the assessment and presentation of autism spectrum ... · asd in genetic syndromes 1 the assessment...

ASD in genetic syndromes

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The assessment and presentation of Autism Spectrum Disorders in Genetic Syndromes: Implications for diagnosis, intervention and understanding the wider

ASD population.

Jo Moss and Patricia Howlin

Cerebra Centre for �eurodevelopmental Disorders,

School of Psychology,

University of Birmingham

and

Institute of Psychiatry, King’s College London

Please use this reference when citing this work:

Moss, J. and Howlin, P. (2009). Invited Annotation - Autism spectrum disorders in genetic syndromes:

Implications for diagnosis, intervention and understanding the wider ASD population.

Journal of Intellectual Disability Research, 53, 852-872.

The Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Edgbaston, Birmingham, B15 2TT Website: www.cndd.Bham.ac.uk E-mail: [email protected]


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Invited Annotation - Autism Spectrum Disorders in Genetic Syndromes: Implications for

diagnosis, intervention and understanding the wider ASD population.

Key Words: autism spectrum disorder, genetic syndromes, behavioural phenotypes

Suggested Running Head: ASD in genetic syndromes

Abstract:

Background: An emerging literature on behavioural phenotypes has highlighted apparent

associations between autism spectrum disorders (ASDs) or ASD related phenomenology and a

number of different genetically determined syndromes.

Method: A systematic review of the current literature regarding the association with ASD and ASD

characteristics was conducted in the following syndrome groups: Fragile X, Rett, Tuberous

Sclerosis Complex, Down, Angelman, CHARGE and Phenylketonuria. Specific consideration was

given to the role of intellectual disability in assessing the association between ASD and these

syndrome groups.

Results: The review highlighted that whilst formal diagnostic assessments may indicate an

association between ASD and specific syndrome groups, detailed investigation has revealed subtle

but qualitative differences in the presentation of ASD like phenomenology in particular syndrome

groups. The degree of intellectual disability of the individual clearly has a role to play with regard

to the development and presentation of ASD like characteristics, and caution should be taken when

assessing ASD symptomatology in genetically determined syndromes associated with severe

intellectual disability. However, degree of intellectual disability cannot solely account for the

heightened prevalence of ASD characteristics in some specific syndrome groups.

Conclusions: There is a need for caution in interpreting the significance of superficial similarities

between ASD and the behavioural phenotypes of certain genetically determined syndromes.


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However, recognition of ASD like characteristics (even where a true diagnosis of ASD may not be

relevant) in individuals with genetic syndromes is crucial in ensuring that individuals receive

appropriate behavioural management and educational placement. Further research in this field

requires fine-grained investigation of behavioural phenomenology within individual syndrome

groups.

Introduction:

Autism spectrum disorders (ASDs) are classified by DSM-IV-TR (APA, 2000) and ICD-10 (WHO,

1992) as pervasive developmental disorders (PDD) characterised by the presence of three core

features: qualitative impairments in communication and in social interaction and the presence of

repetitive behaviour and restricted interests. ASDs1 occur in up to 1% of children in the general

population (Baird et al., 2006) and in up to 40% of individuals with intellectual disability (ID; La

Malfa et al., 2004).

The specific causes of ASD remain unknown but are largely considered to be genetically linked

(Abrahams & Gerschwind, 2008). However, whilst a number of chromosomes and genetic loci have

been implicated, there is little evidence to suggest that any one of these is solely linked to ASD

diagnosis. The large number of identified risk loci has led researchers to suggest that ASD is caused

by complex multigenetic interactions rather than simple single gene mutations (Zhao et al., 2007).

Recent evidence from a population based study suggests that there may be different aetiological

pathways contributing to each of the different diagnostic domains of ASD (Ronald et al., 2006).

Some researchers, therefore, consider it to be more helpful to conceptualise the aetiology of ASD in

terms of a ‘network’ of dysfunctions that occur on a number of levels, including genetic and

neuronal pathways. The underlying aetiology of ASD now appears to be a highly complex process,

1 For the purposes of this review the term Autism Spectrum Disorder (ASD) will be employed throughout the text to

refer to all conditions classified by the DSM-IV-TR (2000) within the category of Pervasive Developmental Disorder

with the exception of Rett syndrome and Child Disintegrative Disorder. When referring to particular studies, the

terminology used by the authors of the study will be employed.


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involving various genes that effect downstream proteins and neural substrates that subsequently

lead to the behavioural manifestations of ASD (Abrahams & Gerschwind, 2008; Belmonte &

Bourgeron, 2006; Persico & Bourgeron, 2006). An alternative approach to the multigenetic

hypothesis is proposed by Zhao et al. (2007) who suggest that most cases of autism are due to de

novo mutations in the paternal germ line which can affect any number of critical loci. It is suggested

that de novo mutations may be carried by some protected and asymptomatic individuals,

particularly females, who will transmit the mutation in a dominant pattern to male offspring.

There has been an increasing interest in the association between ASD and a number of genetically

linked conditions. The presence of ASD or autistic characteristics has been reported in a wide

variety of disorders including those with variable aetiology (e.g. anorexia nervosa, Tourette

syndrome, ADHD); physical and sensory disorders (cerebral palsy, muscular dystrophy, Leber's

congenital amaurosis), and syndromes with a known genetic cause (e.g. Tuberous Sclerosis

Complex, Fragile X, Down, Angelman, Coffin-Lowry, Cohen Laurence-Moon-Biedel, Marinesco-

Sjogren, Moebius, Rett and Williams syndromes; see Fombonne, 1999; Gillberg & Coleman, 2000

for reviews).

The apparent overlap between various syndromes with known genetic causes and ASD

symptomatology clearly has implications with regard to our understanding of ASD at both the

behavioural and biological level. Some researchers propose that genetic syndromes may be

influential in identifying and understanding the genetic and neural pathways underlying ASD more

widely (Persico & Bourgeron, 2006). One suggestion is that although each syndrome may arise

from different genetic abnormalities, with multiple molecular functions, the effects of these

abnormalities give rise to common effects downstream, in the biological pathway or neural circuits,

that result in the presentation of ASD characteristics (Abrahams & Gerschwind, 2008) An

alternative stance is proposed by Skuse (2007) who suggests that the list of genetic syndromes with


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an apparent association with ASD is growing to such an extent and with such diversity, that these

associations are unlikely to provide specific answers with regard to the gene loci and network

pathways involved in ASD. In fact, this emergence of association across a range of genetically

determined syndromes makes the interpretation and understanding of their significance more

complex. Skuse argues that genetic susceptibility for ASD does not manifest in the behavioural

phenotype of specific genetic syndromes. Rather, the intellectual disability associated with many

genetic syndromes simply increases the risk that ASD or autistic characteristics will be revealed.

Skuse suggests that this is due to the fact that impaired intellectual ability diminishes the possibility

for cognitive compensation of independently inherited autistic-type traits. In this way, the presence

of a genetic syndrome and the associated degree of intellectual disability may simply act as an

additional risk marker for ASD characteristics, rather than playing a causal role. According to this

model of association we would expect to find that genetic syndromes associated with more severe

intellectual disability will be more likely to manifest ASD like symptoms. In the following review,

we consider this position in a range of syndrome groups that have been reported to be associated

with ASD.

The following annotation is divided into two sections. Section I presents a brief systematic review

of the association between ASD and a number of different genetic syndromes. In this section we

aim to provide a broad understanding of the nature of the association between ASD and these

various genetic syndromes. We also consider the role of intellectual disability in the association

between a given syndrome and ASD. Section II focuses on the specific clinical implications of

understanding the association between ASD and genetic syndromes in terms of diagnosis and

intervention and also the conceptual implications of these associations.

Section I: The association between ASD and genetic syndromes


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For the purpose of this review a systematic search, using the Web of Science, of papers published

since 1970 was conducted. All articles with the terms ‘autism’ OR ‘autistic’ AND each of the

different neurodevelopmental genetic syndromes identified as having an association with ASD in

the reviews of Gillberg and Coleman (2000) or Fombonne, (1999) were scrutinised. Only papers in

which the title indicated an association between ASD and the syndrome concerned were considered.

