Joel Pearson


May 2010

Document Type


Degree Name



Dept. of Public Health and Preventive Medicine


Oregon Health & Science University


Background The diagnosis of autism spectrum disorders (ASDs) has increased in prevalence 5 fold over the past two decades, leading to enormous medical costs and great public concern. These disorders may manifest in well described medical conditions, but their cause is usually unexplained. Recently, ASDs have been described in individuals with Smith-Lemli-Opitz syndrome (SLOS), which is caused by deficient cholesterol synthesis due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7). This suggests a role for cholesterol metabolism in the pathophysiology of ASDs. Cholesterol is known to be necessary for brain development, including myelination, synaptogenesis, and neurosteroid signalling. This study will employ SLOS as a disease model by which to examine cholesterol’s role in ASDs. Objectives To analyze blood samples from children with and without an ASD for levels of cholesterol, a cholesterol precursor (7-dehydrocholesterol), a cholesterol metabolite indicating levels of cholesterol turnover in the brain (24S-hydroxycholestrol, “24S”), and mutations of DHCR7 and to test the hypothesis that cholesterol metabolism is impaired in children with an ASD, specifically that plasma cholesterol and cholesterol metabolites are decreased, cholesterol precursors are increased, and mutations of DHCR7 are more common. Methods A case/control study was designed, with recruitment through the OHSU/CDRC Autism Clinic, consisting of children (≤18 years old) who were referred for a behavioral evaluation. Cases were defined as those who were diagnosed with an ASD and controls defined as those determined not to have an ASD. Levels of sterols and the frequency of nucleotide variants and pathologic mutations of DHCR7 were compared across cases and controls and multiple regression analysis to compared sterol levels while controlling for the possible confounding variables of age, gender, race, and BMI. Results Among 42 cases and 27 controls, baseline characteristics of age (78.5 vs. 93.4 months, p=0.15), gender (83% male vs. 81% male, p=1), race (85% white vs. 77% white, p=0.43), and BMI (17.3 vs. 19.0, p=0.11) did not differ significantly across case and control groups, respectively. In cases, blood levels of 24S (104.1 ng/mL vs. 78.6 ng/mL, p=0.002) and the 24S/Cholesterol ratio (71.6 vs. 57.4, p=0.015) were found to be significantly different, although cholesterol (146.6 mg/dL vs. 140.2 mg/dL, p=0.27) and 7-DHC (7.3 μg/dL vs. 13.8 μg/dL, p=0.22) levels were not. Cases were found to more frequently have nucleotide variants of the DHCR7 gene (50% vs. 19%, p=0.01), specifically in the locations of Exon 4(189A>G) (43% vs. 15%, p=0.02) and Exon 9(1272 T>C) (43% vs. 19%, p=0.04), and although the proportion carrying a pathologic mutation did not differ statistically (cases: 7%, controls: 0%, p=0.28), it is notable that 3 cases carried pathologic mutations of DHCR7 while no controls where carriers. This case carrier frequency of 1/14 is compared to a published carrier frequency of 1/30. Using multiple regression to control for the known confounder of age, 24S levels were significantly different between cases and controls (coefficient=17.01, p=0.01), although this difference became marginal when age was transformed to it natural logarithm (coefficient=13.10, p=0.051). Conclusion Children with an ASD had more nucleotide variants and pathologic mutations of the DHCR7 gene compared to those without an ASD (although the difference in pathologic mutations was statistically non-signficant). Also, 24S levels were found to be significantly greater in the ASD group when controlling for age. However, this difference became marginal when age was transformed to better fit the relationship between age and 24S. No significant difference was observed in cholesterol or 7-DHC. No child met the diagnostic criteria for SLOS. These findings suggest that those with an ASD may have increased genetic variability in loci involved in cholesterol synthesis and that those with an ASD may experience greater cholesterol turnover or neuronal dengeneration in their brain.




School of Medicine



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