Individuals with Smith-Magenis syndrome display profound neurodevelopmental behavioral deficiencies and exhibit food-related behaviors equivalent to Prader-Willi syndrome
Introduction
Smith-Magenis syndrome (SMS) is a complex neurodevelopmental disorder caused by haploinsufficiency of RAI1 due to either a deleterious point mutation or an interstitial deletion of chromosome band 17p11.2. SMS is routinely characterized by variable intellectual disability, sleep disturbances, craniofacial and skeletal changes, early onset obesity and a number of distinctive behavioral abnormalities including self-injury, aggression, and stereotypies (Elsea & Girirajan, 2008). Maladaptive behaviors are common among individuals with intellectual disability, but some neurodevelopmental disorders have a more severe manifestation than others. Maladaptive behaviors in SMS vary with age but are a key component for identifying the disorder; however, it is unclear how frequent and severe SMS behavioral problems are relative to disorders with intellectual disability (Edelman et al., 2007, Gropman et al., 2007, Smith et al., 1998, Wolters et al., 2009).
In addition to specific behavioral hallmarks, hypotonia and feeding difficulties during infancy are very common among individuals with SMS (Gropman, Duncan, & Smith, 2006). Interestingly, 90% of individuals with SMS are at or above the 90th percentile for weight by age 14 (Burns et al., 2010). The transition in food-related behavioral patterns during infancy to the onset of obesity in early adolescence is not well understood. SMS mouse model work has demonstrated a similar feeding behavioral pattern where Rai1 haploinsufficient (Rai1+/−) mice throughout early development are similar in weight relative to wild-type littermates but transition to an obese phenotype in early adulthood (Burns et al., 2010). However, a recent study has shown that the growth rate and weight gain during early developmental stages significantly increased when Rai1+/− mice are fed either a high carbohydrate or a high fat diet, suggesting that dietary content early in development is important in obesity outcomes in SMS (Alaimo, Hahn, Mullegama, & Elsea, 2014). In addition, Rai1+/− mice also consume more food and have reduced satiation compared to wild type mice implicating a dysregulation of signaling systems underlying eating behavior (Burns et al., 2010).
Phenotypic food-related behaviors are found across a variety of neurodevelopmental disorders and cohorts of subjects with intellectual disability. One such neurodevelopmental disorder with phenotypic food-related behaviors is Prader-Willi syndrome (PWS). PWS is the leading known genetic cause of obesity and has a very similar phenotype to SMS including intellectual disability, comparable behavioral problems, early onset of obesity and hyperphagia. In early infancy, individuals with PWS have severe hypotonia and feeding difficulties, but by 6–10 years of age individuals are typically obese (Wollmann, Schultz, Grauer, & Ranke, 1998). Targeted interventions that consist of a strict diet of reduced fat, modified carbohydrates and limited access to food are extremely effective in limiting weight gain in these individuals, despite the juncture of time when the interventions are introduced (Bonfig et al., 2009, Schmidt et al., 2008). Therefore, PWS weight management treatments provide a model for intervention, which may also discriminate, to SMS individuals; however, the degree of similarity between the food-related behavioral patterns observed in each disorder remains unclear.
Comparing phenotypically similar but genetically different neurodevelopmental syndromes may reveal a comprehensive understanding of the genetic basis of behavioral problems. Therefore, the aim of the present study was two-fold. The first aim was to discern the nature and extent of neurobehavioral deficits in SMS and to compare these deficits to a sample with intellectual disability using the Behavior Problems Inventory-01. The second aim was to compare food-related behavioral phenotypes using the Food Related Problems Questionnaire in adults with SMS relative to an adult sample with intellectual disability and to PWS to determine behavioral similarities between each disorder.
Section snippets
Participants
Of the 100 respondents of the surveys 85% were female and either the biological or the adoptive parent (95%) of the SMS individual. All SMS individuals had a confirmed diagnosis of SMS and a chromosomal deletion (90%) was predominantly reported as the molecular finding. Additionally, 91% resided at home while 9% resided in a residential facility. Seventy-seven percent of the responders identified that their child has or had received special education services or remedial education. All 100
SMS BPI-01 scores are significantly greater relative to individuals with intellectual disability of a heterogeneous etiology
We analyzed each subscale BPI-01 score from the SMS cohort relative to a reference sample of adults with intellectual disability of heterogeneous etiology. Our SMS cohort had a mean frequency score for self-injurious behaviors of 11.65 (SD = 6.09) ranging from 0 to 28 while the mean severity score was 9.296 (SD = 4.866) ranging from 1 to 24. A one-sample t-test found that both frequency and severity of self-injurious behaviors in the SMS sample were significantly greater than the intellectual
SMS behavioral problems
Individuals with SMS have a wide range of behavioral problems that are often variable across age and the most difficult to manage (Elsea and Girirajan, 2008, Elsea and Williams, 2011, Smith et al., 1998). Using the BPI, we found that our SMS cohort displayed a significantly increased frequency and severity of self-injurious, stereotyped, and aggressive/destructive behaviors relative to individuals with intellectual disability (Fig. 1A–G).
Our cohort displayed similar percentages of
Acknowledgements
The authors would like to thank the PRISMS organization for providing their members with the opportunity to participate in our research. Additionally, we would like to thank Amanda Heber for initial assistance in study planning. We would also like to thank Dr. Johannes Rojahn from George Mason University, Fairfax, Virginia, USA for the use of the BPI and Dr. Chris Oliver from University of Birmingham, Birmingham, West Midlands, UK for the use of the FRPQ.
This work was partly supported by the
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