View source for Smith–Lemli–Opitz syndrome

{{Short description|Recessive genetic condition}}
{{Infobox medical condition (new)
| name            = Smith–Lemli–Opitz syndrome
| image           = Smith-Lemli-Opitz Syndrome 1.jpg
| caption         = Child with Smith-Lemli-Opitz syndrome
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| pronounce       =
| field           =
| synonyms        = '''SLOS''', or '''7-dehydrocholesterol reductase deficiency'''
| symptoms        =
| complications   =
| onset           = Present at birth
| duration        =
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| risks           =
| diagnosis       =
| differential    =
| prevention      =
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| prognosis       =
| frequency       = 1 in 20,000 to 1 in 60,000
| deaths          =
}}

'''Smith–Lemli–Opitz syndrome''' is an [[inborn error of metabolism|inborn error]] of cholesterol synthesis.<ref name="DHCR7 and SLOS">{{cite journal |doi=10.1016/j.ymgme.2004.09.017 |title=3β-Hydroxysterol Δ7-reductase and the Smith–Lemli–Opitz syndrome |year=2005 |last1=Correa-Cerro |first1=Lina S. |last2=Porter |first2=Forbes D. |journal=Molecular Genetics and Metabolism |volume=84 |issue=2 |pages=112–26 |pmid=15670717|url=https://zenodo.org/record/1259481 }}</ref> It is an [[autosome|autosomal]] [[recessive (genetics)|recessive]], multiple malformation syndrome caused by a [[mutation]] in the [[enzyme]] [[7-Dehydrocholesterol reductase]] encoded by the DHCR7 gene. It causes a broad spectrum of effects, ranging from mild [[intellectual disability]] and behavioural problems to lethal malformations.<ref name="SLOS review">{{cite journal |doi=10.1038/ejhg.2008.10 |title=Smith–Lemli–Opitz syndrome: Pathogenesis, diagnosis and management |year=2008 |last1=Porter |first1=Forbes D |journal=European Journal of Human Genetics |volume=16 |issue=5 |pages=535–41 |pmid=18285838|url=https://zenodo.org/record/1233247 |doi-access=free }}</ref>

==Signs and symptoms==

SLOS can present itself differently in different cases, depending on the severity of the mutation and other factors. Originally, SLOS patients were classified into two categories (classic and severe) based on physical and mental characteristics, alongside other clinical features. Since the discovery of the specific biochemical defect responsible for SLOS, patients are given a severity score based on their levels of cerebral, ocular, oral, and genital defects. It is then used to classify patients as having mild, classical, or severe SLOS.<ref name="SLOS novel met" />

===Physical characteristics===
[[File:Smith-Lemli-Opitz Syndrome 5.jpg|thumb|Polydactyly of the hand in SLOS]]
[[File:Feets with partial simple syndactyly.jpg|thumb|Syndactyly of the second and third toes]]
The most common facial features of SLOS include [[microcephaly]], bitemporal narrowing (reduced distance between temples), [[Ptosis (eyelid)|ptosis]], a short and upturned nose, [[micrognathism|micrognathia]], [[epicanthic fold|epicanthal folds]], and [[hemangioma|capillary hemangioma]] of the nose.<ref name="SLOS novel met" /> Other physical characteristics include:<ref name="SLOS review"/>
* low-set and posteriorly rotated ears
* high-arched, narrow, hard palate
* [[Cleft lip and palate|cleft lip/palate]]
* [[agenesis of the corpus callosum|agenesis]] or [[hypoplasia]] of the [[corpus callosum]]
* cerebellar [[hypoplasia]]
* increased [[ventricular system|ventricular]] size
* decreased [[frontal lobe]] size
* [[polydactyly]] of hands or feet
* short, proximally placed thumb
* other finger malformations
* [[syndactyly]] of second and third toes
* ambiguous or female-like male genitalia
* congenital heart defects
* renal, pulmonary, liver and eye abnormalities

===Behavioural characteristics===

Certain behaviours and attributes are commonly seen among patients with SLOS. They may have low normal intelligence, and react negatively or with hypersensitivity to different sensory stimuli. This is particularly true for certain auditory and visual stimuli. Many patients show aggressiveness and [[self-harm|self-injurious]] behaviours, and sleep disturbances are common.<ref name="SLOS novel met" /> Specific behaviours resembling those of people with [[autism]] are often present as well as [[hyperactivity]], which provides genetic and biological insights into autism spectrum disorders. The autistic behaviours most characteristic of SLOS patients are opisthokinesis (an upper body movement), stretching of the upper body, and hand flicking.<ref name="ASD Met">{{cite journal |doi=10.1016/j.pediatrneurol.2013.05.013 |title=Autism Spectrum Disorders and Inborn Errors of Metabolism: An Update |year=2013 |last1=Ghaziuddin |first1=Mohammad |last2=Al-Owain |first2=Mohammed |journal=Pediatric Neurology |volume=49 |issue=4 |pages=232–6 |pmid=23921282}}</ref> Autism is typically diagnosed separately from SLOS using the [[Diagnostic and Statistical Manual of Mental Disorders|DSM-V]], and approximately 50–75% of SLOS patients meet the criteria for autism.<ref name=AutCaseStud>{{cite journal |doi=10.1176/appi.ajp.2007.07020315 |title=Smith-Lemli-Opitz Syndrome and Autism Spectrum Disorder |year=2007 |last1=Bukelis |first1=I. |last2=Porter |first2=F. D. |last3=Zimmerman |first3=A. W. |last4=Tierney |first4=E. |journal=American Journal of Psychiatry |volume=164 |issue=11 |pages=1655–61 |pmid=17974928}}</ref>

