AUTISM SPECTRUM DISORDERS：THE ROLE OF GENETICS IN DIAGNOSIS AND TREATMENT（Edited by Stephen I. Deutsch and Maria R. Urbano）

Part 1 Early Recognition and Diagnosis Chapter 1 Early Detection of Autism Spectrum Disorders Part 2 Nosology and Diagnostic Criteria: Chapter 2 Pervasive Developmental Disorder- not Otherwise Specified: Specifying and Differentiating Koray Karabekiroglu Chapter 3 Autism and Genetic Syndromes Willem Verhoeven, Jos Egger and Ilse Feenstra Part 3 Genetics and Pathophysiology of Autism Spectrum Disorders Chapter 4 The Genetics of Autism Spectrum Disorders Chapter 5 Genetic Heterogeneity of Autism Spectrum Disorders Catherine Croft Swanwick, Chapter 6 The Genetic Basis of Phenotypic Diversity: Autism as an Extreme Chapter 7 A New Genetic Mechanism for Autism Chapter 8 Common Genetic Etiologies and Biological Pathways Shared Between Autism Spectrum Disorders and Intellectual Disabilities Part 4 Treatment and Genetic Counseling Chapter 9 Microgenetic Approach to Therapy of Girls with ASD Chapter 10 Genetic Counseling in Autistic Phenotypes

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Preface The broadening of the definitional criteria of autism spectrum disorders(ASDs)and increased recognition of these syndromes have led to dramatic increases in their es- timated prevalence; prevalence estimates of ASDs in the USa are approximately 1 in 110 children with a three to four time greater male to female predominance. These disorders occur commonly as co-morbid conditions in several Mendelian genetic disorders due to the effects of a single major gene(e. g, tuberous sclerosis). Im- portantly, although these Mendelian disorders appear to be unrelated to each other, recent advances in bioinformatics and"network analyses"suggest that they may in deed be related to each other; the points of convergence can include development and architecture of the synapse, and early developmental events in neurogenesis, neuronal cell migration and synaptogenesis. Additionally, areas along the human genome are emerging as"hotspots"for microdeletions and microduplications, re- ferred to as Copy Number Variants(CNVs); the density of these CNVs may contrib- ute to increased risk of neurodevelopmental syndromes, including ASDs Remarka- bly, although the 1970s was focused on elucidating descriptive differences between ASDs and schizophrenia presenting in childhood; the emerging data on CNVs sug- gest that ASDs and schizophrenia, or at least their genetic mechanisms, may be more similar than initially appreciated. In any event, the genetic data are also suggesting molecular targets; for example, microdeletions at the 15q133 locus suggest that hap- insufficiency of a gene product of this locus (i.e., CHRNAZ, which codes for the a7 nicotinic acetylcholine receptor(a7 nAChR) subunit, may be causally associated with ASDs. Thus, selective nicotinic acetylcholine receptor agonist strategies should be explored for their potential therapeutic benefit. The high prevalence of these dis- orders, their impact on the identified affected patient and the unrecognized unaf fected family members(including sibs, accessibility of Array Comparative Genomic Hybridization screening technologies, elucidation of associations with candidate susceptibility genes, along with CNVs and complex genetics are raising profound ethical questions, heightening the challenges of genetic counseling. The staggering alleges of genetic cour (i.e, homologous maternal and paternal chromosomes may have different patterns of cytosine methylations and certain genetic disorders differ depending on genetic variations within one of the affected parer ntal chromosomes [e. g, Angelman and

Preface The broadening of the definitional criteria of autism spectrum disorders (ASDs) and increased recognition of these syndromes have led to dramatic increases in their estimated prevalence; prevalence estimates of ASDs in the USA are approximately 1 in 110 children with a three to four time greater male to female predominance. These disorders occur commonly as co-morbid conditions in several Mendelian genetic disorders due to the effects of a single major gene (e.g., tuberous sclerosis). Importantly, although these Mendelian disorders appear to be unrelated to each other, recent advances in bioinformatics and “network analyses” suggest that they may indeed be related to each other; the points of convergence can include development and architecture of the synapse, and early developmental events in neurogenesis, neuronal cell migration and synaptogenesis. Additionally, areas along the human genome are emerging as “hotspots” for microdeletions and microduplications, referred to as Copy Number Variants (CNVs); the density of these CNVs may contribute to increased risk of neurodevelopmental syndromes, including