Challenging behavior in smith-lemli-opitz syndrome: initial test of biobehavioral influences.
ABSTRACT : To study challenging behavior (destruction, aggression, self-injury, stereotypy) in children with Smith-Lemli-Opitz syndrome (SLOS) using a biobehavioral model that helps distinguish biological from socially mediated variables influencing the behavior.
: SLOS is an autosomal-recessive syndrome of multiple malformations and intellectual disability resulting from a genetic error in cholesterol synthesis in all cells and tissues, including brain. The exact cause of the challenging behavior in SLOS is unclear, but defective brain cholesterol synthesis may contribute. Because the precise genetic and biochemical etiology of SLOS is known, this disorder is a good model for studying biological causes of challenging behavior.
: In a preliminary application of a biobehavioral model, we studied the association between cholesterol levels (as a biochemical indicator of disease severity) and behavior subtype ("biological" vs "learned") in 13 children with SLOS. Parents completed a questionnaire that categorized challenging behavior as influenced primarily by social or nonsocial (thus, presumably biological) factors.
: The severity of the cholesterol synthesis defect correlated significantly with behavior subtype classification for 1 of 2 challenging behaviors. Greater severity of the cholesterol synthesis defect was associated with behavior being classified as primarily influenced by biological factors.
: The interplay between challenging behavior and defective cholesterol synthesis in SLOS may help explain biological influences on the behavior. Our findings have implications for research on the effectiveness of behavioral and medical treatments for behavioral difficulties in SLOS and other neurodevelopmental disorders.
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ABSTRACT: We report on a family in which four males over three generations are affected with X-linked recessive developmental delay, learning difficulties, severe behavioral difficulties and mild dysmorphic features. Plasma sterol analysis in three of the four affected males demonstrated increased concentrations of 8-dehydrocholesterol (8-DHC) and cholest-8(9)-enol. All four affected males had a novel hemizygous missense mutation, p.W47R (c.139T>C), in EBP. Functional studies showed raised levels of cholest-8(9)-enol in patient's cultured fibroblast cells, which were suppressed when the cells were incubated with simvastatin. EBP encodes 3β-hydroxysteroid-delta8, delta7-isomerase, a key enzyme involved in the cholesterol biosynthesis pathway. Mutations in EBP have previously been associated with Conradi-Hunermann-Happle syndrome (CHH), an X-linked dominant disorder characterized by skeletal dysplasia, skin, and ocular abnormalities, which is usually lethal in males. Four previous reports describe X-linked recessive multiple anomaly syndromes associated with non-mosaic EBP mutations in males, two at the same amino acid position, p.W47C. This phenotype has previously been described as "MEND" syndrome (male EBP disorder with neurological defects). The family reported herein represent either a novel phenotype, or an expansion of the MEND phenotype, characterized by extreme behavioral difficulties and a scarcity of structural anomalies. Simvastatin therapy is being evaluated in two males from this family. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 04/2014; 164(4). DOI:10.1002/ajmg.a.36368 · 2.05 Impact Factor
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ABSTRACT: Cholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources through the uptake of low-density lipoproteins. Cholesterol biosynthesis is a complex, multienzyme-catalyzed pathway involving a series of sequentially acting enzymes. Inherited defects in genes encoding cholesterol biosynthetic enzymes or other regulators of cholesterol homeostasis result in severe metabolic diseases, many of which are rare in the general population and currently without effective therapy. Historically, these diseases have been viewed as discrete disorders, each with its own genetic cause and distinct pathogenic cascades that lead to its specific clinical features. However, studies have recently shown that three of these diseases have an unanticipated mechanistic convergence. This surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.Annual Review of Genomics and Human Genetics 08/2014; 15:173-94. DOI:10.1146/annurev-genom-091212-153412 · 9.13 Impact Factor
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ABSTRACT: Objective To quantitatively evaluate feeding impairment in children with Smith-Lemli-Opitz syndrome (SLOS) and to correlate feeding impairment with clinical and biochemical indices of disease severity. Study design The study subjects were 26 children with SLOS ranging in age from 0.4 to 19 years. Clinical severity was measured using an existing scoring system. We created a tool to quantitatively evaluate feeding. Plasma sterol concentrations were measured, and statistical associations (correlations) with feeding scores were calculated. Results Oral hyposensitivity or hypersensitivity, adverse behaviors, and risk for dysphagia were seen in ∼65% of the children with SLOS. Thirteen of the 26 children experienced failure to thrive, and 10 children required gastrostomy. Plasma concentration of 7-dehydrocholesterol, as a measure of severity, was correlated with total feeding score and oral function subcategory score (P < .001) and less so with oral structure score, adverse behaviors, or dysphagia. Correlations with cholesterol concentrations were less statistically significant. A plasma 7-dehydrocholesterol concentration >0.24 mmol/L or cholesterol concentration <1.95 mmol/L was predictive of gastrostomy tube use. Feeding impairments may improve with age. Conclusion Feeding impairment is common and complex in patients with SLOS. Our findings confirm that oral sensitivities, adverse feeding behaviors, and risk of oral phase dysphagia are amenable to quantitative evaluation and analysis. Feeding difficulties in children with SLOS are correlated with plasma sterol concentrations, suggesting a link between the biochemical severity of SLOS and feeding function. These findings expand the behavioral phenotype of SLOS and begin to provide insight into the biological causes of feeding difficulties.Journal of Pediatrics 10/2014; 165(4). DOI:10.1016/j.jpeds.2014.06.010 · 3.74 Impact Factor