Series of papers involving the same participant samples were counted as a single study. Table 1

summarises the dates/number of articles identified. For some syndromes (eg Klein-Levin, Smith

Magenis, Sanfilippo and Steinert’s myotonic dystrophy), although an association with ASD has

been suggested, no articles with the words ‘autism’ or ‘autistic’ in the title were identified, hence

these are not included in Table 1.

(Insert Table 1 about here)

Based on this search, this section of the annotation focuses first on syndromes in which the

association with ASD has been most frequently reported - Fragile X and Rett syndromes and

Tuberous Sclerosis Complex. We include here only studies that have employed standardised

assessments with good psychometric properties /diagnostic criteria. We then consider several other

genetic disorders that have received comparatively less attention in the literature, but where at least

five published papers on the association with ASD are described. These include: Down, CHARGE

and Angelman syndromes and Phenylketonuria.

1. Fragile X syndrome:


Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability, occurring

in 1 in 3,600 males and 1 in 8,000 females (Cornish et al., 2008). It results from an excess of CGG


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trinucleotide repeats on the FMR1 (Fragile X Mental Retardation- 1) gene at location Xq27-3

(Dykens et al., 2000). In FXS males, the degree of intellectual disability is usually reported to be

within the mild to severe range while FXS females usually demonstrate a mild degree of learning

disability although this can be more severe in a small percentage of females (approximately 25%;

Cornish et al., 2008).

Reported prevalence rates of ASD in FXS vary widely from 0 to 60%, although the most recent

estimates from studies conducted between 2001 to date are more consistent, ranging from 21% to

50%. The percentage of ASD in females with FXS is lower, between 1 and 3% (see Table 2). The

variation in estimates of ASD among the earlier studies is likely to result from the use of different

methodologies and diagnostic criteria; the more consistent findings in recent years are likely to

reflect an increased reliability in both ASD diagnosis and genetic testing for FXS. Recent studies

report a strong correlation between the associated degree of intellectual disability and, in particular,

impairments in verbal skills and the presence of ASD characteristics in FXS (Demark et al., 2003;

Kaufmann et al., 2004; Lewis et al., 2006; Loesch et al., 2007). This seems to support Skuse’s

suggestion that the severity of intellectual disability increases the risk of ASD symptomatology in

genetic syndromes. However, ASD has also been identified in individuals with the pre-mutation

FXS with mild cognitive impairments or IQ in the normal range (Hagerman et al., 2005).

Dissanayake et al., (20009) report that while individuals with FXS and ASD demonstrate a similar

profile of scores on the ADOS (Lord et al., 2000) to individuals with idiopathic ASD, individuals

with FXS score significantly lower on tests of performance and verbal IQ. The authors suggest that

the common pathway underlying the shared characteristics of FXS and ASD is likely to be neural

rather than genetic, in which diverse biological pathways may lead to a common cognitive and

behavioural outcome.


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Studies that have focused on the specific phenomenology of ASD in FXS have raised doubts about

the strength of association. Bailey et al.( 2001) and Demark et al.( 2003) suggest that severe autism

is relatively rare and that a milder presentation of ASD symptomatology is more characteristic of

individuals with FXS. Fine-grained analysis has identified specific areas of behaviour which,

although they may appear initially to be ASD related, seem to be qualitatively different from the

characteristics identified in idiopathic autism. Individuals with FXS are more likely to demonstrate

social anxiety, extreme shyness and gaze avoidance alongside seemingly preserved emotion

sensitivity and willingness to interact (Cornish et al., 2007; Hall et al., 2006; Lesniak-Karpiak et al.,

2003; Roberts et al., 2007; Turk & Cornish, 1998). This profile is somewhat different to the social

impairments that are characteristic of idiopathic autism. Moreover, the gaze avoidance and

perseverative speech described in FXS are reported to be unrelated to verbal ability or age (in

contrast to the autism population) and are more marked in FXS than they are in autism or ‘non-

specific’ intellectual disability (Sudhalter et al., 1990). Recent research suggests that in FXS it is the

impairments in social interaction that are most likely to contribute to an individual meeting criteria

for ASD (Budimirovic et al., 2006; Kaufmann et al., 2004). The developmental trajectory of ASD

in FXS is also reported to differ from idiopathic autism and, according to some studies, the rate of

autism and social avoidance behaviours increases with age in males with full mutation FXS (Hatton

et al., 2006; Roberts et al. 2007). These findings suggest that even when individuals with FXS meet

criteria for ASD on autism specific assessments, they may do so for somewhat different reasons to

those with idiopathic ASD.

Recent findings also suggest that in addition to subtle differences at the behavioural level regarding

apparently shared ASD characteristics in FXS, differences between these two populations may be

observed at the level of social-cognition (Cornish et al., 2008). For example, detailed analysis of

ToM skills in individuals with FXS with and without ASD and individuals with intellectual

disability indicates that, while all three groups seem to perform at a similar level on ToM tasks,


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differences in error patterns suggest that the underlying bases for these deficits are syndrome

specific. Grant et al. (2007) reported that impaired false belief reasoning in FXS was downstream of

a more primary impairment in working memory in those with and without ASD characteristics. In

contrast to individuals with ASD, emotion perception in FXS is reported to be commensurate with

overall level of ability (Turk & Cornish, 1998; Wishart et al., 2007).

It is clear that whilst the association between ASD and FXS is considered to be reasonably robust,

this may only be evident at the level of overt symptomatology/diagnostic cut-off scores. When the

specific profile of behaviours is considered in more detail, those characteristics that initially appear

to be autism related, in fact demonstrate qualitative differences with idiopathic autism at both the

behavioural and socio-cognitive level. Thus, although individuals with FXS may appear to share a

number of core characteristics with individuals with ASD, the underlying aetiological pathways

involved may differ between these two disorders (Cornish et al., 2008). The study of ASD

characteristics in FXS provides a good example of why careful, detailed assessment and

identification of ASD related characteristics is important in order to avoid erroneous conclusions

concerning the association between ASD and genetic syndromes.

Summary: FXS is a genetic syndrome associated with mild to severe intellectual impairments.

Current estimates suggest that ASD occurs in 21% to 50% of males with FXS, with ASD being

more likely to be identified in individuals with a greater degree of intellectual disability. Studies

that have considered the phenomenology of ASD in FXS in more detail have identified differences

in the nature, quality and development of ASD characteristics in FXS that raise questions regarding

the strength of association between these two disorders.

2. Rett syndrome:



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Rett syndrome (RS) is a neurological disorder, predominantly affecting females, occurring in

between 1 in 15,000 to 22,800 live female births (Kozinetz et al., 1993). It is caused by mutations

on the X-linked MECP2 gene (Amir et al., 1999). In the classic form of RS, development often

appears relatively normal for the first six to eighteen months. This is followed by a period of

regression resulting in a reduction in head circumference growth, onset of seizures and loss of

language and motor skills, leading to severe or profound intellectual and physical disabilities

(Nomura & Segawa, 2005). However, there is a range of severity of RS, and some individuals have

been reported to retain and develop their language skills further (Kerr et al., 2001; Smeets et al.,

2005). These milder cases of RS are more likely to be associated with a slightly different type and

location of genetic mutation on the MECP2 gene than those with classic RS (Kerr et al., 2001; Neul

et al., 2008; Smeets et al., 2005).

In Rett’s initial account of the syndrome (1966; cited in Van Acker, 1997) ‘autistic-like’ behaviour

was noted as being characteristic of the disorder. Subsequently, estimates of rates of ASD in RS

range from 25% to 40% and up to 97% in individuals with the preserved speech variant of RS (See

Table 3). ASD is also the most common initial misdiagnosis in children with RS, with 18% of

individuals being diagnosed with ASD prior to receiving a diagnosis of RS (Young et al., 2007).