Other behaviours associated with SLOS can be linked directly to physical abnormalities. For example, infants often show feeding problems or feeding intolerance, and patients may require increased caloric intake due to accelerated metabolism. Recurrent infections, including ear infections and pneumonia, are also common.<ref name="SLOS novel met" />

===Biochemical phenotype===

Given that SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis, the resulting biochemical characteristics may be predictable. Most patients have lowered plasma cholesterol levels ([[hypocholesterolemia]]). However, approximately 10% may show normal cholesterol levels,<ref name="SLOS novel met" />  and decreased concentrations of cholesterol are not solely indicative of SLOS. Increased levels of cholesterol precursors are also common in SLOS. In particular, elevated levels of [[7-dehydrocholesterol]] are fairly specific to SLOS.<ref name="SLOS review" />

==Genetics==

===DHCR7===
[[File:7-Dehydrocholesterol.svg|thumb|[[7-Dehydrocholesterol]] is a toxic steroidal metabolite that accumulates in the bodies of those with SLOS]]
The gene encoding [[7-Dehydrocholesterol reductase|DHCR7]] (labeled as ''DHCR7'') was cloned in 1998, and has been mapped to [[chromosome 11|chromosome 11q12-13]].<ref name="DHCR7 and SLOS" /> It is 14100 [[base pair]]s of DNA in length, and contains nine [[exon]]s,<ref name="SLOS review" /> the corresponding [[messenger RNA|mRNA]] is 2786 base pairs in length (the remaining DNA sequence is intronic). The structure of the ''DHCR7'' rat gene is very similar to the structure of the human gene.<ref name="DHCR7 and SLOS" />

The highest levels of ''DHCR7'' [[gene expression|expression]] have been detected in the adrenal gland, the testis, the liver and in brain tissue. Its expression is induced by decreased [[sterol]] concentrations via sterol regulatory binding proteins (SREBP). There is also evidence that its activity may be regulated by tissue specific transcription, and [[alternative splicing]].<ref name="DHCR7 and SLOS" />

As outlined above, the enzyme DHCR7 catalyzes the reduction of 7DHC to cholesterol, as well as the reduction of 7-dehydrodesmosterol to desmosterol. It requires NADPH as a cofactor for this reduction, and may involve the activity of [[cytochrome P450|cytochrome-P450 oxidoreductase]]. It is also thought to contain iron.<ref name="DHCR7 and SLOS" /> DHCR7 is an [[integral membrane protein]] of the endoplasmic reticulum, and computer models have predicted up to nine [[transmembrane domain]]s.<ref name="SLOS review" /> DHCR7 is most efficient at reducing 7DHC, but it is known to reduce the carbon 7 double bond of other sterols, indicating a range of [[enzyme substrate (biology)|substrate]] [[specificity constant|specificity]]. The human version of this enzyme is predicted to have a [[molecular mass|molecular weight]] of 54,489 [[atomic mass unit|kDa]], and an [[isoelectric point]] of 9.05.<ref name="DHCR7 and SLOS" />

The [[amino acid]] sequence that encodes DHCR7 is predicted to contain 475 amino acids, as well as several [[sequence motif|protein motifs]]. It contains multiple sterol reductase motifs, as would be expected given its function. It contains a potential sterol-sensing domain (SSD), whose function is unknown but thought to be necessary for binding sterol substrates. It also includes multiple sites of phosphorylation, including potential [[protein kinase C]] and [[tyrosine kinase]] sites (regulatory enzymes responsible for phosphorylation). The exact function of phosphorylating DHCR7 is yet unknown, but it is thought to be involved in the regulation of its activity.<ref name="DHCR7 and SLOS" />

===Mutations and incidence===
[[File:Missense Mutation Example.jpg|thumb|400px|Missense mutations account for 87.6% of the SLOS spectrum]]
SLOS is an [[autosome|autosomal]] [[recessive trait|recessive]] disorder.<ref name=insight>{{cite journal |doi=10.1111/j.1399-0004.2005.00515.x |title=Recent insights into the Smith-Lemli-Opitz syndrome |year=2005 |last1=Yu |first1=H |last2=Patel |first2=SB |journal=Clinical Genetics |volume=68 |issue=5 |pages=383–91 |pmid=16207203 |pmc=1350989}}</ref> More than 130 different types of mutations have been identified.<ref name="SLOS review" />  [[Missense mutation]]s (single nucleotide change resulting in a code for a different amino acid) are the most common, accounting for 87.6% of the SLOS spectrum. These typically reduce the function of the enzyme but may not inhibit it completely. Much depends on the nature of the mutation (i.e. which amino acid is replaced and where). [[Null allele|Null mutations]] are much less common, these mutations produce either a completely dysfunctional enzyme, or no enzyme at all. Thus, missense mutations may be more common overall because they are less lethal than nonsense mutations; nonsense mutations may simply result in [[miscarriage|spontaneous abortion]].<ref name=insight />

