It causes a broad spectrum of effects, ranging from mild intellectual disability and behavioural problems to lethal malformations.

Originally, SLOS patients were classified into two categories (classic and severe) based on physical and mental characteristics, alongside other clinical features.

[3] Given that SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis, the resulting biochemical characteristics may be predictable.

[2] Missense mutations (single nucleotide change resulting in a code for a different amino acid) are the most common, accounting for 87.6% of the SLOS spectrum.

It is thought that this mutation first occurred in the British Isles, and it has a carrier (those that are heterozygous for the allele but not affected) frequency of 1.09% for Caucasians of European heritage.

[1] Regulation of cholesterol synthesis is complex and occurs primarily through the enzyme HMG-CoA reductase (catalyst of the rate-limiting step).

The four main steps of regulation are:[8] Cholesterol is an important lipid involved in metabolism, cell function, and structure.

Given that neurons rely heavily on exocytosis for the transmission of impulses, cholesterol is a very important part of the nervous system.

This pathway is very important during embryonic development, and involved in deciding the fate of cells (i.e., which tissue they need to migrate to).

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.

SLOS patients may show cell membranes with abnormal properties or composition, and reduced cholesterol levels greatly affect the stability and proteins of lipid rafts.

[16] In addition, a lack of cholesterol contributes to the increased fluidity of the cell membrane, and may cause abnormal granule secretions.

[6] 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).

Thus, prenatally, SLOS is diagnosed upon finding an elevated 7DHC:total sterol ratio in fetal tissues, or increased levels of 7DHC in amniotic fluid.

Amniocentesis and chorionic villus sampling leave very little time to make this decision (abortions become more difficult as the pregnancy advances), and can also pose severe risks to the mother and baby.

These are novel metabolites due to the presence of a normally reduced double bond at carbon 7 (caused by the inactivity of DHCR7), and may be used as indicators of SLOS.

[19] Other cholesterol derivatives which possess a double bond at the 7th or 8th position and are present in maternal urine may also be indicators of SLOS.

Their excretion indicates that neither the placenta nor the maternal organs have necessary enzymes needed to reduce the double bond of these novel metabolites.

[18] If SLOS goes undetected until after birth, diagnosis may be based on the characteristic physical features as well as finding increased plasma levels of 7DHC.

[21] Other methods include time-of-flight mass spectrometry, particle-beam LC/MS, electrospray tandem MS, and ultraviolet absorbance, all of which may be used on either blood samples, amniotic fluid, or chorionic villus.

Measuring levels of bile acids in patients urine, or studying DCHR7 activity in tissue culture are also common postnatal diagnostic techniques.

This is likely because most developmental delays stem from malformations of the brain, which dietary cholesterol cannot ameliorate due to its inability to cross the blood–brain barrier.

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.

Furthermore, vitamin E specifically is known to decrease DHCEO levels, which is an indicator of oxidative stress in SLOS, as well as present beneficial changes in gene expression.

Vitamin E appears to be the most powerful antioxidant for treating SLOS, and in mouse models has reduced the levels of oxysterols in the brain.

Most importantly, mice possess both DHCR7 (the enzyme responsible for SLOS), and HMG-CoA reductase (the rate limiting step of cholesterol synthesis.

Although these pups died within the first day of life due to their inability to feed, they showed characteristics similar to humans with SLOS.

Overall however, the pups had fewer dysmorphic features than human patients with SLOS; they did not present limb, renal, adrenal or central nervous system malformations.

This is explained by the fact that in rodents, maternal cholesterol can cross the placenta, and actually appears to be essential for the development of the fetus.

[32] Mouse models have also been used to develop diagnostic techniques; multiple studies have examined biomarkers that result from the oxidation of 7DHC, such as DHCEO.