The overlap between RS and ASD has previously been considered to be so robust that RS is

currently classified as a pervasive developmental disorder alongside autism, according to both the

DSM-IV-TR (APA, 2000) and the ICD-10 (WHO, 1992) diagnostic criteria. However, the inclusion

of RS within the PDD category is now considered inappropriate by many (Tsai, 1992), due to

distinct differences in phenomenology. For example, many (although not all) individuals with RS

develop simple speech prior to regression and despite the marked deterioration in social skills, eye

contact is often maintained; social impairments and autistic characteristics also tend to improve

with age (Nomura & Segawa, 2005). Furthermore, the characteristic repetitive hand movements in


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RS are very different to the motor stereotypies observed in individuals with ASD (Howlin, 2002). It

is important to ensure that unique syndrome characteristics such as these are not misclassified in

assessments of ASD symptomatology. Even when diagnostic criteria for autism are met, individuals

with RS demonstrate an atypical profile of phenomenology. They manifest fewer of the core

features of autism and are more likely to score on non-autism specific items, such as ‘sleeps too

much’, ‘under active’ and ‘unhappy’ (Mount et al., 2003a).

The severity of intellectual disability typically associated with RS also confounds the distinction

between ASD and RS. The ability reliably to identify ASD specific impairments in the areas of

communication, social interaction and repetitive behaviours becomes far more difficult as the

degree of intellectual disability increases (Howlin, 2000). However, Mount et al. (2003b) reported

that individuals with RS scored significantly higher on the Autism Behavior Checklist (Krug et al.,

1980) than individuals with a matched level of intellectual disability, indicating that ASD

characteristics in RS are not solely accounted for by the degree of intellectual disability. Moreover,

estimated prevalence rates of ASD characteristics are actually higher in more mildly affected

individuals with RS (up to 97%; Zappella et al., 2001; Zappella et al., 1998) although other studies

report that these individuals demonstrate good social interaction skills (Kerr et al., 2006).

Summary: Early studies indicated an increased prevalence of ASD in RS and led to the inclusion of

RS under the PDD category within DSM and ICD criteria. Recent, more fine-grained assessments

suggest that the inclusion of RS in the PDD category is inappropriate. Although the prevalence of

ASD in RS is heightened when compared to individuals matched for degree of intellectual

disability, and individuals with RS who are more mildly affected have been reported to demonstrate

a higher prevalence of ASD characteristics, individuals with RS demonstrate an atypical profile of

characteristics compared to those with idiopathic autism.


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3. Tuberous Sclerosis Complex.

Insert Table 4 about here

Tuberous Sclerosis Complex (TSC) occurs in 1 in 6,000 live births (O’Callaghan, 1999) and is

caused by a mutation in the TSC1 (9q34) or TSC2 genes (16p13; Povey et al., 1994). Mutations in

either gene result in dysregulated cell development, giving rise to abnormal tissue growth or benign

tumours in the brain, skin, kidneys and heart (Crino et al., 2006). The TSC phenotype is extremely

variable with some individuals having only superficial skin problems or mild seizures; others show

severe physical effects and profound intellectual disability (de Vries & Howe, 2007).

Autistic-type symptoms in TSC were first noted by Critchley and Earl (1932) who described 29

individuals with impaired social contact, stereotyped behaviours, absent or abnormal speech and

social withdrawal. However, it was only after Kanner’s description of autism in 1943 that the

behaviours noted by Critchley and Earl were recognised as being characteristic of ASD. Despite

these early descriptions, the association between ASD and TSC has only recently been

systematically explored. Reported rates of ASD in TSC range from 5% to 89% although the more

consistently reported prevalence figures range from 24% to 60% (see Table 4). Although it has been

suggested that comorbidity of ASD in TSC is associated with the presence of temporal-lobe tubers

(Bolton et al., 2002), not all individuals with temporal-lobe tumours meet ASD criteria and this

association has not been replicated by others (Asano et al., 2001).

Few studies have considered the phenomenology of ASD in TSC in detail. Smalley et al. (1992)

reported that individuals with TSC had somewhat higher (though non-significant) scores than

individuals with autism on the social and communication domains of the Autism Diagnostic

Interview-Revised (ADI-R; Rutter et al., 2003). However, TSC individuals scored significantly

lower on the repetitive behaviour domain of this measure. Interestingly, Jeste et al. (2008) reported


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a global deficit in play skills (assessed by the Autism Diagnostic Observation Schedule; ADOS

Lord et al., 2000) in all children with TSC regardless of ASD status, suggesting that deficits in this

particular area may be syndrome specific. Moreover, the male: female ratio in TS is reported to be

approximately equal (Smalley, 1998; de Vries et al., 2007), in contrast to the much higher

proportion of males found in ASD (Baird et al., 2006). Such findings suggest that ASD features in

TSC may differ from those identified in idiopathic ASD.

The role of intellectual disability in the association between ASD and TSC is unclear. Earlier

studies suggested that the association between ASD and TSC was independent of degree of

intellectual disability, with up to 25% of individuals who met autism criteria having an IQ >70.

(Harrison & Bolton, 1997; Smalley, 1998). However, more recent studies have identified a greater

risk of autism and ASD with increased degree of intellectual disability in TSC (de Vries et al.,

2007; Jeste et al., 2008; Wong, 2006). The latter findings are consistent with Skuse’s model of

overall increased risk of ASD with increased degree of intellectual disability. Nevertheless, current

research indicates that up to 17% of individuals with TSC with an IQ in the normal range are

reported to meet criteria for ASD (de Vries et al., 2007; Prather & de Vries, 2004). This is still a

heightened rate in comparison to the prevalence of ASD in the general population, suggesting that

the degree of intellectual disability associated with TSC cannot solely account for the raised

prevalence of ASD in TSC.

Summary: Although research suggests a strong association between ASD and TSC at the diagnostic

level, few studies have considered the precise nature of ASD phenomenology in this condition. The

degree to which the associated intellectual disability contributes to the association between ASD

and TSC is unclear but recent studies indicate that, as is the case with FXS, the prevalence of ASD

increases with the degree of intellectual disability.


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In the final part of this section, we consider four genetic disorders where the association with ASD

has received comparatively less attention within the literature but where at least five published

papers on the association with ASD have been identified. Since the evidence concerning their

association with ASD is limited, the discussion here includes case-reports and studies that have

either investigated the prevalence of ASD or have described ASD-like behaviours within the

syndrome. Only studies using standardised assessments and diagnostic criteria are included within

the tables.

4. Down Syndrome:

Down syndrome (DS) is the most common chromosomal cause of intellectual disability, occurring

in approximately 10.3 in 10,000 live births (Bell et al., 2003). Typically, DS is caused by the

presence of a full or partial trisomy of chromosome 21, although occasionally an unbalanced

translocation involving chromosome 21 has been identified (Dykens et al., 2000). Intellectual

disability in DS ranges from mild to severe (Capone et al., 2005).

Previously, the association between ASD and DS was considered to be relatively rare; indeed, there

were suggestions that DS might actually be protective against autistic like behaviours (Turk, 1992).

However, several case studies have described individuals with DS who also met ASD criteria

(Bregman & Volkmar, 1988; Ghaziuddin et al., 1992; Howlin et al., 1995; Wakabayashi, 1979) and

recent research indicates that co-morbidity may be more common than previously thought with

prevalence rates ranging from 5% to 39% (see Table 5). Difficulties in social-cognition, notably in

areas related to ToM and emotion perception have also been reported in some children with DS

(Hippolyte et al., 2008; Wishart, 2007; Wishart et al., 2007; Zelazo et al., 1996). Higher rates of

impaired social skills have also been reported in family members of individuals with DS and ASD

in comparison to individuals with DS without ASD (Lowenthal et al., 2007).


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Individuals with DS and ASD are reported to have a greater degree of intellectual disability and

higher rates of stereotyped behaviours, hyperactivity and inappropriate speech, than those with DS

without ASD (Capone et al., 2005). However, it remains unclear how far the increased severity of

intellectual impairment can explain the increased prevalence of ASD symptomatology in this

subgroup. Further research is required to investigate the phenomenology of these characteristics in

DS more carefully, in order to clarify whether these characteristics are indeed shared, are

superficially similar to that of idiopathic ASD or perhaps associated with different underlying

aetiologies.


5. Phenyketonuria:

Phenylketonuria (PKU) is a genetic disorder associated with defects in protein metabolism,

resulting in an inability to break down the amino acid phenylalanine. PKU occurs in approximately

1 in 10,000 live births (Scriver et al., 1994). Pre/post natal screening has significantly reduced PKU

in developed countries and with early diagnosis and a controlled diet the effects of PKU are

minimal. However, in cases of late diagnosis, high levels of protein in the diet can produce toxic

levels of phenylalanine hydroxylase (PAH) resulting in ID, seizures and many physical difficulties.

