Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis due to mutations of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol 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, crossover 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.

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Summary Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ7-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.