Given that the function of cholesterol encompasses a very wide range, it is unlikely that the symptoms of SLOS are due to a single molecular mechanism. Some of the molecular effects are yet unknown, but could be extrapolated based on the role of cholesterol. In general, the negative effects are due to decreased levels of cholesterol and increased levels of cholesterol precursors-most notably, 7DHC. Although 7DHC is structurally similar to cholesterol, and could potentially act as a substitute, the effects of this are still being studied. Most patients with SLOS present decreased cholesterol levels, particularly in the brain (where cholesterol levels rely primarily on new synthesis). This also means that any sterol derivatives of cholesterol would also have reduced concentrations. For example, reduced levels of neurosteroids may be seen in SLOS. These are lipids which take part in signaling within the brain, and must be produced within the brain itself. They are responsible for interacting with nuclear steroid receptors, and bind to neurotransmitter-gated ion channels. Specifically, they modulate the effects of GABA and NMDA receptors, resulting in calming effects, improved memory, and more. Thus, given that some characteristics of SLOS are the opposite of these effects (hyperactivity, anxiety), a reduction in neurosteroids could influence both neurological development and behaviour. Pathogenesis of Smith-Lemli-Optiz syndrome. Furthermore, as outlined above, cholesterol is an important aspect in Hedgehog signaling. With lower levels of cholesterol, hedgehog proteins would not undergo the necessary covalent modification and subsequent activation. This would result in impaired embryonic development, and may contribute to the observed physical birth defects in SLOS. One particular hedgehog signaling protein, sonic hedgehog (SHH), is important in the pattern of the central nervous system, facial features, and limbs. Other hedgehog proteins may be involved in the development of the genital tract and the skeleton. The altered sterol levels in SLOS are particularly relevant to cell membranes, which are made primarily of lipids. SLOS patients may show cell membranes with abnormal properties or composition, and reduced cholesterol levels greatly affect the stability and proteins of lipid rafts. Despite their structural similarity, 7DHC is unable so replace cholesterol in lipid rafts. In addition, a lack of cholesterol contributes to the increased fluidity of the cell membrane, and may cause abnormal granule secretions. 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. DHCEO is toxic to cortical neuronal and glial cells, and accelerates their differentiation and arborization. Through oxidative stress, 7DHC is thought to be responsible for the increased photosensitivity shown in SLOS patients. Normal UVA exposure may lead to oxidative stress in skin cells. Given that 7DHC is more readily oxidized, it enhances the effects of UVA, leading to increased membrane lipid oxidation and increased production of reactive oxygen species (ROS). Typically, more altered the levels of 7DHC and cholesterol lead to more severe symptoms of SLOS. The levels of these metabolites also correspond to the severity of the mutation (nonsense versus missense); some mutations of DHCR7 may still show residual cholesterol synthesis, and others may not. However, even individuals with the same mutations or genotype may still show variability in their symptoms. This may be due to maternal factors, such as the transfer of cholesterol to the fetus during pregnancy, as well as the amount of cholesterol present in the brain before the blood–brain barrier forms prenatally. The rate of accumulation and excretion of toxic metabolites may vary from person to person. Maternal apolipoprotein E has also been implicated in individual variability in SLOS, although the exact nature of this relationship is unknown. There are likely more factors contributing to the wide spectrum of effects in SLOS which have not yet been discovered.
Smith–Lemli–Opitz syndrome
DiGeorge syndrome
Li–Fraumeni syndrome
Smith–Magenis syndrome
Wilson–Turner syndrome
Simpson–Golabi–Behmel syndrome
Landau–Kleffner syndrome
Kapur–Toriello syndrome