Challenging behavior in Smith-Lemli-Opitz syndrome: initial test of biobehavioral influences.

OBJECTIVE: 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. BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Smith Lemli-Opitz syndrome: a contribution to the delineation of a cognitive/behavioral phenotype.

AIM: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive congenital malformation syndrome caused by an inborn error of cholesterol biosynthesis. The incidence is around 1:20000-1:70000. SLOS phenotype is very broad: severe phenotypes show exitus in perinatal period while milder phenotypes only show behavioral and learning problems. The purpose of this study is to further contribute to the delineation of a cognitive and behavioral phenotype in SLOS. METHODS: Nine patients with SLOS aged between 22 months and 25 years have been followed at the Department of Pediatrics, University of Naples "Federico II" for 2 years. A neuropsychologic study has been carried out in order to assess motor development, adaptive skills, social behavior, communication and language, temperament, aggressive behavior, symptoms typical of autism spectrum disorders (ASDs). RESULTS: The overall assessment of cognitive/behavioral phenotype showed severe / profound mental retardation in most of them (8/9) with a quite homogeneous neuropsychological profile. The language area was deficient both in expressive and receptive skills. Adaptive skills were in line with mental development. The presence of behavior problems (self-injury and stereotypies) was detected in 6 patients. The study of temperament showed a trend towards a sedentary lifestyle, lack of inhibition against novelty and danger, and reduced interest in the stimuli. None of our patients could be diagnosed as having ASDs. CONCLUSION: Although a specific behavioral phenotype for SLOS has gained support in the literature, we believe that many of the features described in individuals with SLOS are common to other mental retardation syndromes.

Cognitive and behavioral aspects of Smith-Lemli-Opitz syndrome.

The brain's high concentrations of cholesterol make it especially vulnerable to the cholesterol biosynthetic defect that characterizes Smith-Lemli-Opitz syndrome (SLOS). An attempt to characterize the cognitive and behavioral phenotype of SLOS has identified increased rates of intellectual disability, language and motor developmental delay, repeated self-injury behaviors, sensory hyperreactivity, hyperactivity, affect dysregulation, and sleep disturbances. Some research has suggested that carriers of the gene mutation that results in SLOS display increased risk of suicidal behavior. Cholesterol dysregulation impairs neuroplasticity, which may be a mechanism underlying some of the mentioned abnormalities. Discrete positive effects have been reported with the use of cholesterol supplementation in the treatment of SLOS. Research has been limited by the small number of subjects available, and a limited understanding of lipid metabolism in the brain. Hopefully future research will help clarify the role that cholesterol plays in cognitive and behavioral abnormalities like the ones associated with SLOS. This would accelerate the development of treatments for SLOS, and perhaps also further understanding of non-syndromic psychiatric disorders such as autism and attention deficit hyperactivity disorder.

Analysis of short-term behavioral effects of dietary cholesterol supplementation in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis due to mutations of 7-dehydrocholesterol reductase (DHCR7). DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to yield cholesterol in the final step of cholesterol biosynthesis. Phenotypically patients with SLOS have multiple malformations, cognitive deficits, and behavioral difficulties. Impaired DHCR7 activity results in the accumulation of 7DHC and frequently decreased cholesterol in blood and tissues. Dietary cholesterol supplementation has become standard therapy for SLOS, and anecdotal reports suggest rapid, marked clinical improvement of behavior problems. Although reported in the literature, beneficial behavioral effects of dietary cholesterol supplementation have not been formally documented through a randomized clinical trial. To address this we initiated a double-masked, placebo-controlled, cross-over trial to test the hypothesis that dietary cholesterol supplementation has rapid beneficial effects on behavior. Our primary outcome measure was the hyperactivity subscale of the Aberrant Behavior Checklist (ABC). Hyperactivity is a symptom that has been reported to respond rapidly to dietary cholesterol supplementation. Secondary outcome measures included the total ABC score and other ABC subscale scores. Ten subjects completed this study. Although the trial was done under conditions similar to those reported to induce marked behavioral changes in SLOS patients, we observed no differences between treatment and placebo phases. The results of this study call into question anecdotal reports supporting rapid behavioral benefits previously reported for dietary cholesterol supplementation in SLOS and underscore the need for a larger placebo-controlled trial.

The challenge of providing continuity in the care of a disabled child: Smith-Lemli-Opitz syndrome.

The health of a disabled child can be adversely affected if parents and health care providers are not informed regarding the need for ongoing care and consultation. This case illustrates the ways in which failure to obtain appropriate consultation and breakdown in communication between parents, health care providers, and community agencies negatively impacted the health of a young child with Smith-Lemli-Opitz Syndrome (SLOS). Although the disorder was detected in the child, information regarding treatment was not communicated to those caring for the child, resulting in serious and potentially life-threatening consequences. In this case study, we review the pathophysiology of SLOS, the positive impact of making use of expert consultation, and the complexities of navigating multiple systems when advocating for a child with a serious developmental disorder. The role of nursing in facilitating collaboration among families, members of the health care team, and advocacy agencies, particularly in children with complex medical and psychiatric difficulties, is highlighted.

Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome.

The behavior phenotype of Smith-Lemli-Opitz syndrome (SLOS) was studied by assessing behavior, social, and communication abilities, sensory hyperreactivity, and the deficits associated with autistic disorder. Fifty-six SLOS subjects, age 0.3 to 32.3 years, were evaluated by multiple age-dependent questionnaires and telephone interviews. Of the 56 subjects, 50 (89%) had a history of repeated self-injury: 30 (54%) bit themselves; 27 (48%) head-banged; and 30 (54%) threw themselves backward in a highly characteristic upper body movement ("opisthokinesis"). Forty-seven of these subjects were also evaluated by direct observation and by direct interview of the parent or caregiver. Of 11 subjects 10 years or older, three (27%) had a stereotypic stretching motion of the upper body accompanied by hand flicking. Additional measures showed sensory hyperreactivity, temperament dysregulation, sleep disturbance, and social and communication deficits. Nine of 17 subjects (53%) met the diagnostic criteria for autistic disorder by the Autism Diagnostic Interview-Revised (ADI-R) algorithm questions [Lord et al., 1993, 1994]. Thus, SLOS is a metabolic disorder that can be associated with autism and other behavioral characteristics that define a distinctive and diagnostically important behavioral disorder.

Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS, RSH/SLO syndrome, MIM 270400) is an autosomal recessive multiple malformation/mental retardation syndrome initially described by Smith et al. [1964] that is due to a defect in cholesterol biosynthesis. The behavioral phenotype of Smith-Lemli-Opitz syndrome demonstrates cognitive abilities from borderline intellectual functioning to profound mental retardation, sensory hyperreactivity, irritability, language impairment, sleep cycle disturbance, self-injurious behavior, and autism spectrum behaviors. In a recent study of 28 subjects, 14 subjects (50%) with SLOS also exhibited the behavior of throwing themselves backward in a characteristic upper body movement ("opisthokinesis") and 2 adolescents had a stretching motion of the upper body accompanied by hand flicking [Tierney et al., 1999]. In that same study, 6 of 13 subjects (46%) met the Autism Diagnostic Interview-Revised (ADI-R) algorithm criteria (Lord et al. [1993] Infant Mental Health 14:234-252; Lord et al. [1994] J Autism Dev Disord 24:659-685) and the Diagnostic and Statistical Manual (APA [1994] DSM-IV) diagnostic criteria for autistic disorder. Smith-Lemli-Opitz syndrome is a metabolic disorder that is associated with autism. MRDD Research Reviews 2000;6:131-134.