The majority of individuals with PKU have an IQ within the normal range (Yalaz et al., 2006)

although intellectual disability can range from mild to severe, particularly in late diagnosis cases.

Co-occurrence of autism and PKU has been described in several case reports (Chen & Hsiao, 1989;

Lowe et al., 1980; Steiner et al., 2007), although the strength of the association is inconsistent and

difficult to determine due to significant improvements in early identification and treatment. In a

recent study of 243 individuals with PKU, Baieli et al. (2003) reported that autism was only

identified (based on ADI-R and Childhood Autism Rating Scale criteria; CARS Schopler et al.,

1988) in those with a late PKU diagnosis (2 cases among 35 (5%) late diagnosed individuals). This


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is somewhat different to the rate reported by Reiss et al. (1986) who suggested that the prevalence

of ASD in PKU may be as high as 20%. These discrepancies are likely to be accounted for by the

increased availability of early identification methods and treatment. Dennis et al. (1999) reported

substantial overlap in the cognitive profiles (notably good performance on Block Design and low

scores on Comprehension) of individuals with autism and poorly controlled PKU, matched for age

and IQ. Those with better controlled PKU did not demonstrate this profile. The link between poor

control/late diagnosis PKU and ASD suggests that with improvements in diagnosis and treatment of

PKU, the association with ASD will likely decrease (Gillberg & Coleman, 2000). The association

between ASD in PKU has important implications for understanding possible underlying factors in

the development of ASD. In the case of PKU, the toxic levels of PAH appear to play a significant

role in the development of ASD symptomatology. In the wider ASD population, this is unlikely to

be a common underlying factor. This suggests that the presence of ASD characteristics may be a

common end state of a number of different aetiological pathways.

6. CHARGE Syndrome:


CHARGE Syndrome occurs in approximately 1 in 10,000-12,000 live births (Issekutz et al., 2005).

The underlying genetic cause has yet to be established although recent studies have identified

mutations on the CHD7 gene (Vissers et al., 2004). The syndrome’s acronym, CHARGE, refers to

the characteristic physical deficits: Coloboma of the eye, Heart defects, Atresia of the choanae,

Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear

abnormalities and deafness. There is great variability in the presence and severity of these

abnormalities. Many children with CHARGE syndrome have IQs in the normal range although

intellectual disability can occur.


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The behavioural phenotype of CHARGE has not been widely studied but hyperactivity, obsessions,

compulsions and tic disorders have been noted (Kuijpers et al., 2007; Wachtel & Hartshorne, 2006).

Autistic like behaviours have been described in several case reports (Davenport et al., 1986; Fernell

et al., 1999; Kuijpers et al., 2007; Sabaratnam et al., 2000; Wachtel & Hartshorne, 2006). Larger

scale studies suggest that the prevalence of ASD ranges from 15% to 50% (see Table 6).

Information is limited regarding the degree of intellectual disability and sensory deficits associated

with CHARGE-ASD co-morbidity. The two cases described by Smith et al. (2005) suggest that

ASD is more likely in nonverbal individuals with severe-profound intellectual disability. In a larger

study, Hartshorne et al. (2005) found some variability in the severity of autistic symptomatology in

comparison to individuals with ASD but the results indicated that the presence of autism

characteristics in CHARGE could not be wholly accounted for by the visual and hearing

impairments typically associated with the syndrome

7. Angelman Syndrome:


Angelman Syndrome (AS) occurs in approximately 1 in 12,000 to 15,000 live births (Clayton-

Smith & Pembry, 1992; Kyllerman, 1995) and is caused by maternally inherited anomalies on

chromosome 15. Approximately 70% of cases of AS are due to maternal deletions; between 2 and

5% are caused by paternal uni-parental disomy. Approximately 2 to 3% of cases have imprinting

defects, including deletions of the imprinting centre, and a further 1% have other unusual mutations

on chromosome 15. The remaining 22-25% of individuals with AS have mutations in the UBE3A

critical region (Dykens et al., 2000). AS is associated with a severe to profound ID (Peters et al.,

2004), poor mobility and communication skills and seizure disorder (Dykens et al., 2000).


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Reported prevalence rates of ASD in AS range from 50% to 81% (see Table 7). Inherited

duplications involving the chromosomal region 15q11-15q13 (the same region affected in

individuals with Angelman and Prader-Willi Syndromes) are among the most commonly reported

genetic abnormalities identified in individuals with ASDs and account for 1 to 2% of cases

(Abrahams & Gerschwind, 2008). Peters et al. (2004) reported a significant difference between AS

individuals with and without autism, with the former group being significantly more intellectually

impaired. Thus, it is possible that, in line with Skuse’s model, the presence of ASD in AS is an

artefact of the profound intellectual disability associated with the syndrome. Trillingsgaard and

Østergaard (2004) found that individuals with AS and autism were significantly less impaired in

areas such as social smile, facial expression directed to others, shared enjoyment in interaction,

response to name and unusual interests or repetitive behaviour (all of which are less reliant on

developmental level) than individuals with idiopathic autism. Bonati et al. (2007) also reported that

individuals with AS with better expressive language skills did not meet ASD or autism criteria on

the ADOS or ADI-R. These findings indicate that the associated degree of intellectual disability in

AS may play a significant role in the association with ASD rather than representing a syndrome

specific associated between ASD and AS.

With regard to the profile of ASD behaviours in AS, Walz and Benson (2002) and Walz (2007)

found that some of the characteristic features of ASD, such as finger/hand flicking, object spinning,

lining up objects, looking through people and lack of affection, were rarely reported in AS. This

may suggest that even when individuals with AS meet diagnostic criteria for ASD, the profile of

behaviours may be somewhat different to that of idiopathic ASD.

Summary of syndrome review:



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Table 8 provides a summary of the prevalence figures reported and associated degree of intellectual

disability. It is clear that, in each of these syndromes, there is some degree of association with ASD

and in many cases heightened prevalence of ASD can be accounted for, to some degree, by

associated intellectual disability. In particular, Capone et al. (2005) demonstrate that individuals

with DS who meet criteria for ASD have a greater degree of intellectual disability compared to

those with DS without ASD. Furthermore, research findings indicate that the association between

AS and ASD may be attributed to the degree of intellectual disability associated with this syndrome.

Some research studies of FXS and TSC also suggest that individuals who meet criteria for ASD are

more likely to be those with more severe intellectual disability (Demark et al., 2003; de Vries et al.,

2007; Jeste et al., 2008; Kaufmann et al., 2004; Lewis et al., 2006; Loesch et al., 2007; Wong,

2006), although the findings in these two syndrome groups are inconsistent. However, it is also

clear that in many syndromes, particularly those associated with a moderate to mild level of

intellectual disability, the associated cognitive impairment cannot solely account for the raised

prevalence of ASD. Of the three most commonly researched syndromes, with regard to their

association with ASD, (i.e. FXS, RS and TSC) only RS is characterised by severe and profound

intellectual disability. TSC and FXS are both associated with a milder degree of intellectual

disability and yet the reported prevalence rate of ASD in all three groups is upwards of 15%. The

role that the degree of intellectual disability plays in the manifestation of ASD in these syndrome

groups is, therefore, unclear and further work is required, particularly in AS and TSC, in order to

establish further the specificity of the syndrome-ASD association. It is clearly important that

individuals’ degree of intellectual disability be taken into account when considering whether or not

they meet diagnostic criteria. This is relevant to both research and clinical assessments of ASD.

A final point to note is that within each of the syndrome groups reviewed above, clinical diagnosis

or formal, algorithm based cut off criteria have been used to determine the prevalence or rate of

ASD. However, further detailed examination of the specific ASD profile in these syndromes reveals


20

a range of similarities and differences in the specific behavioural pattern of ASD within each group.

It seems that each syndrome group may have their own, unique, syndrome specific ‘signature’ of

ASD characteristics and impairments that are different to those observed in idiopathic ASD. It is

these atypical profiles that may prove to be of most importance in further understanding the

aetiology of ASD and the conceptualisation of the triad of impairments and the spectrum of autism.