ASDs. Remarkably, although the 1970’s was focused on elucidating descriptive differences between ASDs and schizophrenia presenting in childhood; the emerging data on CNVs suggest that ASDs and schizophrenia, or at least their genetic mechanisms, may be more similar than initially appreciated. In any event, the genetic data are also suggesting molecular targets; for example, microdeletions at the 15q13.3 locus suggest that haploinsufficiency of a gene product of this locus (i.e., CHRNA7), which codes for the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit, may be causally associated with ASDs. Thus, selective nicotinic acetylcholine receptor agonist strategies should be explored for their potential therapeutic benefit. The high prevalence of these disorders, their impact on the identified affected patient and the unrecognized unaffected family members (including sibs), accessibility of Array Comparative Genomic Hybridization screening technologies, elucidation of associations with candidate susceptibility genes, along with CNVs and complex genetics are raising profound ethical questions, heightening the challenges of genetic counseling. The staggering challenges of genetic counseling are further compounded by issues of imprinting (i.e., homologous maternal and paternal chromosomes may have different patterns of cytosine methylations and certain genetic disorders differ depending on genetic variations within one of the affected parental chromosomes [e.g., Angelman and

Early Detection of Autism Spectrum Disorders Jariya Chuthapisith and Nichara Ruangdaraganon Department of Paediatrics, Faculty of medicine Ramathibodi Hospital Mahidol university, Bangkok Thailand 1 Introduction Autism spectrum disorders(ASDs) are neurodevelopmental disorders characterized by distinctive language impairments, social and communicative deficits, and patterns of restricted and stereotyped behavior. In the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision(DSM-IV-TR)(American Psychiatric Association, 2000), pervasive developmental disorders(PDDs)are also referred to as autistic disorder (AD), Aspergers disorder, PDD not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett Disorder. However, the diagnostic boundaries between these PDD subtypes remain unclear, the symptoms and behaviours lie on a continuum and have considerable clinical heterogeneity(Szatmari, 1999). In this review, therefore, ASDs are referred to as the diagnostic category of PDDs 2. Diagnosis of ASD The manifestations of ASDs vary from mild to severe and pervasive impairment. Currently the diagnosis of ASDs is based on the criteria developed in the DSM-IV-TR and the ternational Classification of Diseases, 10th revision(ICD-10)(World Health Organization (WHO), 1992) and is supported by standardized diagnostic instruments. According to the DSM-IV-TR criteria, the impairments of ASDs consist of three main impairments which must all be presented for diagnosis 2.1 Impairment in social interaction is defined by various symptoms including impairment in the use of nonverbal behaviours(e.g. eye contact, use of gestures and facial expressions) lack of showing, bringing or pointing out objects; odd relationships of approaches to others; and lack of social or emotional reciprocity 2.2 Impairments in communication consist of delay in or total lack of spoken language, inability to initiate or sustain a conversation with others, stereotyped or repetitive use of language, and lack of social imitative play. 2.3 Restricted repetitive and stereotyped patterns are behaviours, interests and activities as manifested by an inability to cope with change, a dislike for any interruption to routine, preoccupation with specific subjects or activities, repetitive or stereotyped motor mannerisms such as hand flapping or twisting, and persistent preoccupation with parts of objects Early diagnosis for ASDs is undoubtedly important and is considered as a clinical best practice. Early detection of ASDs leads to an early intervention(Rutter et al., 2006)

1 Early Detection of Autism Spectrum Disorders Jariya Chuthapisith and Nichara Ruangdaraganon Department of Paediatrics, Faculty of Medicine Ramathibodi Hospital Mahidol University, Bangkok Thailand 1. Introduction Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by distinctive language impairments, social and communicative deficits, and patterns of restricted and stereotyped behavior. In the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) (American Psychiatric Association, 2000), pervasive developmental disorders (PDDs) are also referred to as autistic disorder (AD), Asperger’s disorder, PDD not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett Disorder. However, the diagnostic boundaries between these PDD subtypes remain unclear, the symptoms and behaviours lie on a continuum and have considerable clinical heterogeneity (Szatmari, 1999). In this review, therefore, ASDs are referred to as the diagnostic category of PDDs. 2. Diagnosis of ASDs The manifestations of ASDs vary from mild to severe and pervasive impairment. Currently, the diagnosis of ASDs is based on the criteria developed in the DSM-IV-TR and the International Classification of Diseases, 10th revision (ICD-10) (World Health Organization (WHO), 1992) and is supported by standardized diagnostic instruments. According to the DSM-IV-TR criteria, the impairments of ASDs consist of three main impairments which must all be presented for diagnosis. 