bourgeron.qxp 30/6/08 02:42 Page 58
Autism Spectrum Disorders
Genetic, Neurobiological and Clinical Findings Related to SHANK3 Mutations and
22q13 Chromosomal Rearrangements in Autism Spectrum Disorders
a report by
Thomas Bourgeron
1
and Christelle M Durand
2
1. Professor of Genetics, University of Paris; 2. Human Genetic and Cognitive Functions Unit, Neuroscience Department, Institut Pasteur, Paris
Autism, first described by the psychiatrist Leo Kanner in 1943, is the motives, knowledge and beliefs of others. Individuals with ASDs do
diagnosed on the basis of three behaviourally altered domains: social not develop a theory of mind or have a delay in the acquisition of it.
deficits; impaired language and communication; and stereotyped This deficit is certainly one of the major causes of their difficulties with
and repetitive behaviours.
1
Beyond this unifying definition lies an social interactions.
extreme degree of clinical heterogeneity, ranging from debilitating
impairments to mild personality traits. Hence, autism is not a single Epidemiological studies report a dramatic rise of ASDs during the last
disease entity, but rather a complex phenotype encompassing either two decades (from two to five to 60 per 10,000 children). However,
multiple ‘autistic disorders’ or a continuum of autistic-like traits and this recent increase is most likely explained by the use of broader
behaviours. To take into account this heterogeneity, the term autism diagnostic criteria and increased attention of the medical community.
2
spectrum disorders (ASDs) is now used and includes autistic syndrome, For still unknown reasons, males are more frequently affected than
pervasive development disorder not otherwise specified (PDD-NOS), females. The male-to-female ratio is 4:1, but this increases to 23:1 in
Asperger’s syndrome, childhood disintegrative disorder (CDD) and Rett individuals without identified morphological or brain abnormalities.
3
syndrome. While CDD and Rett syndrome are severe neurological
disorders, Asperger’s syndrome refers to the portion of the ASD Autism is associated with a known genetic disorder in only 10–25% of
continuum characterised by higher cognitive abilities and more normal cases, with the most frequent disorders being fragile X syndrome,
language function. tuberous sclerosis and chromosomal abnormalities such as
translocations or copy number variations (CNVs) on chromosomes 15q,
The majority of individuals with ASDs (75%) also present with learning 16p, 22q and 7q.
4
Recently, several synaptic genes have been
disabilities (LDs) characterised by an intelligence quotient (IQ) <70. The associated with ASD, providing a better view of the complex pathways
behavioural singularities that occur in ASDs are related to a wide involved that may alter properties of the neuronal networks and likely
spectrum of cognitive functions such as language, memory and visual contribute to the disorders
5,6
(see Figure 1). Among these genes, the
and auditive attention. Two of these cognitive deficits are somewhat SHANK3 gene (also known as ProSAP2) located at chromosome 22q13
characteristic of ASDs: a weak ‘central coherence’ and the lack of a was repeatedly found altered in patients with ASD.
‘theory of mind’. Central coherence defines our ability to understand
context. Individuals with ASDs are sometimes better than age-matched Deletion of 22q13 and Mutations of SHANK3
controls in detecting details in a picture, but they have great difficulty The 22q13 deletion syndrome, also known as Phelan-McDermid
in seeing ‘the bigger picture’ and in understanding the context of the syndrome (MIM 606232), is characterised by moderate to profound LD,
situation. Theory of mind describes an individual’s understanding of delay/absence of expressive speech and hypotonia. The first case of
22q13 deletion was described in 1985,
7
and was the result of a
rearrangement of a maternal peri-centric inversion of chromosome 22.
Thomas Bourgeron is a Professor of Genetics at the
University of Paris, researching the role of the synaptic and
Since this first report, at least 116 cases with a 22q13 deletion and five
circadian-clock genes in the development of language and cases with a duplication of this region have been described (see Table 1).
communication in humans, and the identification of synaptic
For still unknown reasons, anomalies of the 22q13 region are more
pathways associated with autism spectrum disorders.
Professor Bourgeron completed his PhD in human genetics
frequently observed in girls than in boys. The female-to-male ratio is
on mitochondrial diseases in children, also studying
53:37 for the 22q13 deletions and 20:11 for the remaining 22q13
mitochondrial DNA deletions and identifying the first
mutation of the Krebs cycle (FH) and of the nuclear genes of
anomalies (duplication 3:2). Overall, patients with a 22q13 deletion are
the respiratory chain (SDHA) in humans. characterised by neonatal hypotonia (84/116, 72%), absent or severely
E: thomasb@pasteur.fr
delayed expressive speech (95/116, 82%), global developmental delay
(105/116, 91%) and LD (39%); however, in some cases global
Christelle M Durand works in the Human Genetic and
development is too delayed to measure IQ (see Table 2). Other less
Cognitive Functions Unit of the Neuroscience Department at
common features associated with this syndrome include minor
the Pasteur Institute. She completed her PhD in human
genetics in the laboratory of Professor Bourgeron. During her
dysmorphic features (large and dysplasic ears were frequently observed),
PhD, she studied susceptibility to autism spectrum disorders increased tolerance to pain, abnormal toe nails, chewing behaviour and
(ASDs), focusing on two genes that encode synaptic proteins:
tendency to overheat.
protocadherin X/Y, which are cell adhesion molecules, and
SHANK3, a scaffolding protein.
In most cases (90/116), patients present with a single deletion at 22q13.
When the DNA of the parents was analysed (43/90), all deletions were
58 © TOUCH BRIEFINGS 2008
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