Hedgehog proteins are also involved in the transcription of genes that regulate cell proliferation and differentiation. Cholesterol is important to this pathway because it undergoes covalent bonding to Hedgehog proteins, resulting in their activation. Without cholesterol, the signaling activity is disrupted and cell differentiation may be impaired.Cholesterol is a precursor for many important molecules. These include bile acids (important in processing dietary fats), oxysterols, neurosteroids (involved in neurotransmission and excitation), glucocorticoids (involved in immune and inflammatory processes), mineralocorticoids (osmotic balance), and sex steroids (i.e. estrogen and testosterone; wide range of function but involved in genital development prenatally). Finally, cholesterol is a major component of myelin, a protective layer around neurons. Myelination occurs most rapidly during prenatal development, meaning that the demand for cholesterol biosynthesis is very high. Pathogenesis
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.
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. Screening and diagnosis
Prenatally
The most characteristic biochemical indicator of SLOS is an increased concentration of 7DHC (reduced cholesterol levels are also typical, but appear in other disorders as well).