Section II: Diagnostic considerations of differential diagnosis in genetic syndromes and

implications for intervention, conceptual and theoretical frameworks

Studies identifying ASD symptomatology in specific genetic conditions have provided valuable

information on the behavioural phenotypes of the syndromes described in this review. However,

research in this area has also highlighted some important diagnostic, intervention-related and

conceptual issues.

Diagnostic considerations:

Recent research regarding the boundaries of the autism spectrum has tended to support a continuous

severity gradient (Constantino et al., 2004; Ring et al. 2008, Spiker et al., 2002), rather than a clear

distinction between “affected” and “non-affected” individuals. Family genetic studies clearly show

that among first-degree relatives of probands with ASD, up to 20% show difficulties associated

with social functioning, communication or rigid behaviours/beliefs (Bolton et al., 1994; Fombonne,

et al., 1997). Indeed, none of the core characteristics of ASD are unique to individuals with ASD.

Most people have fixed patterns of doing certain things; sociability varies widely, and few people

are fully competent in all aspects of verbal and non-verbal communication. In the absence of any

genetic test for ASD, diagnosis is based on clinical judgement of when such problems extend

beyond the normal range. However, as yet, there is no definition of where the boundaries of the


21

“normal range” lie and it should be remembered that even when standardised instruments such as

the ADI-R or ADOS (both of which are becoming increasingly considered as the ‘gold standard’

instruments for assessment of ASD) are used, cut-off scores are determined by statistically

significant group differences. This is why, for reliable diagnosis, such assessments must be used in

conjunction with expert clinical judgement (Lord, 1995; Lord et al., 2006). Similarly, caution

should be taken when relying on clinical judgement alone without the use of standardised measures

to guide diagnosis. The nature of the ICD-10 and DSM-IV-TR diagnostic manuals is such that,

inevitably, diagnoses using these descriptive criteria alone are based on a subjective judgement only

and this may lead to problems of validity and with reliability, even between expert clinicians.

The diagnosis of ASD and identification of ASD symptomatology is particularly problematic in

individuals affected by genetic disorders in which social, communication and behavioural

difficulties are also present, and particularly in those syndromes associated with a severe to

profound degree of intellectual disability. As noted in Section I, it is extremely difficult to identify

ASD specific behaviours and impairments in individuals with such complex difficulties. Many of

the diagnostic criteria outlined in the DSM-IV-TR and ICD-10 manuals are heavily reliant upon the

individual reaching a certain level of development. Thus, individuals with a more severe degree of

intellectual impairment may appear to fulfil certain criteria for ASD purely because they have not

yet reached the developmental level required to demonstrate these behaviours. Moreover, recent

studies that have investigated the validity of assessments such as the ADOS and ADI-R in children

with intellectual disability have indicated poor to moderate agreement between the ADI-R and

clinical judgement and between the ADI-R and ADOS. There are also indications that sensitivity

and specificity of both the ADI-R and the ADOS are reduced in very young children and in

individuals with low developmental age (Chawarska et al., 2007; Gray et al., 2008; Ventola et al.,

2006). However, other studies have reported validity and reliability to be good in individuals with

severe intellectual disability (deBilt et al., 2004). It must also be recognised that standardised


22

assessments such as the ADI-R (Rutter et al., 2003) or ADOS (Lord et al., 2000), were not designed

to distinguish between neurodevelopmental conditions in which social-communication impairments

are common but complex and somewhat different in nature to those that are typical of idiopathic

autism; nor were they designed to be sensitive to often subtle differences between groups.

The importance of employing a detailed and fine grained analysis of the relationship between ASD

and other conditions is well illustrated in the examples of Fragile X and Rett syndromes (see section

I). Initial descriptions at a superficial behavioural level suggested a significant, even causal,

relationship with ASD. However, further systematic and standardised investigation of the specific

phenomenology of ASD characteristics within these groups revealed very different developmental,

behavioural and cognitive profiles to those found in individuals with idiopathic ASD. For example,

eye gaze avoidance in FXS and ASD was initially considered to be a shared characteristic in both

populations. However, it is now suggested that in FXS eye gaze avoidance occurs in response to

hypersensitivity to sensory stimuli, hyperarousal and social anxiety, while in ASD the same

behaviour is reported to result from a more general impairment in understanding social interaction

(Cornish et al., 2007; Cornish et al., 2008). These examples highlight the need for caution in

drawing conclusions about the relationship between ASD and a given syndrome group. The

complex and often unusual behavioural and cognitive patterns that are characteristic of many

genetic syndromes may result in individuals obtaining scores above the autism cut-off on a standard

assessment, even when the underlying mechanisms of these characteristics are different to those of

individuals with idiopathic ASD. It is therefore important that investigations of the association

between ASD and a genetic disorder be conducted meticulously, at both the

classification/diagnostic and behavioural level.

Implications for intervention in individuals with differential diagnosis


23

There is sometimes a tendency within clinical and educational settings to attribute all the

behaviours and difficulties shown by an individual, directly to the specific genetic syndrome from

which he/she suffers, rather than considering the possibility of other additional or differential

diagnoses. ‘Diagnostic overshadowing’ (Dykens, 2007; Reiss et al., 1982) of this kind can be a

particular problem in the case of rare genetic syndromes, with the result that other causes and, more

importantly, possible interventions may not be considered by parents or professionals.

For example, Jeremy2 was an 18 year-old with Cornelia de Lange syndrome (CdLS). In his teens he

became progressively more withdrawn and uncommunicative and was diagnosed as being

selectively mute. However, his eye contact had always been poor and since childhood he had a

keen preference for routine and engaged in various repetitive and stereotyped behaviours. The

possibility of ASD was not considered until he was 17 years old, despite his parents’ previous

requests for assessment. The move to college, where the emphasis was on flexibility and student

choice, rather than the structure and routine he needed, led to significant deterioration in his mood

and behaviour. The college were unwilling to modify their programme, insisting that Jeremy needed

to ‘learn to be more flexible and cope with the changes’. Jeremy became increasingly tearful and

withdrawn, stopped taking part in his usual daily activities and refused to go to college. Although he

has since received a formal diagnosis of ASD, Jeremy still remains at home, with no educational

provision. His outcome contrasts markedly with that of David, another 18 year-old with CdLS for

whom, following a period of regression in his late teens, the recognition that he showed many

characteristics of ASD, led to his being transferred to specialist autism provision, resulting in

significant improvements in his mood and behaviour.

Leber's congenital amaurosis is another condition that has been linked to ASD (Rogers & Newhart-

Lawson, 1989). Ivan was an 11 year-old boy with this disorder, attending a school for visually

2 Please note that each of the case studies reported here use individual cases that have been observed/assessed by the

authors in clinical or research settings, all cases are reported using pseudonyms.


24

impaired children. Although he had some very specific areas of skill, especially in music, he

showed no interest in other children, had very stereotyped and repetitive language and very fixed

routines. The headmaster did not agree with the possibility that he might have ASD and therefore

did not support his parents’ request for transfer to a specialist ASD unit. Ivan became increasingly

isolated, self-injurious behaviours increased, and his parents found it more and more difficult to

cope. He eventually required placement in a residential school.

In another case, Jake an eight year-old boy with Down syndrome, showed a typical ASD profile of

repetitive, non-communicative speech, poor eye contact, limited interaction with other people and a

host of repetitive and restricted interests. Although his parents had become increasingly concerned

about his lack of progress, school staff interpreted his behaviours as being ‘difficult’ or ‘naughty’

and again rejected the possibility of comorbid ASD. Over time, Jake’s behaviour became steadily

more disruptive and aggressive. Diagnostic assessment for ASD indicated that he met all the criteria

for this disorder and transfer to a specialist autism unit was recommended (see Howlin, Wing &

Gould 1995 for further examples).

