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Insights for autism from Williams syndrome

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Andreas Meyer-Lindenberg
18 September 2012

Broken bike: Children with Williams syndrome have trouble understanding how different parts make up a whole object, such as a bicycle.

Understanding the complex syndrome of autism and pushing research towards new therapies is a formidable task. Where should one begin?

One option is to look at well-characterized genetic syndromes, such as Williams-Beuren syndrome, that overlap with autism. Williams syndrome is a neurodevelopmental disorder affecting as many as 1 in 7,500 births1.

In general, given the high heritability of autism, starting with genetics might seem like the obvious choice. Researchers are reporting some successes with this, such as finding common genetic variants through genome-wide association studies (GWAS). Still, it has become clear that the genetic architecture of autism is complex. As with other heritable psychiatric disorders, such as schizophrenia and bipolar disorder, multiple genes play a role and each gene contributes to only a relatively minor risk.

The problem is compounded by the way that psychiatric diagnoses work: A phenotype composed of behavioral symptoms and how they develop may be too far removed from the actual biology to link it to genetic data. This is partly why our understanding of the molecular pathophysiology of these conditions is limited2.

If we stick with the genetics approach, we need to decide which genes to focus on. GWAS are the best way to find variants that occur frequently in the population, but these tend to have only small-to-moderate effects on complex behavioral phenotypes3. If one is interested in high-risk variants, these will, correspondingly, turn out to be rare and so not explain much about the risk. However, they have the great advantage of a potentially more straightforward route from genotype to phenotype.

Our understanding of other complex illnesses, such as Alzheimer’s disease, has been advanced considerably by this strategy of solving the problem ’from the edges.’ In autism, studying conditions such as Rett syndrome or fragile X syndrome has yielded important therapeutic clues that may be relevant for autism in general.

Good points of departure for applying such a strategy are copy number variants (CNVs), in which a known group of genes along a chromosome is deleted or duplicated. CNVs are instructive experiments of nature affording researchers the opportunity to identify distinct, but also interacting, contributions of genes to brain development, structure and function4. In the case of autism, for example, CNVs linked to autism have also been found in people with related disorders.

Related syndrome:

An excellent example for this strategy is afforded by Williams syndrome. This syndrome is caused by the deletion of one copy of approximately 1.6 megabases of DNA, encompassing about 25 genes on chromosome 7q11.235.

Neuropsychiatric problems in Williams syndrome are common and include developmental delay, coordination difficulties, hearing loss and hypersensitivity to sound6,7. The syndrome is also associated with a distinctive cognitive profile8,9, characterized by severe difficulty understanding how a whole is made out of parts, as, for example, in a puzzle. This ‘visuoconstructive’ weakness, together with a relative strength in verbal short-term memory and language, distinguishes Williams syndrome significantly from other disorders10.

A particularly striking feature of children with Williams syndrome is their high sociability and their empathy for others11,12. Individuals with the disorder are typically socially fearless and engage eagerly and often impulsively in social interaction, even with strangers.

This characteristic has led some clinicians and researchers to consider Williams syndrome as a kind of ‘anti-autism.’ In contrast with the hypersociability, increased empathy and fascination with faces in Williams syndrome, autism is characterized by deficits in social interaction. Unlike the relative language strengths in Williams syndrome, language in autism is usually relatively weak: Many individuals do not develop spoken language, and others have marked impairment in initiating conversation or speak in a repetitive or idiosyncratic way. 

Researchers thus see autism and Willams syndrome as clinical opposites. However, several cognitive domains are impaired in both. These include deficits in nonverbal behaviors — such as eye contact, facial expressions, body postures and gestures — during social interaction and difficulty judging facial expressions13,14. The two disorders may also coexist more frequently than was previously appreciated15.

Genetic opposites:

Clinically, the theory that Williams syndrome and autism are opposites does not stand up to scrutiny. However, the idea gains traction from a causal, genetic point of view.