2.1 Impairment in social interaction is defined by various symptoms including impairment in the use of nonverbal behaviours (e.g. eye contact, use of gestures and facial expressions); lack of showing, bringing or pointing out objects; odd relationships of approaches to others; and lack of social or emotional reciprocity. 2.2 Impairments in communication consist of delay in or total lack of spoken language, inability to initiate or sustain a conversation with others, stereotyped or repetitive use of language, and lack of social imitative play. 2.3 Restricted repetitive and stereotyped patterns are behaviours, interests and activities as manifested by an inability to cope with change, a dislike for any interruption to routine, preoccupation with specific subjects or activities, repetitive or stereotyped motor mannerisms such as hand flapping or twisting, and persistent preoccupation with parts of objects. Early diagnosis for ASDs is undoubtedly important and is considered as a clinical best practice. Early detection of ASDs leads to an early intervention (Rutter et al., 2006)

Autism Spectrum Disorders: The Role of Genetics in Diagnosis and Treatment However, diagnosis before the age of 3 years remains a challenge(Baron-Cohen et al., 1996) Some symptoms of ASDs may overlap with normal developmental variance. Also, ASDs are a continuum of disease which has a wide range of individual differences. Distinctions between autistic disorder and PDD-NOS remain unstable. a study reported that up to 50% of PDD-NOS cases, who were diagnosed before age 3 years, could have been overdiagnosed, whereas around 22% were underdiagnosed( Chawarska et al, 2007). This was due to the fact that diagnosis depends on clinical judgments which sometimes may not agree with the DSM-IV-tR diagnostic criteria especially evaluating a young child. Some of the criteria in the DSM-IV-TR can not apply to young children. In other words, many of the characteristic behaviours in the DSM-IV-TR are not apparent before 36 months. For example, a child age less than 16-month-old typically can engage in parallel play but has not yet developed reciprocal peer relationships. Thus, the criteria of failure to develop age- appropriate peer relationships need to be adapted(Martinez-Pedraza &z Carter, 2009). The criteria of stereotyped and repetitive use of language can be difficult to discriminate between repetitions of the last word in young typically developing children and echolalia in children with ASDs. Furthermore, the criteria"restricted repetitive and stereotyped patterns of behaviour, interests and activities"may not appear in young children. These may appear later after the third birthday in some cases (gray Tonge, 2001; Turner, 1999). Therefore, making a diagnosis in children younger than 2 years of age is very challenging 3. Early signs of ASDs Many research studies have concluded that the first signs and symptoms of ASDs are evident by 12 to 18 months of age(De giacomo &z Fombonne, 1998; Young et Research on early signs and symptoms of ASDs in young children have focused on p retrospective reports, early home videos of children later diagnosed with ASDs, and on siblings of children with ASDs. The emergence of ASDs signs and symptoms involve the area of social skill deficits, language skill deficits and unusual repetitive or stereotypical behavioural patterns. Signs and symptoms that are predictive of ASDs in young children are, name 3.1 Social skills deficits Social skills are one of the most important areas in defining ASDs in very young children. In typically developing children, social development is acquired parallel to overall levelopment(e.g. language, motor and cognitive development). In the very young children whose language skills are limited, social development depends very much on clinical observations. The manifestation is a lack of or a decreased drive to connect with others including share feelings, thoughts and actions. Children who have ASDs have limited or reduced eye contact, fail to orient their name being called, limited imitation, limited responding to reciprocal social games, and lack of showing or bringing an object to a caregiver. The important characteristic in helping make a diagnosis in very young children is lack of joint attention"(A)(Charman, 2003; Dawson et al., 2002 Turner et al., 2006). JA refers to the capacity of the child to coordinate attention with a social partner in relation to an object or event(Rapin tuchman, 2008 ). JA normally appears to develop between 8-16 months. In 8-10 months old typically developing children, the child will follow the caregivers gaze

