Pilot work suggests that some individuals with autism spectrum disorders (ASD) have very low blood cholesterol levels. This low cholesterol level and other abnormal sterol levels may be important markers for subtypes of ASD. The proposed trial aims to characterize any clinical differences between low-cholesterol ASD and normal-or-high-cholesterol ASD and to test the response of individuals with ASD and low cholesterol to increased cholesterol in the diet.
Evidence for the role of low cholesterol in causing ASD in a subgroup of individuals comes from five sources. First, half of individuals with Smith-Lemli-Opitz syndrome (SLOS) meet the behavioral criteria for autistic disorder (Tierney et al, 2001), and three quarters have some type of ASD (Sikora et al, 2006). Second, in individuals with SLOS, the lower the cholesterol was in the blood and cerebrospinal fluid, the more severe were the autism and IQ and adaptive function deficits. Third, in SLOS, improvement was found in social and communication abilities with added dietary cholesterol. Fourth, cholesterol was low in a pilot study of 100 children with autism of unknown cause (Tierney et al, 2006). Fifth, it is becoming increasingly clear that cholesterol plays a pivotal role in several aspects of brain development.
This proposal is designed to 1) determine the prevalence of hypocholesterolemia in ASD individuals (ASD+Hypo); 2) determine the prevalence of hypercholesterolemia (in ASD individuals (ASD+Hyper); 3) determine the rate of SLOS in the ASD subjects; 4) determine the phenotype (physical, behavioral, and developmental) at less than the 5th centile (ASD+Hypo) and greater than the 95th centile (ASD+Hyper) individuals and normal cholesterol (ASD+Normal) in the ASD subjects; 5) test the efficacy of dietary cholesterol supplementation in ASD individuals with hypocholesterolemia; 6) determine whether a raised dose of cholesterol supplementation is more effective than a lower dose; and 7) create a repository of biomaterial samples from individuals with ASD and their biological family members.
Three sites (Kennedy Krieger Institute \[KKI\], Ohio State University \[OSU\], and the National Institutes of Health \[NIH\]) will collaborate to accomplish the objectives of this study. In addition to defining the frequency of altered cholesterol homeostasis in ASD, 60 youths (20 at each site) with ASD plus hypocholesterolemia will enter a 12-week, double-blind, placebo-controlled trial immediately followed by a 12-week open-label cholesterol trial to test the efficacy of dietary cholesterol supplementation. Outcome measures will include standard tests of behavior, communication, and other autism features.
These findings will guide the medical community in identifying individuals who should be tested for sterol disorders. This study will also help researchers learn whether adding extra cholesterol to the diet will improve behavioral and other autism spectrum characteristics seen in individuals with ASD and low cholesterol. The results of this study may help individuals with hypocholesterolemic ASD by the knowledge of the therapeutic value and safety of the use of cholesterol supplementation both biochemically and behaviorally. If improvement is demonstrated, it opens a new window to understanding the neurologic mechanisms of ASD. This knowledge may also be helpful for hypocholesterolemic individuals with ASD in that this newly identified population will benefit from such supplementation. Even if cholesterol supplementation is found to not be effective, important behavioral phenotype and developmental information will be obtained that might be useful in identifying subjects with ASD plus cholesterol abnormalities.