The IVS8-1G>C is the most frequently reported mutation in ''DHCR7''. This disrupts the joining of exons eight and nine, and results in the insertion of 134 [[nucleotide]]s into the ''DHCR7'' transcript. This is a nonsense mutation, thus patients that are [[zygosity|homozygous]] for this allele are severely affected. It is thought that this mutation first occurred in the [[British Isles]], and it has a [[genetic carrier|carrier]] (those that are [[zygosity|heterozygous]] for the allele but not affected) frequency of 1.09% for Caucasians of European heritage. The frequency of mutations differs for various ethnicities, depending on the origin of the mutation. In all Caucasian populations, this particular mutation has an estimated carrier frequency of 3%.<ref name="DHCR7 and SLOS" />

The next most common mutation is 278C>T, and results in a [[threonine]] at the amino acid position 93. It is a missense mutation and tends to be associated with less severe symptoms. This mutation is the most common one seen in patients of Italian, Cuban, and Mediterranean descent.<ref name="DHCR7 and SLOS" />

The third most common mutation is  452G>A. This [[nonsense mutation]] causes protein termination, such that the enzyme DHCR7 would not be formed. It is thought to have arisen in Southern Poland and is most common in Northern Europe.<ref name="DHCR7 and SLOS" />

Other mutations are less common, although appear to target certain protein domains more so than others. For example, the sterol reductase motifs are common sites of mutation.<ref name="DHCR7 and SLOS" /> Overall, there is an estimated carrier frequency (for any DHCR7 mutation causing SLOS) of 3-4% in Caucasian populations (it is less frequent among Asian and African populations<ref name="irons1998">{{cite book |last=Nowaczyk |first=Malgorzata JM |chapter=Smith-Lemli-Opitz Syndrome |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1143/ |title=GeneReviews |publisher=National Library of Medicine |date=June 20, 2013 |pmid=20301322 |access-date=December 5, 2013 |editor1-first=Roberta A |editor1-last=Pagon |editor2-first=Margaret P |editor2-last=Adam |editor3-first=Thomas D |editor3-last=Bird |editor4-first=Cynthia R |editor4-last=Dolan |editor5-first=Chin-To |editor5-last=Fong |editor6-first=Richard JH |editor6-last=Smith |editor7-first=Karen |editor7-last=Stephens}}</ref>). This number indicates a hypothetical birth [[incidence (epidemiology)|incidence]] between 1/2500 and 1/4500. However, the measured incidence is between 1/10,000 to 1/60,000 (it differs depending on heritage and descent).<ref name=insight /> This is much lower than expected. This indicates that many cases of SLOS are undetected, and is likely due to either spontaneous abortion caused by severe mutations (miscarriage), or mild cases that are undiagnosed. Females lack the characteristic genital malformations that affected males have, and thus are less likely to be correctly diagnosed.<ref name="irons1998" />

==Cholesterol metabolism and function==

===Metabolism===

Cholesterol can be obtained through the diet, but it can also be formed by metabolism in the body. Cholesterol metabolism primarily takes place in the liver, with significant amounts in the intestine as well.<ref name=biochembook>{{cite book |last1=Berg |first1=Jeremy M |last2=Tymoczko |first2=John L |last3=Stryer |first3=Lubert |year=2002 |chapter=The Complex Regulation of Cholesterol Biosynthesis Takes Place at Several Levels |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK22336/ |title=Biochemistry |edition=5th |publisher=W H Freeman |location=New York |isbn=978-0-7167-3051-4 |page=Section 26.3 |no-pp=yes |url-access=registration |url=https://archive.org/details/biochemistrychap00jere }}</ref> It should also be noted that cholesterol cannot pass the [[blood–brain barrier]], thus within the brain, biosynthesis is the only source of cholesterol.<ref name="Imaging" />
[[File:MevalonatePNGmade.png|600px|thumb|Mevalonate pathway.]]
In humans, [[cholesterol]] synthesis begins with the [[mevalonate pathway]] (see diagram), leading to the synthesis of [[farnesyl pyrophosphate]] (FPP). This pathway uses two [[acetyl-CoA]] and two [[Nicotinamide adenine dinucleotide phosphate|NADPH]] to make [[mevalonic acid|mevalonate]], which is metabolized to [[isopentenyl pyrophosphate]] (IPP) using three [[adenosine triphosphate|ATP]]. From there, three IPP are needed to make one FPP. The combination of two FPP leads to the formation of [[squalene]]; this represents the first committed step towards cholesterol biosynthesis. Squalene leads to the creation of [[lanosterol]], from which there are multiple pathways that lead to cholesterol biosynthesis. The rate limiting step of cholesterol synthesis is the conversion of [[HMG-CoA|3-hydroxy-3-methylglutaryl-CoA]] (HMG-CoA) to mevalonate, this is an early step in the mevalonate pathway catalyzed by [[HMG-CoA reductase]].<ref name="Cholesterol book">{{cite book |first1=Laura |last1=Liscum |chapter=Cholesterol biosynthesis |chapter-url=https://books.google.com/books?id=LZprTsjcvIMC&pg=PA399 |pages=399–422 |editor1-first=D. E. |editor1-last=Vance |editor2-first=J. E. |editor2-last=Vance |year=2008 |title=Biochemistry of Lipids, Lipoproteins and Membranes |edition=5th |publisher=Elsevier |isbn=978-0-08-055988-9}}</ref>

