Analysis of short‐term behavioral effects of dietary cholesterol supplementation in Smith–Lemli–Opitz syndrome

Abstract

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.

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

“…Earlier studies have indicated that cholesterol therapy provides initial benefit to SLOS patients in terms of development and behavioral issues (52), but more recent research has shown that this may not improve patient health long term (53,54). In our system cholesterol had little effect on the SLOS mutants, which could be expected considering that initial DHCR7 expression was already very low (Fig.…”

Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome

“…Brain cholesterol biosynthesis is independent from whole-body cholesterol biosynthesis ( 27 ); different tissues may accumulate 7-DHC to different degrees and may metabolize 7-DHC or its derivatives differently. In some reported therapeutic studies of SLOS, cholesterol supplementation leads to no signifi cant symptomatic improvement in SLOS patients (28)(29)(30)(31). Thus, it is possible that 7-DHC accumulation within the nervous system, rather than cholesterol defi ciency, may be critical for development of the nervous system pathophysiology associated with SLOS.…”

Modified magnesium and lipoproteins in children with attention deficite hyperactivity disorder (ADHD)

“…Depending on their double bond number and position, fatty acids as main components could modulate the synthesis of lipoproteins. Lipoproteins are considered to be of psychic and behavioural importance (Tierney et al 2010), but their impact on ADHD is not known by now. Mg plays an important role in all major metabolism processes: particularly in oxidation-reduction and ionic regulations (Bourre 2006).…”