was not included in the report by Dykens and Cassidy (1995), so this study was not included in these calculations). The rates ranged from 0 to 36.5%. Combining the cases reported in these five studies, including the updated data provided by one author (Hou, 27 September 2002; personal communication) (see Table 2b), gives an overall rate of 14.5% for all cases reported (n=38/262) and a rate of 25.3% for the genetically confirmed UPD and DEL cases (n=38/150). Six of the PWS cases diagnosed with an ASD did not have that diagnosis later in life (Descheemaeker et al., 2002; Hou, 27 September 2002; both personal communications). Indeed, these transient autistic-like symptoms were also reported in eight of 12 PWS children (youngest group) at approximately age 1–4 years in the Scandinavian study (Akefeldt and Gillberg, 1999; Akefeldt, 11 October 2002, personal communication). It should be noted, however, that four cases, which were diagnosed with ASD in childhood, went on to develop psychosis in adulthood (Descheemaeker et al., 2002).
The final AS study was specifically designed to investigate the rate of ASD in children with Angelman syndrome (Steffenburg et al., 1996). All children with mental retardation and active epilepsy of 5 years duration (n=98) were investigated and four cases of Angelman syndrome were identified (in two there was genetic verification of the diagnosis). The other two cases were described as having mental retardation, typical speech impairment, movement/balance disorder, epilepsy, and typical EEG abnormality (Steffenburg, 11 October 2002, personal communication). All four cases were reported as meeting full behavioral criteria for the diagnosis of autistic disorder/childhood autism.
Within the three AS case-series studies, the rate of ASD, in the 138 patients studied, was 3.6% for all reported cases (n=5/138) (see Tables 3a and 3b). Four of the patients with a diagnosis of ASD came from one epidemiological study (Steffenburg et al., 1996) and were not all genetically verified, thus, for the purposes of this review, limiting the total number of patients identified in that study with AS (n=4; 2 DEL). Furthermore, as stated above, in the case of the single AS female identified with ASD in the Chan et al. (1993) study, no deletion could be identified. No significant distinction could be made between the UPD and DEL cases in the diagnosis of an ASD as only two DEL cases with an ASD were cytogenetically verified; the other three cases were not cytogenetically verified cases of AS. This meant a rate of 1.9% for the genetically confirmed UPD and DEL cases with a diagnosis of ASD (n=2/104).
In addition to these three studies, one descriptive case study was found. The report described a male AS patient with a small maternally derived supernumerary marker chromosome 15 (see Roberts et al., 2002), but there were no signs of ASD (Thompson and Bolton, 2003).
The rates of disorders calculated here might not be representative of the true rate of ASD found in PWS/AS, as not all the studies were population based. In terms of PWS, the rate of ASD in the Hou et al. (1998) study was 15%, lower than the rate found by Veltman et al. (2004), but using more robust ASD assessments. In the two population-based studies that reported rates of ASD in AS, the findings are quite inconsistent. One study reported no AS patients (0/40) with an ASD, although they acknowledged the challenge of diagnosing ASD in severely handicapped children (Hou et al., 1998). The other found that all four patients with AS (4/4) identified in their population had an ASD (Steffenburg et al., 1996). Two of these latter cases, however, were not cytogenetically verified cases of AS (Steffenburg et al., 1996).
The picture concerning AS is further complicated by a newly published study concerning autism in AS (Trillingsgaard and Østergaard, 2004). This study did not meet the inclusion criteria for the systematic review presented here, as the authors were not aware of the study and it had not been published at the time of data collection, inclusion, and synthesis. This recent, carefully conducted study found that 13 of 16 children with AS received an Autism Diagnostic Observation Schedule – Generic (ADOS-G) algorithm classification of ASD. This study based the ASD diagnoses solely on the ADOS-G scores. Furthermore, the mean mental age for the children with an autism diagnosis and AS was 9.5 months (SD=2.4 months) and the validity of using the ADOS-G with children whose mental age is below 12 months old is questionable, as the authors themselves point out. Therefore, this draws into question the appropriateness of using the ADOS-G as the sole diagnostic instrument for this particular group of children. The authors speculated that the impairments in AS may be better understood in terms of developmental delay, compared with autism where the impairments are considered to signify developmental deviance. They also concluded that the rate of ASD in AS in their study might have been overestimated because of the extremely low mental age of the children with AS. Their findings and those of Peters et al., (2004) further underscore the uncertainties regarding the rate of autism and autistic symptomatology in AS. Both these studies suggest that the estimate derived from the studies summarized in the present systematic review is an underestimate and that perhaps reduced expression of maternally expressed genes may also constitute a risk factor for ASD (Peters et al., 2004; Trillingsgaard and Østergaard, 2004). The issue is worthy of further investigation in order to determine whether perturbations in the level of expression of UBe3a (up and/or downregulation) may increase the risk for an ASD.