[[File:Lanosterol from squalene.svg|450px|thumb|right|Reaction scheme of squalene giving lanosterol.]]
[[File:KRpathwaydiagram.png|500px|thumb|right|Multiple pathways leading to cholesterol from lanosterol, including the Kandutsch-Russel pathway. Highlighted in red is the double bond which is reduced by the enzyme DHCR7.]]
Through a complicated series of reactions, lanosterol leads to the formation of [[zymosterol]]. As shown in a diagram to the right, it is at this point that the pathway diverges. In humans, the main pathway leading to cholesterol is known as the Kandutsch–Russell pathway.<ref name="SLOS novel met">{{cite journal |doi=10.1034/j.1399-0004.2001.590601.x |title=The Smith-Lemli-Opitz syndrome: A novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology |year=2001 |last1=Nowaczyk |first1=MJM |last2=Waye |first2=JS |journal=Clinical Genetics |volume=59 |issue=6 |pages=375–86 |pmid=11453964|s2cid=9146017 }}</ref> Zymosterol is metabolized to 5α-cholesta-7,24-dien-3β-ol, then to [[lathosterol]], and then to [[7-dehydrocholesterol]], or 7-DHC. 7-DHC is the immediate precursor to cholesterol, and the enzyme DHCR7 is responsible for converting 7-DHC to cholesterol.<ref name="DHCR7 and SLOS" /> DHCR7 reduces the [[double bond]] on carbon 7 of 7-DHC, leading to the [[ester|unesterified]] product.<ref name="Imaging">{{cite journal |doi=10.1016/j.neuroscience.2010.07.038 |title=Nanostructure-initiator mass spectrometry (NIMS) imaging of brain cholesterol metabolites in Smith-Lemli-Opitz syndrome |year=2010 |last1=Patti |first1=G.J. |last2=Shriver |first2=L.P. |last3=Wassif |first3=C.A. |last4=Woo |first4=H.K. |last5=Uritboonthai |first5=W. |last6=Apon |first6=J. |last7=Manchester |first7=M. |last8=Porter |first8=F.D. |author-link9=Gary Siuzdak |last9=Siuzdak |first9=G. |journal=Neuroscience |volume=170 |issue=3 |pages=858–64 |pmid=20670678 |pmc=2952448 }}</ref> Mutations in this enzyme are responsible for the wide range of defects present in SLOS. In another pathway leading to cholesterol synthesis, DHCR7 is required for the reduction of [[7-Dehydrodesmosterol]] to [[desmosterol]].<ref name="DHCR7 and SLOS" />

===Regulation===

Regulation of cholesterol synthesis is complex and occurs primarily through the enzyme HMG-CoA reductase (catalyst of the rate-limiting step). It involves a [[feedback]] loop that is sensitive to cellular levels of cholesterol. The four main steps of [[regulation of gene expression|regulation]] are:<ref name=biochembook />
* The synthesis of the enzyme HMG-CoA reductase is controlled by sterol regulatory element binding protein (SREBP). This is a [[transcription factor]] that is inactive when cholesterol levels are high, and active when cholesterol levels are low. When cholesterol levels fall, SREBP is released from the [[nuclear membrane]] or [[endoplasmic reticulum]], it then migrates to the [[cell nucleus|nucleus]] and causes the [[transcription (genetics)|transcription]] of the HMG-CoA reductase [[gene]].
* The [[translation (biology)|translation]] (creating the enzyme from the mRNA transcript) of HMG-CoA reductase is inhibited by derivatives of mevalonate and by dietary cholesterol.
* The degradation of HMG-CoA reductase is tightly controlled. The part of the enzyme that is bound to the endoplasmic reticulum senses signals, such as increased cholesterol levels, that lead to its degradation or [[proteolysis]].
* When HMG-CoA reductase is [[phophorylation|phosphorylated]], its activity decreases. This means cholesterol synthesis is reduced when cell energy (ATP) levels are low.

===Function===

Cholesterol is an important [[lipid]] involved in metabolism, cell function, and structure. It is a structural component of the [[cell membrane]],<ref name="DHCR7 and SLOS" /> such that it provides structure and regulates the [[membrane fluidity|fluidity]] of the [[lipid bilayer|phospholipid bilayer]]. Furthermore, cholesterol is a constituent in [[lipid raft]]s. These are congregations of [[protein]]s and lipids (including [[sphingolipid]]s and cholesterol) that float within the cell membrane, and play a role in the regulation of membrane function. Lipid rafts are more ordered or rigid than the membrane bilayer surrounding them. Their involvement in regulation stems mostly from their association with proteins; upon binding substrates, some proteins have a higher affinity for attaching to lipid rafts. This brings them in close proximity with other proteins, allowing them to affect [[signal transduction|signaling pathways]]. Cholesterol specifically acts as a spacer and a glue for lipid rafts; absence of cholesterol leads to the dissociation of proteins.<ref name=Lipidraft>{{cite journal |doi=10.1172/JCI16390 |title=Cholesterol, lipid rafts, and disease |year=2002 |last1=Simons |first1=Kai |last2=Ehehalt |first2=Robert |journal=Journal of Clinical Investigation |volume=110 |issue=5 |pages=597–603 |pmid=12208858 |pmc=151114}}</ref>