Such vignettes illustrate how failure to recognise the possibility of ASD or the implications of ASD

symptomatology can have negative and long lasting effects. However, whilst clinically it is

important to recognise that individuals with a given genetic syndrome may have similar educational

and support needs to those with idiopathic autism (Rutter et al., 1994), there is a need to be cautious

about over-inclusive use of the term “autistic”. Mathew, for example, was a young man with

Williams Syndrome who, unusually for this condition, also had profound learning disabilities. His

limited communication skills, lack of sociability and highly stereotyped behaviours resulted in his

being given the additional diagnosis of ASD, despite the fact that these difficulties were explicable

in terms of his very low IQ. His parents, having read about various “cures” for ASD, believed that


25

enrolment in an intensive behavioural autism unit would solve all his difficulties, and were bitterly

disappointed when the unit would not accept him because of his severe intellectual impairment.

Whilst recognition of shared ASD characteristics may be extremely important for appropriate

behaviour management and school placement, we are not aware of any research to date that has

considered the suitability and effectiveness of ASD specific interventions for use in children and

adults with genetic syndromes who have a differential diagnosis of ASD or ASD related

characteristics. Children with genetic syndromes may not receive a differential diagnosis of ASD

until much later than individuals in the wider ASD population. Given the late diagnosis and

considering the complex behavioural, communication and intellectual impairments that are often

associated with genetic syndromes, adaptation to current autism specific interventions may be

required in order to be effective in such cases. Additionally, better dissemination of information to

professionals and care workers, regarding the association between ASD symptomatology and

genetically determined syndromes may be important for increasing recognition of these shared

characteristics. Future research to consider the effectiveness of various autism specific interventions

may be helpful in guiding appropriate management and educational placement of individuals with

genetic syndromes and ASD.

Implications for understanding the wider ASD population

Unsubstantiated claims that X % of children with condition Y have ASD, or conversely that X % of

children with ASD have condition Y, are not helpful for advancing research or clinical practice.

Many of the earlier claims about the association between Fragile X syndrome and ASD, for

example, were made in the absence of reliable genetic testing or standardised diagnostic

assessments. When standardised diagnostic and behavioural assessments of ASD began to be used,

a far weaker association was identified and studies have since identified specific differences that

may distinguish the two disorders (See Section I for details).


26

Rutter et al. (1994) made the point that in a number of conditions that are claimed to have a high

association with autism (e.g. Phenylketonuria, Rubella), the ASD profile tends to be atypical. The

fact that so many different syndromes are associated with communication and social deficits and

stereotyped behaviours raises the issue of how unique this ‘triad of impairments’ is to ASD.

Moreover, even those individuals who clearly fall within the ‘broader’ autism spectrum and show a

number of ASD related characteristics, do not always demonstrate the full triad of impairments

(Charman & Swettenham, 2001). The fact that the phenomenology of ASD appears to differ, not

only across genetic syndromes but also between individuals with an ASD diagnosis, has particular

implications for the debate concerning the boundaries of the autism spectrum.

The apparent heterogeneity of autism spectrum phenomenology across different syndrome groups is

also relevant at the level of aetiology. Traditionally, it has been considered that the three core

characteristics of ASD share a single underlying aetiological pathway (Morton & Frith, 1994).

However, there is now some evidence that the components of the triad are in fact, fractionated at the

level of aetiology. Thus, the different domains have different developmental trajectories (Charman

et al., 2005; Charman & Swettenham, 2001). Repetitive behaviours, in particular, may become

evident later than social and communication impairments; they are also less likely to improve over

time (Charman et al., 2005; Fécteau et al., 2003; Piven et al., 1996). Genetic studies of the general

population (Ronald et al., 2006) also suggest that the three domains are only moderately associated

with one another and that there may be different aetiological explanations underlying each domain.

This observed divergence at the aetiological level might account for the different types of profiles

observed across genetic syndromes, particularly in conditions where one or two components of the

triad of impairments are more evident than others.

Summary of diagnostic considerations and implications for intervention and conceptual and

theoretical frameworks.


27

There is sometimes a tendency, when working with individuals with genetic syndromes, to attribute

all behavioural and emotional difficulties to the presence of the syndrome itself, rather than to

consider that there may be shared characteristics with other disorders and that in many cases a co-

morbid diagnosis might be appropriate. As indicated in the vignettes described above, recognition

of shared features between specific genetic syndromes and ASD may be crucial in ensuring that

individuals receive appropriate and effective behaviour management and educational placement.

However, it is also important to apply the differential diagnosis of ASD appropriately and

cautiously. The review of ASD and associated characteristics in the specific syndrome groups

outlined above highlights the importance of conducting fine-grained assessment of ASD in these

syndromes. Subtle differences in the quality and nature of specific ASD-like impairments may only

be revealed when conducting detailed analyses of behavioural characteristics, and may be masked at

the broader level of clinical or algorithm based diagnoses. Recognition of atypicalities in the profile

and phenomenology of ASD in genetic syndromes may be crucial for developing appropriate,

individually tailored, interventions. Continued research in this area is also important in further

understanding the aetiology or underlying mechanisms and network structures involved in

idiopathic ASD and in further unravelling the structure of the triad of impairments.


28

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44

Table 1: 8umber of articles identified via literature search.

Syndrome

Dates of studies

8umber of articles with different samples

Fragile X 1982-2006 95

Tuberous Sclerosis 1979-2006 32

Rett 1985-2006 31

Down 1979-2006 16

Phenylketonuria 1969-2003 9

CHARGE 1998-2006 7

Angelman 1996-2004 6

Neurofibromatosis 1998-2007 4

Joubert 1991-2005 4

Williams 1985-2006 2

Goldenhar 1992-2002 2

Hypomelanosis of Ito 1991-2002 2

Noonan 1983-1994 2

Sotos 1990-2001 2

VCF 1998-2006 2

Leber’s amaurosis 1989-2007 2

Cohen syndrome 2001-2005 1

CdLS 2006 1

Ehlers-Danlos 1992 1

Lujan-Fryns 2005 1

Moebius 1989 1

ASD

in

gen

etic

syn

dro

mes

4

5

Ta

ble

2:

Pre

vale

nce

stu

die

s of

AS

D i

n F

ragil

e X

Sy

nd

rom

e.

Au

thor

8 P

art

icip

an

ts w

ith

FX

S

Au

tism

Dia

gn

ost

ic

Ass

ess

men

t/C

rite

ria

8 (

%)

meet

ing a

uti

sm/A

SD

cri

teri

a

Levit

as e

t al.

,

19

83

10

mal

es

DS

M-I

II1

6 (

60%

)

Bro

wn e

t al.

,

19

86

15

0 m

ales

D

SM

-III

1

26

(17%

)

Hag

erm

an e

t

al.

, 1

986

50

mal

es

DS

M-I

II1

AB

C2

16

(32%

); 1

5 (

30%

) ad

dit

ion

al p

arti

cipan

ts m

et

crit

eria

in e

arly

ch

ild

hood b

ut

not

on c

urr

ent

beh

avio

ur.

15

(31%

) m

et A

BC

cri

teri

a; ‘

Au

tist

ic t

rait

s’

iden

tifi

ed i

n a

lmost

all

cas

es.

Rei

ss &

Fre

und,

19

90

17

mal

es

DS

M-I

II-R

1

3 (

18%

); 3

add

itio

nal

cas

es m

et c

rite

ria

in e

arly

chil

dh

oo

d;

7

(41%

) m

et P

DD

-NO

S c

rite

ria

Coh

en e

t a

l.,

19

91

13

mult

iple

x

fam

ilie

s (t

ota

l N

= 3

5)

DS

M-I

II1

11

(31%

); 3

of

7 p

rob

and

s (4

3%

); 4

of

28 (

15%

)

rem

ainin

g m

ales

in f

amil

y m

et c

urr

ent

crit

eria

.

Ker

by &

Daw

son,

19

94

9 m

ales

9 I

D c

ontr

ols

DS

M-I

II-R

1

FX

S s

ign

ific

antl

y >

auti

stic

ch

arac

teri

stic

s th

an

con

tro

ls w

ith I

D.

Turk

&

Gra

ham

, 1

997

49

mal

es

45

Do

wn

Syn

dro

me

mal

es (

DS

)

42

mal

es w

ith ‘

idio

pat

hic

HB

S3;

DS

M-I

II-R

1

14

(29%

) F

XS

5 D

S (

11%

)

18

ID

(43

%)

ASD

in

gen

etic

syn

dro

mes

4

6

inte

llec

tual

dis

abil

ity’

(ID

).