Not all studies had the PWS/AS status of their participants confirmed by genetic testing; indeed, one study relied on parental reports of genetic status (Dykens and Cassidy, 1995). Reliance upon parental information regarding genetic status may be problematic as it has been found that this may not always be a reliable method of deciding upon genetic subgroup (see Veltman et al., 2004). Furthermore, molecular genetics is now able to identify different classes within each syndrome (e.g. UPD or DEL) that are linked with differences in phenotype associated with each syndrome. Therefore, this review examined rates in genetically verified cases and the clinically diagnosed samples.
Another consideration is the possibility that other studies concerning this topic were missed in this systematic review. In order to minimize this possibility, the present review adhered to standard systematic review procedures and employed both electronic-search and hand-search strategies. Although some authors advocate not making the effort to identify the ‘gray literature’ identified through hand-searching as not all of it may have undergone peer-review (Chalmers et al., 1987), excluding data from studies thus identified may lead to a loss in precision of the estimate of an effect size (Dickersin et al., 1994).
Studies, however, have included individuals with PWS/AS in testing hypotheses relating to the cognitive deficits comprising autism, although these did not look at ASD specifically and as such were not included in the current review. For example, Tager-Flusberg et al. (1998) used a matched PWS contrast group to Williams syndrome (WS) and ‘normal’ cases in a study examining social cognition or more specifically the domain of understanding other people's minds, otherwise termed ‘mentalizing’. Weaknesses in this domain have been shown to be associated with ASD (Baron-Cohen et al., 1985; Baron-Cohen and Howlin, 1993). Interestingly, the finding showed that the PWS group performed significantly worse than the WS group and the ‘normal’ groups in this domain and indeed they performed about as poorly as participants with autism who were tested by Baron-Cohen et al. in 1997. This latter finding was, at least partially, explained by the difference in intellectual ability as the PWS group tested was intellectually disabled whereas the participants with autism tested by Baron-Cohen et al. were of normal intelligence (Tager-Flusberg et al., 1998).
It is also necessary to consider the possibility of publication and reporting bias further, as it is quite possible that some studies examined the issue addressed here, but because no differences were observed, the findings have not been reported or published. Although this remains a possibility, this is deemed unlikely, as the importance and rationale for undertaking a study of ASD in PWS/AS has only recently become apparent and that most studies identified here did not focus on the prevalence of ASD in their sample. This is perhaps one of the most significant shortcomings in the extant literature. The fact that very few of the studies have focused on evaluating the rate of ASD in their sample, using standardized procedures, is a real limitation in the current literature. Taken together, the methodological limitations identified in the reported studies preclude any firm conclusions being drawn. Despite this, it is noteworthy and of interest that the pooled rate of ASD in the UPD PWS cases was significantly higher than the rate in other forms of 15q11–13 abnormality and that there was a similar significant tendency for the rate of ASD in UPD PWS cases to be higher than in the DEL PWS cases. Further indications that these findings may reflect a true difference is provided by the two studies that examined the frequency of autistic behaviors/social impairments in PWS, as both showed a higher rate in the UPD group (Dykens and Cassidy, 1995; Veltman et al., 2004a). It should be noted that although Veltman et al. found that the total symptom score of the Autism Screening Questionnaire was significantly elevated for the UPD PWS cases compared with the DEL PWS cases, the difference in rate of ASD was not statistically significant. Also, as discussed, the study reported by Tager-Flusberg et al. above is also in keeping with the findings reported here. It seems clear, therefore, that there is a case for investigating ASD and autistic-like behaviors further in PWS and, to a lesser extent, in AS. Studies in the future will need to investigate sufficiently large numbers of cases to ensure adequate power and they will have to employ state of the art diagnostic measures for ASD. It is also evident that there will have to be careful attention to the developmental course of the disorder as the current findings raise the possibility that autistic-like behaviors may be most prominent in early childhood. Of course, one should not forget that a number of other reasons exist for studying phenotypic manifestations of individuals with 15q11–13 abnormalities, quite apart from the desire to investigate the prevalence of autistic-like impairments and social dysfunction. The current evidence suggests interesting differences in the pattern of cognitive strengths and difficulties in subgroups and further clarification of these patterns may throw light on the nature of genetic influences on cognitive development. Also of great potential interest are the reports suggesting an association between genetic subtype and the development of psychosis in PWS, especially as some cases were reported to have ASD-like problems prior to the onset of the psychosis (e.g. Clarke, 1998; Clarke et al., 1998; Verhoeven et al., 1998; Boer et al., 2002).
As such, this should be an encouragement to research groups to pursue these topics of enquiry in more detail.
The authors would like to thank Dr Siân Roberts, Wessex Regional Genetics Service, for her help in interpreting some of the genetic findings.
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