Given its prevalence in cell membranes, cholesterol is highly involved in certain [[membrane transport|transport]] processes. It may influence the function of [[ion channel]]s and other membrane transporters. For example, cholesterol is necessary for the [[ligand (biochemistry)|ligand]] binding activity of the [[serotonin]] [[receptor (biochemistry)|receptor]].<ref name=serotonin>{{cite journal |doi=10.1016/j.bbrc.2007.04.135 |title=Differential effects of cholesterol and 7-dehydrocholesterol on the ligand binding activity of the hippocampal serotonin1A receptor: Implications in SLOS |year=2007 |last1=Singh |first1=Pushpendra |last2=Paila |first2=Yamuna Devi |last3=Chattopadhyay |first3=Amitabha |journal=Biochemical and Biophysical Research Communications |volume=358 |issue=2 |pages=495–9 |pmid=17493586}}</ref> In addition, it appears to be very important in [[exocytosis]]. Cholesterol modulates the properties of the membrane (such as membrane curvature), and may regulate the fusion of [[vesicle (biology and chemistry)|vesicles]] with the cell membrane. It may also facilitate the recruitment of complexes necessary for exocytosis. Given that [[neuron]]s rely heavily on exocytosis for the transmission of [[action potential|impulses]], cholesterol is a very important part of the [[nervous system]].<ref name=vesicle>{{cite journal |doi=10.1242/jcs.060681 |title=Cholesterol reduction impairs exocytosis of synaptic vesicles |year=2010 |last1=Linetti |first1=A. |last2=Fratangeli |first2=A. |last3=Taverna |first3=E. |last4=Valnegri |first4=P. |last5=Francolini |first5=M. |last6=Cappello |first6=V. |last7=Matteoli |first7=M. |last8=Passafaro |first8=M. |last9=Rosa |first9=P. |journal=Journal of Cell Science |volume=123 |issue=4 |pages=595–605 |pmid=20103534 |doi-access=free }}</ref>

[[File:Cholesterolfunction.jpg|thumb|400px|Functions and derivatives of cholesterol.]]
One particularly relevant pathway in which cholesterol takes place is the [[Hedgehog signaling pathway]]. This pathway is very important during [[human embryogenesis|embryonic development]], and involved in deciding the fate of cells (i.e., which tissue they need to migrate to). Hedgehog proteins are also involved in the transcription of genes that regulate cell [[cell growth|proliferation]] and [[cellular differentiation|differentiation]]. Cholesterol is important to this pathway because it undergoes [[covalent bond]]ing to Hedgehog proteins, resulting in their activation. Without cholesterol, the signaling activity is disrupted and cell differentiation may be impaired.<ref name=Hedgehog>{{cite journal |doi=10.1016/j.cub.2008.01.050 |title=Hedgehog signalling |year=2008 |last1=Ingham |first1=Philip W. |journal=Current Biology |volume=18 |issue=6 |pages=R238–41 |pmid=18364223|doi-access=free }}</ref>

Cholesterol is a precursor for many important molecules. These include [[bile acid]]s (important in processing dietary fats), [[oxysterols]], [[neuroactive steroid|neurosteroids]] (involved in neurotransmission and excitation), [[glucocorticoid]]s (involved in immune and inflammatory processes), [[mineralocorticoid]]s (osmotic balance), and [[sex steroid]]s (i.e. [[estrogen]] and [[testosterone]]; wide range of function but involved in genital development prenatally).<ref name="DHCR7 and SLOS" /> 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.<ref name="Imaging" />

==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, [[7-Dehydrocholesterol|7DHC]]. Although 7DHC is structurally similar to cholesterol, and could potentially act as a substitute, the effects of this are still being studied.<ref name="SLOS review" />

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 [[Neuroactive steroid|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 receptor|nuclear steroid receptors]], and bind to [[neurotransmitter]]-gated ion channels. Specifically, they modulate the effects of [[gamma-Aminobutyric acid|GABA]] and [[N-Methyl-D-aspartic acid|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.<ref name=neurosteroid>{{cite journal |doi=10.1016/j.steroids.2003.09.013 |title=The implications of 7-dehydrosterol-7-reductase deficiency (Smith–Lemli–Opitz syndrome) to neurosteroid production |year=2004 |last1=Marcos |first1=Josep |last2=Guo |first2=Li-Wei |last3=Wilson |first3=William K |last4=Porter |first4=Forbes D |last5=Shackleton |first5=Cedric |journal=Steroids |volume=69 |pages=51–60 |pmid=14715377 |issue=1|s2cid=900728 }}</ref>
[[File:PathogenesisSLOS.png|thumb|right|500px|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 [[congenital disorder|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.<ref name="SLOS review" /> Other hedgehog proteins may be involved in the development of the genital tract and the skeleton.<ref name="SLOS novel met" />