4 Autism Spectrum Disorders: The Role of Genetics in Diagnosis and Treatment However, diagnosis before the age of 3 years remains a challenge (Baron-Cohen et al., 1996). Some symptoms of ASDs may overlap with normal developmental variance. Also, ASDs are a continuum of disease which has a wide range of individual differences. Distinctions between autistic disorder and PDD-NOS remain unstable. A study reported that up to 50% of PDD-NOS cases, who were diagnosed before age 3 years, could have been overdiagnosed, whereas around 22% were underdiagnosed (Chawarska et al., 2007). This was due to the fact that diagnosis depends on clinical judgments which sometimes may not agree with the DSM-IV-TR diagnostic criteria especially evaluating a young child. Some of the criteria in the DSM-IV-TR can not apply to young children. In other words, many of the characteristic behaviours in the DSM-IV-TR are not apparent before 36 months. For example, a child age less than 16-month-old typically can engage in parallel play but has not yet developed reciprocal peer relationships. Thus, the criteria of failure to develop ageappropriate peer relationships need to be adapted (Martinez-Pedraza & Carter, 2009). The criteria of stereotyped and repetitive use of language can be difficult to discriminate between repetitions of the last word in young typically developing children and echolalia in children with ASDs. Furthermore, the criteria “restricted repetitive and stereotyped patterns of behaviour, interests and activities” may not appear in young children. These may appear later after the third birthday in some cases (Gray & Tonge, 2001; Turner, 1999). Therefore, making a diagnosis in children younger than 2 years of age is very challenging. 3. Early signs of ASDs Many research studies have concluded that the first signs and symptoms of ASDs are evident by 12 to 18 months of age (De Giacomo & Fombonne, 1998; Young et al., 2003). Research on early signs and symptoms of ASDs in young children have focused on parental retrospective reports, early home videos of children later diagnosed with ASDs, and studies on siblings of children with ASDs. The emergence of ASDs signs and symptoms involve the area of social skill deficits, language skill deficits and unusual repetitive or stereotypical behavioural patterns. Signs and symptoms that are predictive of ASDs in young children are, namely: 3.1 Social skills deficits Social skills are one of the most important areas in defining ASDs in very young children. In typically developing children, social development is acquired parallel to overall development (e.g. language, motor and cognitive development). In the very young children whose language skills are limited, social development depends very much on clinical observations. The manifestation is a lack of or a decreased drive to connect with others, including share feelings, thoughts and actions. Children who have ASDs have limited or reduced eye contact, fail to orient their name being called, limited imitation, limited responding to reciprocal social games, and lack of showing or bringing an object to a caregiver. The important characteristic in helping make a diagnosis in very young children is lack of “joint attention” (JA) (Charman, 2003; Dawson et al., 2002; Turner et al., 2006). JA refers to the capacity of the child to coordinate attention with a social partner in relation to an object or event (Rapin & Tuchman, 2008). JA normally appears to develop between 8-16 months. In 8-10 months old typically developing children, the child will follow the caregiver’s gaze

Early Detection of Autism Spectrum Disorders when the caregiver looks at an object or event. This development milestone is called"gaze monitoring". Around 10-12 months of age the child can follow the caregivers point and can look back at the caregiver. At approximately 12-14 months the child will request for objects by pointing In detail, the child will look back and forth between the object and caregiver to reassure that the caregiver understands his or her need, so called protoimperative point At 14-16 months when the protodeclarative pointing develops, the child will look alternatively between the object and the caregiver. The goal is to share social experience, not the desired object ohnson Myers, 2007). Other nonverbal gestures, including facial expression, usually help