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  Disease Summary:

  
  
  
  
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    Autism spectrum disorders (ASD) are a heterogeneous group of disorders characterized by impairments in social communication and the presence of restricted interests or repetitive behaviors.

    
    
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    With increasing recognition of autism, it may also be diagnosed in adults who have received other diagnoses in the past (e.g. Intellectual Disability).

    
    
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    Autism is usually a lifelong condition. However, the range of disability is variable. Some individuals may be able to function in the community with variable levels of supports, whereas others may require more intensive residential based supports.

    
    
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    Management of Autism is multidisciplinary and involves addressing the core deficits (communication and restricted/repetitive behaviors) as well as comorbid psychiatric and medical conditions.

  
  
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  Differential Diagnosis:

  
  
  
  
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    Autism is often confused with intellectual disability. Although the two conditions often co-occur, intellectual disability is not a core diagnostic feature of autism. Other disorders with features that may be confused with autism include social anxiety/selective mutism, obsessive-compulsive disorder, expressive/receptive language delay, Attention Deficit Hyperactivity Disorder, schizophrenia, acute psychological trauma, and rare epilepsy syndromes leading to speech regression and hearing loss.

  
  
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  Monogenic Forms:

  
  
  
  
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    Monogenic forms of autism include both “syndromic” and “non-syndromic” autism. “Syndromic” autism includes disorders associated with congenital malformations, facial dysmorphic features, abnormal head sizes or linear growth, seizures, and hypotonia and/or muscle weakness. Monogenic “non-syndromic” autism is often due to genes that encode neuronal and synaptic proteins; they are typically not associated with other clinical features, except for intellectual disability.

  
  
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  Family history:

  
  
  
  
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    Monogenic autism can be inherited in an autosomal dominant, autosomal recessive, and X-linked pattern, but there can be variable expressivity and variable penetrance.

    
    
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    Some individuals with autosomal dominant forms of autism have de novo mutations and hence would not have any family history of the condition.

    
    
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    Female carriers of X-linked syndromic autism may have mild manifestations of some autistic features such as rigid personality and a strong desire for routines. The empiric recurrence risk of having a second child with autism (ie, having a sibling with autism) in cases where the underlying etiology is unknown is about 3%-5%.

  
  
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  Environmental factors:

  
  
  
  
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    Prenatal exposure to specific teratogens can be associated with syndromic autism. Postnatal exposure to lead in young children may also result in autism. Gene-environment interactions may also play a role in the pathogenesis of autism in some individuals.

  
  
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  Genome Wide Association Studies:

  
  
  
  
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    These studies have identified numerous chromosomal loci associated with autism. The causative genes at a few of these loci are now known, but the causative genes at many of these loci are still unknown.

  
  
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  Pharmacogenomics:

  
  
  
  
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    Considering the genetic heterogeneity in autism, pharmacogenomics are of great interest. However, at the time of writing no specific pharmacogenomically driven intervention strategies are approved.

Clinical Characteristics

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders characterized by impairments in social communication and the presence of restricted interests or repetitive behaviors. Although autistic disorder, Asperger syndrome, and pervasive developmental disorder were identified as separate diagnoses within the category of pervasive developmental disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) (DSM-IV), the proposed DSM-V uses the term ASD as a single category that encompasses all of these diagnoses. Across individuals with ASD, there is tremendous variability in intellectual skills, adaptive and communicative competency, and behavioral regulation. Other features often associated with ASD include intellectual disability, reduced verbal cognition, anxiety, attention problems, obsessive-compulsive disorder, sleep difficulties, and seizures. Macrocephaly may be present by 2 to 3 years old in about 20% of children with ASD, including those with nonsyndromic ASD. ASDs are usually lifelong.

Approximately 10% of individuals with ASD have an underlying genetic syndrome along with syndrome-specific congenital malformations or dysmorphic features. The remaining 90% of individuals with ASD have “nonsyndromic” ASD and do not have any specific malformations nor dysmorphic features.