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 raft]]s.<ref name="SLOS review" /> Despite their structural similarity, 7DHC is unable to replace cholesterol in lipid rafts.<ref name=UVA>{{cite journal |doi=10.1016/j.freeradbiomed.2006.09.006 |title=7-Dehydrocholesterol enhances ultraviolet A-induced oxidative stress in keratinocytes: Roles of NADPH oxidase, mitochondria, and lipid rafts |year=2006 |last1=Valencia |first1=Antonio |last2=Rajadurai |first2=Anpuchchelvi |last3=Carle |first3=A. Bjorn |last4=Kochevar |first4=Irene E. |journal=Free Radical Biology and Medicine |volume=41 |issue=11 |pages=1704–18 |pmid=17145559 |pmc=1880892}}</ref> In addition, a lack of cholesterol contributes to the increased fluidity of the cell membrane, and may cause abnormal [[granule (cell biology)|granule]] secretions.<ref name="SLOS review" /> All of these changes in the membrane likely contribute to changes in transport functions that are observed in SLOS. They may cause defects in [[Immunoglobulin E|IgE]] receptor-mediated [[mast cell]] degranulation and [[cytokine]] production, which are cells involved in allergic and immune responses.<ref name="SLOS review" /> The NMDA receptor is affected, as well as the binding capability of the [[hippocampus|hippocampal]] [[5-HT receptor|serotonin receptor]].<ref name=serotonin /> [[Cell signaling|Cell to cell interaction]], which is very important in development, may be impaired.<ref name="SLOS novel met" /> [[Exocytosis]] in [[synaptic vesicle]]s has been shown to be reduced, likely due to impaired vesicle fusion to the cell membrane, or poor vesicle recycling.<ref name=vesicle /> Finally, cholesterol is highly prevalent in [[myelin]], therefore SLOS patients show reduced myelination of the [[cerebral hemisphere]]s, [[peripheral nervous system|peripheral nerves]], and [[cranial nerve]]s.<ref name=neurosteroid />

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.<ref name="SLOS review" /> 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 [[organelle]]s. 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 [[cerebral cortex|cortical neuronal]] and [[neuroglia|glial cells]], and accelerates their [[cellular differentiation|differentiation]] and [[dendrite|arborization]].<ref name=biomarker>{{cite journal |doi=10.1007/s10545-012-9504-z |title=Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome |year=2012 |last1=Korade |first1=Zeljka |last2=Xu |first2=Libin |last3=Mirnics |first3=Karoly |last4=Porter |first4=Ned A. |journal=Journal of Inherited Metabolic Disease |volume=36 |pages=113–22 |pmid=22718275 |issue=1 |pmc=3674764}}</ref> Through oxidative stress, 7DHC is thought to be responsible for the increased [[photosensitivity in humans|photosensitivity]] shown in SLOS patients. Normal [[ultraviolet|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).<ref name=UVA />

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.<ref name=insight />

==Screening and diagnosis==

===Prenatally===

The most characteristic biochemical indicator of SLOS is an increased concentration of [[7-dehydrocholesterol|7DHC]] (reduced [[cholesterol]] levels are also typical, but appear in other disorders as well). Thus, [[prenatal diagnosis|prenatally]], SLOS is diagnosed upon finding an elevated 7DHC:total sterol ratio in fetal tissues, or increased levels of 7DHC in [[amniotic fluid]]. The 7DHC:total sterol ratio can be measured at 11–12 weeks of [[gestation]] by [[chorionic villus sampling]], and elevated 7DHC in amniotic fluid can be measured by 13 weeks. Furthermore, if parental mutations are known, DNA testing of amniotic fluid or chorionic villus samples may be performed.<ref name="SLOS novel met" />
[[File:Chorionic villi - high mag.jpg|thumb|right|350px|Micrograph showing chorionic vili, the tissue that is collected with chorionic villus sampling and used to test for SLOS.]]
[[Amniocentesis]] (process of sampling amniotic fluid) and chorionic villus sampling cannot be performed until approximately 3 months into the pregnancy. Given that SLOS is a very severe syndrome, parents may want to choose to terminate their pregnancy if their fetus is affected. 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. Thus, there is a very large desire for noninvasive midgestation diagnostic tests.<ref name=midgestation>{{cite journal |doi=10.1016/S0039-128X(99)00026-4 |title=Midgestational maternal urine steroid markers of fetal Smith–Lemli–Opitz (SLO) syndrome (7-dehydrocholesterol 7-reductase deficiency) |year=1999 |last1=Shackleton |first1=C |journal=Steroids |volume=64 |issue=7 |pages=446–52 |pmid=10443900 |last2=Roitman |first2=E |last3=Kratz |first3=LE |last4=Kelley |first4=RI|s2cid=42834575 }}</ref> Examining the concentrations of [[sterol]]s in maternal urine is one potential way to identify SLOS prenatally. During pregnancy, the fetus is solely responsible for synthesizing the cholesterol needed to produce [[estriol]]. A fetus with SLOS cannot produce cholesterol, and may use 7DHC or 8DHC as precursors for estriol instead. This creates 7- or 8-dehydrosteroids (such as 7-dehydroestriol), which may show up in the maternal urine. 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.<ref name=pregmouse>{{cite journal |doi=10.1016/j.jsbmb.2009.04.011 |title=Steroid production and excretion by the pregnant mouse, particularly in relation to pregnancies with fetuses deficient in Δ7-sterol reductase (Dhcr7), the enzyme associated with Smith–Lemli–Opitz syndrome |year=2009 |last1=Matabosch |first1=Xavier |last2=Rahman |first2=Mahbuba |last3=Hughes |first3=Beverly |last4=Patel |first4=Shailendra B. |last5=Watson |first5=Gordon |last6=Shackleton |first6=Cedric |journal=The Journal of Steroid Biochemistry and Molecular Biology |volume=116 |pages=61–70 |pmid=19406241 |issue=1–2 |pmc=2929956}}</ref> 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. 7- and 8-dehydropregnanetriols have been shown to be present in the urine of mothers with an affected fetus but not with an unaffected fetus, and thus are used in diagnosis. These [[pregnadiene]]s originated in the fetus and traveled through the [[placenta]] before reaching the mother. Their excretion indicates that neither the placenta nor the maternal organs have necessary enzymes needed to reduce the double bond of these novel metabolites.<ref name=midgestation />