discriminate the difference between these two types of pointing Children with ASDs can not achieve these skills at an age-expected time or some can achieve he skill completely. Some children pointing at all but use their caregivers hands point to the desired object. Some children look the object but do not look at the caregiver to connect socially. a study in infant siblings of children with ASDs stated that the inability to shift one's attention(between child, parent nd object) may be the first reliable sign of ASDs(Zwaigenbaum et al, 2005). In brief, lack of or delayed JA skill that is discrepant from overall functioning is a core feature of the ASDs Since JA skills may not be observed in typically developing children younger than 1 year of age, responding to their name being called is a skill that the child should achieve. Children with ASDs usually fail to respond to their name being called. Some children with ASDs may respond to environmental sounds well enough to reassure the caregivers that their children can hear. Home videos of 1-year-old children who later were diagnosed with ASDs found that orienting to name being called is one of the most consistent deficits for affected children at that age(Baranek, 1999; Osterling &z Dawson, 1994) Delay in play skills is one of the features associated with diagnosis of ASDs. In respective order, play starts with sensory-motor, functional, constructive, and pretend or imaginary play. In typically developing children, approximately 4 months old, sensory-motor play begins. At 12-14 months of age, the child plays in a more functional manner. Pretend play starts around 16-18 months of age and increases gradually in complexity. Lack of or delay in pretend play or play that never passes the sensory-motor play stage serves as a distinguishing characteristic of ASDs. Although, some children with ASDs progress to functional play, the quality of play is significantly different from typically developing children by around age 2 years i.e. play is less purposeful, less symbolic and less in complexity(McDonough et al., 1997; Sigman et al., 1999; Stone et al., 1990). Some children with ASDs play or manipulate objects in a stereotypic or ritualistic manner such as lining up, banging, and mouthing objects. They usually prefer playing alone and have trouble incorporating into social play. This sophisticated social play may not develop which further worsen social skills development Although, there is a possibility to detect social skills deficits in children younger than 1 year of age, the reliability remain problematic before 18 months(Rutter, 2006). Specia consideration should focus on gaze monitoring, joint attention, responding to being called by name, and play skills 3. 2 Early language skills deficits enerally, absence of language skills appears at around age 2, which may lead to diagnosis of ASDs. In order to diagnose of ASDs earlier, delay in language development should be

Early Detection of Autism Spectrum Disorders 5 when the caregiver looks at an object or event. This development milestone is called “gaze monitoring”. Around 10-12 months of age the child can follow the caregiver’s point and can look back at the caregiver. At approximately 12-14 months the child will request for objects by pointing. In detail, the child will look back and forth between the object and caregiver to reassure that the caregiver understands his or her need, so called protoimperative pointing. At 14-16 months when the protodeclarative pointing develops, the child will look alternatively between the object and the caregiver. The goal is to share social experience, not the desired object (Johnson & Myers, 2007). Other nonverbal gestures, including facial expression, usually help discriminate the difference between these two types of pointing. Children with ASDs can not achieve these skills at an age-expected time or some can achieve partially but do not qualitatively achieve the skill completely. Some children may have no pointing at all but use their caregivers’ hands point to the desired object. Some children look at the object but do not look at the caregiver to connect socially. A study in infant siblings of children with ASDs stated that the inability to shift one’s attention (between child, parent and object) may be the first reliable sign of ASDs (Zwaigenbaum et al., 2005). In brief, lack of or delayed JA skill that is discrepant from overall functioning is a core feature of the ASDs diagnosis. Since JA skills may not be observed in typically developing children younger than 1 year of age, responding to their name being called is a skill that the child should achieve. Children with ASDs usually fail to respond to their name being called. Some children with ASDs may respond to environmental sounds well enough to reassure the caregivers