The first reported case of a duplication of 7q11.23 looks somewhat like the clinical opposite of Williams syndrome16. This individual has severe speech and expressive language delay, reminiscent of autism, whereas visuospatial construction skills are at the level of other family members.

A large 2011 study of rare CNVs in 1,124 autism families showed a significant association between spontaneous duplications of 7q11.23 and autism17. In other words, deletion is associated with Williams syndrome and duplication with autism.

This exciting observation suggests that examining which genes in the Williams syndrome region are most likely to be associated with autism can further our understanding of autism. The most notable of these are LIMK1, CYLN2 and GTF2I18,19,20,21.

A study published earlier this year has shown an association between variants in GTF2I and severe social deficits and excessive repetitive behaviors in autism22.

Comparing the neural mechanisms that underlie the two disorders should also be instructive. For example, in both Williams syndrome and autism the amygdala has more densely packed cells, and both disorders show increased and decreased amygdala volume, compared with controls23.

The amygdala, as well as other key regions for face processing and social function, including the fusiform gyrus, are less active in individuals with autism than in controls24. However, amygdala activity may actually be elevated during face processing in relation to eye contact, suggesting a heightened emotional response25 in some individuals. In Williams syndrome, increased amygdala function along with deficient regulation by regions of the prefrontal cortex is linked to the social symptoms of the disorder26.

In summary, the intriguing idea of autism and Williams syndrome as opposites, while not useful clinically, may become increasingly useful as a research strategy now that a gene dosage-related genetic mechanism at 7q11.23 has been found to contribute to both.

Further studies should clarify the ways by which deletion and duplication at this region contribute to the symptoms of the disorders in the hope of advancing our understanding of the disorders and potentially highlighting therapeutic targets.

Andreas Meyer-Lindenberg is director of the Central Institute of Mental Health at the University of Heidelberg in Mannheim, Germany.

References:

1: Strømme P. et al. J. Child Neurol. 17, 269-271 (2002) PubMed

2: Insel T.R. and E.M. Scolnick Mol. Psychiatry 11, 11-17 (2006) PubMed

3: O'Donovan M.C. et al. Nat. Genet. 40, 1053-1055 (2008) PubMed

4: Meyer-Lindenberg A. et al. Nat. Rev. Neurosci. 7, 380-393 (2006) PubMed

5: Urbán Z. et al. Am. J. Hum. Genet. 59, 958-962 (1996) PubMed

6: Chapman C.A. et al. J. Child Neurol. 11, 63-65 (1996) PubMed

7: Meyer-Lindenberg A. et al. Am. J. Psychiatry 158, 1809-1817 (2001) PubMed

8: Mervis C.B. and B.P. Klein-Tasman Ment. Retard. Dev. Disabil. Res. Rev. 6, 148-158 (2000) PubMed

9: Mervis C.B. et al. Brain Cogn. 44, 604-628 (2000) PubMed

10: Farran E.K. and C. Jarrold Dev. Neuropsychol. 23, 173-200 (2003) PubMed

11: Bellugi U. et al. Neuroreport. 10, 1653-1657 (1999) PubMed

12: Klein-Tasman B.P. and C.B. Mervis Dev. Neuropsychol. 23, 269-290 (2003) PubMed

13: Frigerio E. et al. Neuropsychologia 44, 254-259 (2006) PubMed

14: Pelphrey K. et al. Ment. Retard. Dev. Disabil. Res. Rev. 10, 259-271 (2004) PubMed