===Postnatally===

If SLOS goes undetected until after birth, diagnosis may be based on the characteristic physical features as well as finding increased plasma levels of [[7-dehydrocholesterol|7DHC]].<ref name=LB/>

There are many different ways of detecting 7DHC levels in blood plasma, one way is using the [[Liebermann–Burchard test|Liebermann–Burchard (LB) reagent]]. This is a simple [[colorimetry (chemical method)|colorimetric]] assay developed with the intention of use for large scale screening. When treated with the LB reagent, SLOS samples turn pink immediately and gradually become blue; normal blood samples are initially colorless and develop a faint blue color. Although this method has limitations and is not used to give a definitive diagnosis, it has appeal in that it is a much faster method than using cell cultures.<ref name=LB>{{cite journal |doi=10.1016/S0009-3084(01)00205-5 |title=A colorimetric assay for 7-dehydrocholesterol with potential application to screening for Smith–Lemli–Opitz syndrome |year=2002 |last1=Xiong |first1=Quanbo |last2=Ruan |first2=Benfang |last3=Whitby |first3=Frank G. |last4=Tuohy |first4=Richard P. |last5=Belanger |first5=Thomas L. |last6=Kelley |first6=Richard I. |last7=Wilson |first7=William K. |last8=Schroepfer |first8=George J. |journal=Chemistry and Physics of Lipids |volume=115 |pages=1–15 |pmid=12047895 |issue=1–2}}</ref>

Another way of detecting 7DHC is through [[gas chromatography]], a technique used to separate and analyze compounds. Selected ion
monitoring gas chromatography/mass-spectrometry (SIM-GC/MS) is a very sensitive version of gas chromatography, and permits detection of even mild cases of SLOS.<ref name=gaschrom>{{cite journal |doi=10.1016/0009-8981(95)06038-4 |title=Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts |year=1995 |last1=Kelley |first1=Richard I. |journal=Clinica Chimica Acta |volume=236 |pages=45–58 |pmid=7664465 |issue=1|doi-access=free }}</ref> Other methods include [[time-of-flight mass spectrometry]], [[particle beam|particle-beam]] LC/MS, [[electrospray ionization|electrospray tandem MS]], and [[Ultraviolet–visible spectroscopy|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.<ref name=LB />

==Treatment==

Management of individuals with SLOS is complex and often requires a team of specialists. Some of the congenital malformations (cleft palate) can be corrected with surgery.<ref name="irons1998" /> Other treatments have yet to be proven successful in randomized studies, however anecdotally they appear to cause improvements.<ref name="Svoboda Christie Eroglu Freeman 2012 pp. 285–294">{{cite journal | last1=Svoboda | first1=Melissa D. | last2=Christie | first2=Jill M. | last3=Eroglu | first3=Yasemen | last4=Freeman | first4=Kurt A. | last5=Steiner | first5=Robert D. | title=Treatment of Smith–Lemli–Opitz syndrome and other sterol disorders | journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics | publisher=Wiley | volume=160C | issue=4 | date=October 5, 2012 | issn=1552-4868 | doi=10.1002/ajmg.c.31347 | pages=285–294| doi-access=free | pmid=23042642 | pmc=3890258 }}</ref>