Maz

zocc

o e

t

al.

, 1

997

30

fem

ales

31

age/

IQ

mat

ched

co

ntr

ols

.

ND

I4;

DS

M-I

II-R

1

1(3

%)

FX

S

1 (

3%

) co

ntr

ol

5 (

17%

) F

XS

vs

2 (

6%

) c

on

trols

met

PD

D

crit

eria

FX

S >

auti

stic

ch

arac

teri

stic

s th

an c

ontr

ols

on

ND

I.

Bai

ley e

t a

l.,

20

01

55

mal

es

CA

RS

5

14

(25%

) au

tist

ic b

ehav

iou

r’;

12 (

22%

) ‘m

ild

ly-

mod

erat

ely a

uti

stic

’; 1

(2%

) ‘s

ever

ely a

uti

stic

’

Dem

ark e

t a

l.,

20

03

15

mal

es

21

ch

ildre

n w

ith P

DD

CA

RS

5

6 (

40%

) F

XS

vs.

8 (

38%

) P

DD

‘m

ildly

-

mod

erat

ely a

uti

stic

’;

1 (

7%

) F

XS

vs.

11 (

52%

) P

DD

‘se

ver

ely

auti

stic

’

Sab

arat

nam

et

al.

, 2

003

18

mal

es

DS

M-I

II-R

1

Non

e

Kau

et

al.

,

20

04

55

m

ales

22

mal

es w

ith d

evel

op

men

tal

lan

gu

age

del

ay (

DL

D).

AD

I-R

6

DS

M-I

V1

14

(26%

) F

XS

vs.

7 (

32%

) D

LD

met

auti

sm

crit

eria

18

(33%

) F

XS

vs.

3 (

14%

)DL

D m

et P

DD

cri

teri

a

Hat

ton e

t al.

20

06

14

2 m

ales

&

32

fem

ales

CA

RS

5

38

(21%

; 3

6M

, 2 F

)

1 D

iagn

ost

ic a

nd

Sta

tist

ical

Man

ual

(A

mer

ican

Psy

chia

tric

Ass

oci

atio

n;

19

87

, 19

94).

2

Auti

sm B

ehav

ior

Ch

eckli

st (

Kru

g e

t al.

, 1

98

0)

3 T

he

Sch

edu

le o

f H

andic

aps,

Beh

avio

ur

and S

kil

ls (

HB

S;

Win

g,

19

80)

4 N

euro

psy

chia

tric

Dev

elo

pm

enta

l In

terv

iew

(R

eiss

& F

reu

nd,

199

0)

5 C

hil

dho

od A

uti

sm R

atin

g S

cale

(S

cho

ple

r et

al.

, 19

88

)

ASD

in

gen

etic

syn

dro

mes

4

7

Tab

le 3

: P

rev

ale

nce

of

AS

D i

n R

ett

Sy

nd

rom

e

Au

thor

8 G

irls

wit

h R

S

Au

tism

Dia

gn

ost

ic

Ass

ess

men

t/C

rite

ria

8(%

) m

eet

ing a

uti

sm/A

SD

cri

teri

a

Wit

t-E

nger

stro

m &

Gil

lber

g,

198

7

47

D

SM

-III

1

18

(38%

) au

tism

dia

gn

osi

s &

19 (

40%

) au

tist

ic-l

ike

beh

avio

urs

rep

ort

ed p

rior

to d

iagn

osi

s of

RS

.

Nai

du e

t al.

19

90

22

A

BC

2

No

ne

Zap

pel

la e

t al.

, 19

98

30

(w

ith p

rese

rved

spee

ch

var

iant

)

DS

M-I

V1

29

(97%

)

San

db

erg e

t a

l.,

20

00

8

DS

M-I

V1

2 (

25%

)

Mo

unt

et a

l.,

20

03

b

15

14

gir

ls w

ith

sever

e/pro

fou

nd I

D

AB

C2

6 (

40%

) R

S v

s. 1

(7

%)

ID s

core

d a

bo

ve

auti

sm c

ut-

off

1 D

iagn

ost

ic a

nd

Sta

tist

ical

Man

ual

(A

mer

ican

Psy

chia

tric

Ass

oci

atio

n;

19

87

, 19

94).

2

Auti

sm B

ehav

ior

Ch

eckli

st (

Kru

g e

t al.

, 1

98

0)

ASD

in

gen

etic

syn

dro

mes

4

8

Ta

ble

4:

Prev

ale

nce

of

AS

D i

n T

ub

ero

us

Scl

ero

sis

Co

mp

lex

Au

thor

8 P

art

icip

an

ts w

ith

TS

C

Au

tism

Dia

gn

ost

ic

Ass

ess

men

t/C

rite

ria

8/%

meeti

ng a

uti

sm/A

SD

cri

teri

a

Sm

alle

y e

t a

l. (

19

92)

13

14

co

ntr

ols

wit

h a

uti

sm

AD

I3

ICD

-10

4

7 (

54%

)

Gil

lber

g e

t a

l., 1

99

4

28

C

AR

S5;

DS

M-I

II-R

1

17

(6

1%

)

Hu

nt

& S

hep

her

d

(19

95)

21

D

SM

-III

-R 1

5

(24%

) m

et a

uti

sm c

rite

ria;

9 (

43

%)

met

PD

D c

rite

ria.

Wil

liam

son &

Bolt

on,

19

95

2

sibli

ngs

wit

h T

SC

A

DI

1

:

atypic

al a

uti

sm

1:

no s

ign

s o

f au

tism

.

Web

b e

t al.

, 199

6

13

1

ICD

-10

4

6

(5%

)

Bolt

on &

Gri

ffit

hs

19

97*

18

IC

D-1

04

9 (

50%

; tw

o w

ith I

Q ≥

70)

Bak

er e

t al.

, 199

8

20

AB

C2

AD

I3

DS

M-I

V1

12

(6

0%

) ab

ove

cut-

off

on A

BC

.

8 o

f 9 p

arti

cipan

ts (

89%

) as

sess

ed o

n A

DI

met

auti

sm c

rite

ria,

4 a

lso m

et D

SM

-IV

au

tism

cri

teri

a. (

All

had

IQ

wit

hin

/ab

ove

mil

d I

D r

ange)

Gu

tier

rez

et a

l.,

19

98

28

A

DI3

AD

OS

6

8 (

29%

) m

et a

uti

sm c

rite

ria;

12 (

43

%)

met

PD

D c

rite

ria.

Par

k &

Bo

lto

n,

20

01

*

43

AD

OS

6

AD

I-R

3

ICD

-10

4

14

of

34 f

or

wh

om

a c

on

fiden

t dia

gno

sis

poss

ible

(41%

) m

et

PD

D c

rite

ria;

PD

D s

ub

gro

up

had

sig

nif

ican

tly l

ow

er I

Q

sco

res

than

non

-PD

D g

roup.

ASD

in

gen

etic

syn

dro

mes

4

9

Bolt

on e

t al.

, 2

00

2*

53

A

DO

S6

AD

I-R

3

ICD

-10

4

19

(3

6%

; 14 a

uti

sm,

4 a

typ

ical

auti

sm a

nd 1

PD

DN

OS

)

Hu

mp

hre

y e

t al.

, 2

006

1

A

DO

S

Met

auti

sm c

rite

ria

at 2

4 m

onth

s af

ter

per

iod o

f re

gre

ssio

n

and o

nse

t o

f se

izu

re d

iso

rder

.

* S

tud

y p

arti

cip

ants

over

lap

ped

acro

ss t

hes

e st

udie

s.

1

Dia

gn

ost

ic a

nd

Sta

tist

ical

Man

ual

(A

PA

; 1

987

, 199

4).

2

Auti

sm B

ehav

ior

Ch

eckli

st (

Kru

g e

t al.

, 1

98

0)

3 A

uti

sm D

iagn

ost

ic I

nte

rvie

w (

Lo

rd e

t al.

, 1

994

; R

utt

er e

t al.

, 2

003

) 4

Inte

rnat

ional

Cla

ssif

icat

ion o

f D

isea

ses

(WH

O,

199

0)

5 C

hil

dho

od A

uti

sm R

atin

g S

cale

(S

cho

ple

r et

al.