that their children can hear. Home videos of 1-year-old children who later were diagnosed with ASDs found that orienting to name being called is one of the most consistent deficits for affected children at that age (Baranek, 1999; Osterling & Dawson, 1994). Delay in play skills is one of the features associated with diagnosis of ASDs. In respective order, play starts with sensory-motor, functional, constructive, and pretend or imaginary play. In typically developing children, approximately 4 months old, sensory-motor play begins. At 12-14 months of age, the child plays in a more functional manner. Pretend play starts around 16-18 months of age and increases gradually in complexity. Lack of or delay in pretend play or play that never passes the sensory-motor play stage serves as a distinguishing characteristic of ASDs. Although, some children with ASDs progress to functional play, the quality of play is significantly different from typically developing children by around age 2 years i.e. play is less purposeful, less symbolic and less in complexity (McDonough et al., 1997; Sigman et al., 1999; Stone et al., 1990). Some children with ASDs play or manipulate objects in a stereotypic or ritualistic manner such as lining up, banging, and mouthing objects. They usually prefer playing alone and have trouble incorporating into social play. This sophisticated social play may not develop which further worsen social skills development. Although, there is a possibility to detect social skills deficits in children younger than 1 year of age, the reliability remain problematic before 18 months (Rutter, 2006). Special consideration should focus on gaze monitoring, joint attention, responding to being called by name, and play skills. 3.2 Early language skills deficits Generally, absence of language skills appears at around age 2, which may lead to diagnosis of ASDs. In order to diagnose of ASDs earlier, delay in language development should be

Autism Spectrum Disorders: The Role of Genetics in Diagnosis and Treatment detected as soon as possible. A study among the siblings of children with ASDs demonstrated that during the first year of life, infants later diagnosed with autism vocalized less than low-risk control infants. Moreover, delays in verbal skills and early language comprehension were evident(Zwaigenbaum et al, 2005). Regarding language abnormalities, both expressive and receptive language deficits should be monitored Typically, infants start to babble by 6 months of age, followed by advances in complexity which includes several phe es. Late jargoning (i.e adds inflection to utterances in an attempt to tell a story) develops at approximately 10-12 months of age. Lack or delay of an alternating to-and-fro pattern of vocalizations between infant and parent, delay of onset of g and decrease or no use of pre-speech gestures( e.g. pointing, showing, nodding are characteristic of ASDs(Wetherby et al., 2000; Johnson Myers, 2007) Repeating words in particular the last one or two words of a sentence right after being heard can be observed in typically developing children under the age of 2 years, which mimicks the ASDs symptom of immediate echolalia. However, the typically developing child will pass through this brief stage and will acquire functional language. In children with ASDs, this imitation still persists as expressive language after the age of around 2 years and beyond. Furthermore, the children with ASDs mostly repeat words in an odd intonation or repeat exactly the same intonation as they heard(Martinez-Pedraza Carter, 2009) In young children with ASDs, receptive language ability is often impaired. They initially do not respond to their names when called by a caregiver. After language is present, children with ASDs unable to initiate or sustain conversation. Some children hav comprehension deficits, particularly in complex sentences or questions. Children with ASDs also show deficits in non verbal communication; for example, they look at others less, have less social smile, lack appropriate gestures, have less pointing or have difficulty following a point, show objects less and have a lack of appropriate facial and emotional expression. These non verbal communication deficits are linked closely to lack of social skills development(Martinez-Pedraza Carter, 2009) There is approximately one fourth to one third of children with ASDs whose parents reported a significant loss or regression in language development. The regression characteristically occurs between 15-24 months of age(Lord et al., 2004; Luyster et al, 2005) Although, some parents reported normal development prior to regression, studies showed that some children with ASDs have subtle language and social impairments before the onset of regression(Richler et al., 2006; Werner &z dawson, 2005) 3.3 