- With the body in mind
I.D.C. van Balkom
- Award date
- 10 November 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Self-Injurious Behavior (SIB) is a serious, sometimes life-threatening behavioral problem in individuals with intellectual disabilities. There is no cure or prevention possible at present. SIB etiology and pathogenesis are mainly unknown, although SIB characteristics (prevalence, age of onset, topography) vary widely across syndromes and such variation indicates genetic influences in SIB. Cornelia de Lange Syndrome (CdLS) goes along with a high SIB prevalence. CdLS can be caused by variants in six different genes, all with a cohesin complex function, including NIPBL. SIB occurs in CdLS mainly if NIPBL is mutated.
Molecular diagnoses and detailed physical and behavioral phenotyping were studied. We detected a high rate of somatic mosaicism in CdLS necessitating a change in diagnostics worldwide. Reviews of SIB showed that physical evaluations and direct behavioral assessments have hardly been performed. We proposed a ‘criterion standard’ of methods and instruments. We facilitated data gathering by building wiki databases (waihonapedias) on physical and behavioral characteristics. Comparison of physical and behavioral characteristics between 51 individuals with SMC1A and 67 individuals with NIPBL variants showed that SMC1A variants can result in mild CdLS manifestations or a phenotype resembling Rett syndrome. SIB absence in several cohesinopathies suggested that SIB is caused by a malfunction of NIPBL other than the cohesion function (moonlighting).
We conclude that an integrated approach by behavioral and medical sciences is the key to solving SIB. We present a perspective on how next generation phenotyping is fundamental to targeted therapeutic interventions and personalized care in the future.
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