Genetic, Neurobiological and Clinical Findings Related to SHANK3 Mutations and 22q13 Chromosomal Rearrangements in Autism Spectrum Disorders

Genetic, Neurobiological and Clinical Findings Related to SHANK3 Mutations and 22q13 Chromosomal Rearrangements in Autism Spectrum Disorders

Bourgeron Thomas, Durand Christelle M

European Psychiatric Review 2008;1(1):58-61

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Autism, first described by the psychiatrist Leo Kanner in 1943, is diagnosed on the basis of three behaviourally altered domains: social deficits; impaired language and communication; and stereotyped and repetitive behaviours.1 Beyond this unifying definition lies an extreme degree of clinical heterogeneity, ranging from debilitating impairments to mild personality traits. Hence, autism is not a single disease entity, but rather a complex phenotype encompassing either multiple ‘autistic disorders’ or a continuum of autistic-like traits and behaviours. To take into account this heterogeneity, the term autism spectrum disorders (ASDs) is now used and includes autistic syndrome, pervasive development disorder not otherwise specified (PDD-NOS), Asperger’s syndrome, childhood disintegrative disorder (CDD) and Rett syndrome. While CDD and Rett syndrome are severe neurological disorders, Asperger’s syndrome refers to the portion of the ASD continuum characterised by higher cognitive abilities and more normal language function.

The majority of individuals with ASDs (75%) also present with learning disabilities (LDs) characterised by an intelligence quotient (IQ) <70. The behavioural singularities that occur in ASDs are related to a wide spectrum of cognitive functions such as language, memory and visual and auditive attention. Two of these cognitive deficits are somewhat characteristic of ASDs: a weak ‘central coherence’ and the lack of a ‘theory of mind’. Central oherence defines our ability to understand context. Individuals with ASDs are sometimes better than age-matched controls in detecting details in a picture, but they have great difficulty in seeing ‘the bigger picture’ and in nderstanding the context of the situation. Theory of mind describes an individual’s understanding of the motives, knowledge and beliefs of others. Individuals with ASDs do not develop a theory of mind or have a delay in he acquisition of it. This deficit is certainly one of the major causes of their difficulties with social interactions.

Epidemiological studies report a dramatic rise of ASDs during the last two decades (from two to five to 60 per 10,000 children). However, this recent increase is most likely explained by the use of broader diagnostic criteria and increased attention of the medical community.2 For still unknown reasons, males are more frequently affected than females. The male-to-female ratio is 4:1, but this increases to 23:1 in individuals without identified morphological or brain abnormalities.3

Autism is associated with a known genetic disorder in only 10–25% of cases, with the most frequent disorders being fragile X syndrome, tuberous sclerosis and chromosomal abnormalities such as translocations or copy number variations (CNVs) on chromosomes 15q, 16p, 22q and 7q.4 Recently, several synaptic genes have been associated with ASD, providing a better view of the complex pathways involved that may alter properties of the neuronal networks and likely contribute to the disorders5,6 (see Figure 1). Among these genes, the SHANK3 gene (also known as ProSAP2) located at chromosome 22q13 was repeatedly found altered in atients with ASD.

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