Restrictive interests, stereotypic and repetitive patterns of behaviours Stereotypies and repetitive behaviours are not specific to children with ASDs. Children who have globally developmental delay(GDD)and children with sensory impairment may demonstrate stereotypies. Even in typically developing children, stereotypies may present behaviours in children with ASDs usually are not common in very young childe o e.g. flapping their hands when excited (ohnson, 2008). Stereotypies and repetitiv (Charman Baird, 2002; Cox et al., 1999; Moore &z Goodson, 2003). Children with ASDs are preoccupied with sameness and routines, so interruption or changes in routine lead to tantrum and emotional disturbance. Some display sensory abnormalities: hypo- or hyper responsive to sensory stimuli. Some children show an unusual and preoccupation with a topic of interest such as train schedules, solar system, dinosaurs, etc. However, this stron

6 Autism Spectrum Disorders: The Role of Genetics in Diagnosis and Treatment detected as soon as possible. A study among the siblings of children with ASDs demonstrated that during the first year of life, infants later diagnosed with autism vocalized less than low-risk control infants. Moreover, delays in verbal skills and early language comprehension were evident (Zwaigenbaum et al., 2005). Regarding language abnormalities, both expressive and receptive language deficits should be monitored. Typically, infants start to babble by 6 months of age, followed by advances in complexity which includes several phonemes. Later, jargoning (i.e. adds inflection to utterances in an attempt to tell a story) develops at approximately 10 -12 months of age. Lack or delay of an alternating to-and-fro pattern of vocalizations between infant and parent, delay of onset of babbling, and decrease or no use of pre-speech gestures (e.g. pointing, showing, nodding) are characteristic of ASDs (Wetherby et al., 2000; Johnson & Myers, 2007). Repeating words in particular the last one or two words of a sentence right after being heard can be observed in typically developing children under the age of 2 years, which mimicks the ASDs symptom of immediate echolalia. However, the typically developing child will pass through this brief stage and will acquire functional language. In children with ASDs, this imitation still persists as expressive language after the age of around 2 years and beyond. Furthermore, the children with ASDs mostly repeat words in an odd intonation or repeat exactly the same intonation as they heard (Martinez-Pedraza & Carter, 2009). In young children with ASDs, receptive language ability is often impaired. They initially do not respond to their names when called by a caregiver. After language is present, children with ASDs are unable to initiate or sustain conversation. Some children have comprehension deficits, particularly in complex sentences or questions. Children with ASDs also show deficits in non verbal communication; for example, they look at others less, have less social smile, lack appropriate gestures, have less pointing or have difficulty following a point, show objects less and have a lack of appropriate facial and emotional expression. These non verbal communication deficits are linked closely to lack of social skills development (Martinez-Pedraza & Carter, 2009). There is approximately one fourth to one third of children with ASDs whose parents reported a significant loss or regression in language development. The regression characteristically occurs between 15-24 months of age (Lord et al., 2004; Luyster et al., 2005). Although, some parents reported normal development prior to regression, studies showed that some children with ASDs have subtle language and social impairments before the onset of regression (Richler et al., 2006; Werner & Dawson, 2005). 3.3 Restrictive interests, stereotypic and repetitive patterns of behaviours Stereotypies and repetitive behaviours are not specific to children with ASDs. Children who have globally developmental delay (GDD) and children with sensory impairment may demonstrate stereotypies. Even in typically developing children, stereotypies may present e.g. flapping their hands when excited (Johnson, 2008). Stereotypies and repetitive behaviours in children with ASDs usually are not common in very young children (Charman & Baird, 2002; Cox et al., 1999; Moore & Goodson, 2003). Children with ASDs are preoccupied with sameness and routines, so interruption or changes in routine lead to tantrum and emotional disturbance. Some display sensory abnormalities: hypo- or hyperresponsive to sensory stimuli. Some children show an unusual and preoccupation with a topic of interest such as train schedules, solar system, dinosaurs, etc. However, this strong

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