15: Tordjman S. et al. PLoS One 7, e30778 (2012) PubMed

16: Somerville M.J. et al. N. Engl. J. Med. 353, 1694-1701 (2005) PubMed

17: Sanders S.J. et al. Neuron 70, 863-885 (2011) PubMed

18:  Hoogenraad C.C. et al. Nat. Genet. 32, 116-127 (2002) PubMed

19: Meng Y. et al. Neuron 35, 121-133 (2002) PubMed

20: Durkin M.E. et al. Genomics 73, 20-27 (2001) PubMed

21: Tassabehji M. et al. Science 310, 1184-1187 (2005) PubMed

22: Malenfant P. et al. J. Autism Dev. Disord. 42, 1459-1469 (2012) PubMed

23: Bauman M.L. and T.L. Kemper Int. J. Dev. Neurosci. 23, 183-187 (2005) PubMed

24: Critchley H.D. et al. Brain 123, 2203-2212 (2000) PubMed

25: Dalton K.M. et al. Nat. Neurosci. 8, 519-526 (2005)  PubMed

26: Meyer-Lindenberg A. et al. Nat. Neurosci. 8, 991-993 (2005) PubMed

Comments

Name: Jon Brock
18 September 2012 - 3:15PM

Thanks for this really interesting article. As someone with a long-standing interest in Williams syndrome, I've been fascinated by these recent examples of duplications in the Williams syndrome region.

Two points: One is that the language strengths in Williams syndrome are exaggerated (not just here but in most of the literature). Language is definitely a strength relative to visuo-spatial skills, but EVERYTHING is good relative to visuo-spatial skills in WS. A few years ago I reviewed every published paper on language in WS and, excluding comparisons with visuo-spatial skills, there was not one single finding from one study that showed even a relative strength in language or verbal short-term memory. However, the meme is so strong that researchers still look at the data showing mental-age appropriate language skills and describe it as a language strength. Perhaps there have been studies more recently, but every one I've read seems if anything to be finding new evidence for language weaknesses not strengths.

Second, I'm not sure how relevant the direct comparisons between autism and WS are. Given the extreme heterogeneity of autism at every level of description, it doesn't really make sense to say "autism and Williams syndrome are similar in this respect but different in this other respect." There might well be some overlap between WS and a subgroup of autism. I'm intrigued by the idea that people with Williams might fall into Lorna WIng's "active but odd" social subtype (which Sander Begeer and colleagues have recently revived). Likewise, the duplication cases might have similar behavioural "symptoms" to a different subgroup of the autism population.

More generally, I agree that there are interesting comparisons to be made between genetically defined, relatively homogeneous syndromes and subsets of the heterogeneous, behaviourally defined, idiopathic autism population. It may even be that we can use these syndromes as leverage to pull out the subgroups within autism. My guess is that those will be the most useful insights we get from Williams syndrome.

Brock, J. (2007). Language abilities in Williams syndrome: a critical review. Development and Psychopathology, 19, 97-127.

Brock, J., Einav, S., & Riby, D. (2008). The other end of the spectrum? Social cognition in Williams syndrome. In T. Striano & V. Reid (Eds.), Social Cognition: Development, Neuroscience and Autism. Oxford: Blackwell.

Name: RA Jensen
18 September 2012 - 6:58PM

The article on Williams syndrome claims ‘In general, given the high heritability of autism, starting with genetics might seem like the obvious choice’. Williams Syndrome is a poor model for studying the heritability of autism. Almost all cases are caused by a de novo gene mutation and are not inherited. Rarely, parent to child transmission does occur but the parents aren’t affected as far as autism is concerned (Morris 2006).

William Syndrome is caused by a sperm or egg mutation. It is assumed that 17q11.3 sperm or egg mutations in genotype normal parents are sporadic and a very rare occurrence in the general population.

Not at all. Molina’s laboratory in Spain recruited ten healthy male sperm donors and using advanced FISH technology studied a minimum of 10,000 individual sperm per healthy sperm donors. 17q11.3 sperm mutations, deletions (Williams Syndrome) and duplications (autism) was found in the sperm of all healthy sperm donors (Molina et al 2011).

References

Molina O, Anton E, Vidal R, Blanco J (2011). Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions and duplications: a FISH approach. . Hum Genet. 2011 Jan;129(1):35-44. Epub 2010 Oct 8.

http://www.springerlink.com/content/d53g890m56w6825h/fulltext.pdf

Morris CA. Williams Syndrome. 1999 Apr 9 [Updated 2006 Apr 21]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from:

http://www.ncbi.nlm.nih.gov/books/NBK1249/

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