, 19

88

) 6

Auti

sm D

iagn

ost

ic O

bse

rvat

ion

Sch

edule

(L

ord

et

al.

, 200

0)

ASD

in

gen

etic

syn

dro

mes

5

0

Ta

ble

5:

Stu

die

s o

f A

SD

in

Dow

n S

yn

dro

me

Au

thor

8 P

art

icip

an

ts w

ith

D

S

Au

tism

Dia

gn

ost

ic

Ass

ess

men

t/C

rite

ria

8/%

meeti

ng a

uti

sm/A

SD

crit

eri

a

Gil

lber

g e

t a

l., 1

98

6

20

D

SM

-III

1

1 (

5%

)

Lu

nd

19

88

4

4

HB

S8

5 (

11%

)

Gh

aziu

dd

in e

t al.

,

19

92

40

D

SM

-III

-R1;

AB

C2

Est

imat

ed 4

-5%

Turk

& G

raham

, 1

99

7

45

mal

es

42

mal

es w

ith ‘

idio

pat

hic

ID’.

49

FX

S m

ales

HB

S8;

DS

M-I

II-R

1

5 D

S (

11%

)

14

FX

S (

29%

)

18

ID

(4

3%

)

Ken

t et

al.

, 1

99

9

58

(o

nly

33

co

mp

lete

d a

ll

mea

sure

s)

AS

SQ

7

CA

RS

5

ICD

-10

4

3 (

7%

) m

et c

rite

ria

for

atyp

ical

auti

sm.

1(2

%)

met

auti

sm c

rite

ria

Sta

rr e

t a

l.,

200

5

13

(a

ll I

Q <

50)

PL

-AD

OS

6

AD

I-R

3

5 (

39%

)

Cap

on

e et

al.

, 2

005

4

71 c

linic

ref

erra

ls

DS

M-I

V1

87

(19%

; m

et c

rite

ria

for

an

‘au

tist

ic-l

ike

con

dit

ion’

61

(13%

) m

et A

SD

cri

teri

a; 4

1 (

9%

) fo

r

auti

sm

Lo

wen

thal

et

al.

, 2

007

1

80

AS

Q9

28

(15.6

%)

PD

D,

of

thes

e 10

(5.5

8%

) h

ad

auti

sm a

nd 1

8 (

10.0

5%

) had

PD

D-N

OS

ASD

in

gen

etic

syn

dro

mes

5

1

*S

tud

ies

rep

ort

ed i

n t

his

an

d t

he

foll

ow

ing

tab

les

are

th

ose

th

at

ha

ve e

mp

loye

d s

tan

da

rdis

ed a

sses

smen

t a

nd

dia

gn

ost

ic c

rite

ria

of

au

tism

. C

ase

stu

die

s a

nd

oth

er d

escr

ipti

on

s o

f

au

tist

ic l

ike

beh

avi

ou

r an

d t

ho

se t

ha

t h

ave

no

t em

plo

yed

su

ch m

easu

res

an

d c

rite

ria

are

rep

ort

ed i

n t

he

text

1

Dia

gn

ost

ic a

nd

Sta

tist

ical

Man

ual

(A

PA

, 1

98

7, 1

994

).

2 A

uti

sm B

ehav

ior

Ch

eckli

st (

Kru

g e

t al.

, 1

98

0)

3 A

uti

sm D

iagn

ost

ic I

nte

rvie

w (

Lo

rd,

et a

l., 1

994;

Ru

tter

, et

al.

, 2

00

3)

4 In

tern

atio

nal

Cla

ssif

icat

ion o

f D

isea

ses

(WH

O,

199

0)

5 C

hil

dho

od A

uti

sm R

atin

g S

cale

(S

cho

ple

r et

al.

, 19

88

) 6

P

reli

ngu

isti

c A

uti

sm D

iagnost

ic O

bse

rvat

ion

Sch

edule

(D

iLavo

re e

t a

l.,1

995

) 7

Asp

erger

’s S

ynd

rom

e S

cree

nin

g Q

ues

tion

nai

re (

Eh

lers

& G

illb

erg,

199

3)

8 T

he

Sch

edu

le o

f H

andic

aps,

Beh

avio

ur

and

Skil

ls (

HB

S;

Win

g,

19

80)

9 T

he

Auti

sm S

cree

nin

g Q

ues

tionn

aire

(B

erum

ent

et a

l., 1

999

)

Tab

le 6

: S

tud

ies

of

AS

D i

n C

HA

RG

E S

yn

dro

me

Au

thor

8 P

art

icip

an

ts w

ith

CH

AR

GE

Au

tism

Dia

gn

ost

ic

Ass

ess

men

t/C

rite

ria

8(%

) m

eet

ing a

uti

sm/A

SD

cri

teri

a

Sm

ith e

t al.

, 20

05

1

3

SC

Q4

2 (

15 %

) a

uti

sm

3 (

23%

) A

SD

Har

tsh

orn

e et

al.

,

20

06

160

AB

C2

44

(28%

)

Joh

anss

on e

t al.

,

20

06

18

AB

C2

AD

I-R

3

DS

M-I

V1

9 (

50%

)

1 D

iagn

ost

ic a

nd

Sta

tist

ical

Man

ual

(A

PA

, 1

98

7;

199

4).

2

Auti

sm B

ehav

ior

Ch

eckli

st (

Kru

gg e

t a

l.,

19

80)

3 A

uti

sm D

iagn

ost

ic I

nte

rvie

w (

Lo

rd e

t al.

, 1

994

; R

utt

er e

t al.

, 2

003

) 4

So

cial

Com

mu

nic

atio

n Q

ues

tion

nai

re (

Rutt

er e

t a

l.,

20

03

)

ASD

in

gen

etic

syn

dro

mes

5

2

Ta

ble

7:

Stu

die

s o

f A

SD

in

An

gel

ma

n S

yn

dro

me

Au

thor

8 P

art

icip

an

ts w

ith

AS

Au

tism

Dia

gn

ost

ic

Ass

ess

men

t/C

rite

ria

8(%

) m

eet

ing a

uti

sm/A

SD

cri

teri

a

Tri

llin

gsg

aard

and

Ost

ergaa

rd,

200

4

16

AD

OS

1

10

(63%

) a

uti

sm

13

(81%

) A

SD

(in

clusi

ve

of

tho

se m

eeti

ng a

uti

sm c

ut-

off

)

Pet

ers

et a

l.,

20

04

1

9

AD

OS

1

DS

M-I

V2

8 (

50%

)

1 A

uti

sm D

iagn

ost

ic O

bse

rvat

ion

Sch

edule

(L

ord

et

al.

, 200

0)

2 D

iagn

ost

ic a

nd

Sta

tist

ical

Man

ual

(A

PA

, 1

99

8;

199

4).

ASD

in

gen

etic

syn

dro

mes

5

3

Ta

ble

8:

Su

mm

ary

of

pre

va

len

ce f

igu

res

an

d a

sso

cia

ted

deg

ree

of

inte

llec

tua

l d

isa

bil

ity

wit

hin

sy

nd

rom

e g

rou

ps.

Gen

etic

Sy

nd

rom

e

Ass

oci

ate

d D

egre

e o

f

Inte

llect

ual

Dis

ab

ilit

y

Est

ima

ted

Pre

va

len

ce

of

AS

D

FX

S

Mo

der

ate

to s

ever

e 21

-50%

RS

S

ever

e to

pro

fou

nd

25

-40%

(cl

assi

c), 9

7%

(mil

d)

TS

C

Norm

al t

o p

rofo

und

15

-89%

; 17

% (

no

rmal

IQ

)

DS

M

oder

ate

to s

ever

e 5-3

9%

PK

U

Norm

al t

o s

ever

e 5%

CH

AR

GE

N

orm

al t

o s

ever

e 15

-50%

AS

S

ever

e to

pro

fou

nd

50

-80%


54

Acknowledgements

The authors would like to thank Professor James Harris for his insightful comments and ideas

regarding the association between ASD and genetic syndromes which stimulated the author’s

conceptualisation and review of this area of study.

the assessment and presentation of autism spectrum ... · asd in genetic syndromes 1 the assessment...

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