Simvastatin therapy
HMG-CoA reductase inhibitors have been examined as treatment for SLOS. Given that this catalyzes the rate-limiting step in cholesterol synthesis, inhibiting it would reduce the buildup of toxic metabolites such as 7DHC. Simvastatin is a known inhibitor of HMG-CoA reductase, and most importantly is able to cross the blood–brain barrier. It has been reported to decrease the levels of 7DHC, as well as increase the levels of cholesterol. The increased cholesterol levels are due to simvastatins effect on the expression of different genes. Simvastatin increases the expression of DHCR7, likely leading to increased activity of DHCR7. It has also been shown to increase the expression of other genes involved in cholesterol synthesis and uptake. However, these benefits are dependent on the amount of residual cholesterol synthesis. Because some individuals possess less severe mutations and demonstrate some amount of DCHR7 activity, these people benefit the most from simvastatin therapy as they still have a partially functioning enzyme. For individuals that show no residual DCHR7 activity, such as those homozygous for null alleles or mutations, simvastatin therapy may actually be toxic. This highlights the importance of identifying the specific genotype of the SLOS patient before administering treatment. It is still unknown if simvastatin will improve the behavioural or learning deficits in SLOS. Antioxidant supplementation
Antioxidants are those which inhibit the oxidation of molecules or reduce metabolites that were previously oxidized. Given that some symptoms of SLOS are thought to result from the peroxidation of 7DHC and its derivatives, inhibiting this peroxidation would likely have beneficial effects.
All of these changes in the membrane likely contribute to changes in transport functions that are observed in SLOS. They may cause defects in IgE receptor-mediated mast cell degranulation and cytokine production, which are cells involved in allergic and immune responses. The NMDA receptor is affected, as well as the binding capability of the hippocampal serotonin receptor. Cell to cell interaction, which is very important in development, may be impaired. Exocytosis in synaptic vesicles has been shown to be reduced, likely due to impaired vesicle fusion to the cell membrane, or poor vesicle recycling. Finally, cholesterol is highly prevalent in myelin, therefore SLOS patients show reduced myelination of the cerebral hemispheres, peripheral nerves, and cranial nerves.In addition to lowered levels of cholesterol, many of the symptoms shown in SLOS stem from the toxic effects of 7DHC. 7DHC is known to impair intracellular cholesterol transport. It also increases the degradation of HMG-CoA reductase (the enzyme that catalyzes the rate-limiting step in cholesterol synthesis). 7DHC leads to novel oxysterol and steroid derivatives, and many of their functions or effects are yet unknown. A very important finding with respect to 7DHC is that it is the most reactive lipid for lipid peroxidation, and results in systemic oxidative stress. Lipid peroxidation is known to destroy membranes of both cells and membrane-bound organelles. The derivative of 7DHC that is used to indicate oxidative stress is 3β,5α-dihydroxy-cholest-7-en-6-one (DHCEO); it is formed from a primary product of 7DHC peroxidation, 7-DHC-5α,6α-epoxide.