Autism is increasingly recognized in children. At times, parents may recognize autistic symptoms in themselves at the time of their child’s diagnosis. With increasing recognition of autism, it may also be diagnosed in adults in residential facilities who were previously diagnosed with intellectual disability alone. Such individuals may have remarkable aspects of nonverbal intelligence even though they present with severe deficits in their use of language. Cognitive testing by experienced psychologists and use of augmentative communication strategies may help improve function and demonstrate areas of competency.

Diagnostic Criteria

The diagnosis of ASD that is proposed for the DSM-V is based on a dimensional approach and specific behavioral criteria. Currently proposed criteria state that an individual must manifest all four of the following:

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   Persistent deficits in social communication and social interaction across contexts, not accounted for by general developmental delays and manifest by all three of the following:

   
   
   
   
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      Deficits in social-emotional reciprocity, ranging from abnormal social approach and failure of normal back and forth conversation through reduced sharing of interests, emotions, and affect and respond to total lack of initiation of social interaction

      
      
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      Deficits in nonverbal communicative behaviors used for social interaction, ranging from poorly integrated verbal and nonverbal communication through abnormalities in eye contact and body language, or deficits in understanding and use of nonverbal communication, to total lack of facial expression or gestures

      
      
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      Deficits in developing and maintaining relationships, appropriate to developmental level (beyond those with caregivers), ranging from difficulties adjusting behavior to suit different social contexts through difficulties in sharing imaginative play and in making friends to an apparent absence of interest in people

   
   
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   Restricted, repetitive patterns of behavior, interests, or activities as manifested by at least two of the following:

   
   
   
   
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      Stereotyped or repetitive speech, motor movements, or use of objects (such as simple motor stereotypies, echolalia, repetitive use of objects, or idiosyncratic phrases)

      
      
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      Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change (such as motoric rituals, insistence on same route or food, repetitive questioning or extreme distress at small changes)

      
      
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      Highly restricted, fixated interests that are abnormal in intensity or focus (such as strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests)

      
      
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      Hyper-or hyporeactivity to sensory input or unusual interest in sensory aspects of environment (such as apparent indifference to pain or heat or cold, adverse response to specific sounds or textures, excessive smelling or touching of objects, fascination with lights or spinning objects)

   
   
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   Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities).

   
   
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   Symptoms together limit and impair everyday functioning.

An individual suspected of ASD should be evaluated by a psychologist or a physician who is trained to diagnose ASD using a standardized and validated set of diagnostic developmentally appropriate instruments, such as the Autism Diagnostic Observation Schedule, second edition (ADOS-2) and/or the Autism Diagnostic Interview-Revised (ADI-R). Diagnostic assessment should also include interviewing the parent, spouse, or caretaker regarding the individual’s developmental history, social communication across settings, and behavior.

The ADOS-2 is a semistructured standardized assessment consisting of various activities allowing the experienced clinician to observe social, communication, and play behaviors as they relate to the diagnosis of an ASD. It can be used with toddlers, children, and adults. The ADOS-2 has a module system allowing it to be used with individuals having very little speech to those who are fully verbally fluent. The ADOS-2 results in an algorithm score for classification of ASD or for the narrower definition of autism.

The ADI-R is a comprehensive, standardized interview that is administered to a parent or caretaker who is familiar with the developmental history and current behavior of the individual being evaluated. It is primarily used in research as it generally takes 2 to 3 hours to administer.

Screening tools commonly used for adults include the Social Responsiveness Scale (second edition) and the Social Communication Questionnaire (previously known as the Autism Screening Questionnaire). These are completed by a parent, spouse, or caretaker of an individual suspected of having ASD.

Syndromic ASD: Mitochondrial disorders—various genetic etiologies resulting in mitochondrial dysfunction. Common biochemical finding—high plasma lactate and alanine concentrations. Variable presentations.

Only consistently replicated findings are listed. Many loci have been implicated through various genome-wide association studies (GWASs), but in some cases, the findings have been contradictory among different studies.