===Cholesterol supplementation===
Currently, the most common form of treatment for SLOS involves [[dietary supplement|dietary cholesterol supplementation]].<ref name=residual>{{cite journal |doi=10.1016/j.ymgme.2004.12.009 |title=Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith–Lemli–Opitz syndrome fibroblasts |year=2005 |last1=Wassif |first1=Christopher A. |last2=Krakowiak |first2=Patrycja A. |last3=Wright |first3=Brooke S. |last4=Gewandter |first4=Jennifer S. |last5=Sterner |first5=Allison L. |last6=Javitt |first6=Norman |last7=Yergey |first7=Alfred L. |last8=Porter |first8=Forbes D. |journal=Molecular Genetics and Metabolism |volume=85 |issue=2 |pages=96–107 |pmid=15896653|url=https://zenodo.org/record/1259483 }}</ref> Anecdotal reports indicate that this has some benefits; it may result in increased growth, lower [[irritability]], improved sociability, less [[self-harm|self-injurious behaviour]], less [[sensory processing disorder|tactile defensiveness]], fewer [[infection]]s, more muscle tone, less [[photosensitivity]] and fewer [[autism|autistic behaviours]].<ref name=mousesimvastatin>{{cite journal |doi=10.1093/hmg/ddl003 |title=Development and characterization of a hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy |year=2006 |last1=Correa-Cerro |first1=L. S. |journal=Human Molecular Genetics |volume=15 |issue=6 |pages=839–51 |pmid=16446309 |last2=Wassif |first2=CA |last3=Kratz |first3=L |last4=Miller |first4=GF |last5=Munasinghe |first5=JP |last6=Grinberg |first6=A |last7=Fliesler |first7=SJ |last8=Porter |first8=FD|doi-access=free }}</ref> Cholesterol supplementation begins at a dose of 40–50&nbsp;mg/kg/day, increasing as needed. It is administered either through consuming foods high in cholesterol (eggs, cream, liver), or as purified food grade cholesterol. Younger children and infants may require tube feeding.<ref name="SLOS novel met" /> However, dietary cholesterol does not reduce the levels of 7DHC, cannot cross the [[blood–brain barrier]], and does not appear to improve developmental outcomes.<ref name=mousesimvastatin /> One empirical study found that cholesterol supplementation did not improve [[developmental disability|developmental delay]], regardless of the age at which it began. 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.<ref name=nocholesterol>{{cite journal |doi=10.1016/j.jpeds.2004.02.036 |title=Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome |year=2004 |last1=Sikora |first1=Darryn M |last2=Ruggiero |first2=Mark |last3=Petit-Kekel |first3=Kersti |last4=Merkens |first4=Louise S |last5=Connor |first5=William E |last6=Steiner |first6=Robert D |journal=The Journal of Pediatrics |volume=144 |issue=6 |pages=783–91 |pmid=15192627}}</ref>
[[File:Simvastatin Structural Formulae.svg|thumb|right|350px|Simvastatin is an inhibitor of HMG-CoA reductase and has been used to treat SLOS.]]

===Simvastatin therapy===

[[HMG-CoA reductase]] [[enzyme inhibitor|inhibitors]] have been examined as treatment for SLOS. Given that this [[catalysis|catalyzes]] the rate-limiting step in cholesterol synthesis, inhibiting it would reduce the buildup of toxic metabolites such as 7DHC.<ref name=residual /> [[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 [[7-dehydrocholesterol|7DHC]], as well as increase the levels of [[cholesterol]].<ref name=mousesimvastatin /> The increased cholesterol levels are due to simvastatin's effect on the expression of different genes. Simvastatin increases the [[gene expression|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 [[zygosity|homozygous]] for null alleles or mutations, simvastatin therapy may actually be toxic.<ref name=residual /> 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.<ref name=mousesimvastatin />

===Antioxidant supplementation===

[[Antioxidant]]s 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 [[lipid peroxidation|peroxidation]] of 7DHC and its derivatives, inhibiting this peroxidation would likely have beneficial effects. Antioxidants have been shown to increase the level of lipid transcripts in SLOS cells, these transcripts play a role in lipid (cholesterol) biosynthesis and are known to be down-regulated in SLOS. 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 [[oxysterol]]s in the brain. However, antioxidants have only been studied in animal models of SLOS or isolated SLOS cells. Thus, their clinical significance and negative side effects are still unknown, and their use has yet to be studied in humans.<ref name=antioxidant>{{cite journal |doi=10.1016/j.biopsych.2013.06.013 |pmid=23896203 |title=Antioxidant Supplementation Ameliorates Molecular Deficits in Smith-Lemli-Opitz Syndrome |year=2013 |last1=Korade |first1=Zeljka |last2=Xu |first2=Libin |last3=Harrison |first3=Fiona E. |last4=Ahsen |first4=Refayat |last5=Hart |first5=Sarah E. |last6=Folkes |first6=Oakleigh M. |last7=Mirnics |first7=Károly |last8=Porter |first8=Ned A. |journal=Biological Psychiatry|volume=75 |issue=3 |pages=215–22 |pmc=3874268 }}</ref>

===Further considerations===

When treating SLOS, a recurring issue is whether or not the intellectual and behavioral deficits are due to fixed developmental problems (i.e. fixed brain malformations), or due to ongoing abnormal sterol levels that interrupt the normal function of the brain and other tissues.<ref name=residual /> If the latter is true, then treatments which change the sterol levels and ratios, particularly in the brain, will likely improve the developmental outcome of the patient. However, if the former is true, then treatment is likely to help only with symptoms and not with specific developmental deficits.<ref name=residual />

==Research==
The most common animal used to study SLOS is the [[mouse]]. According to [[BioCyc database collection|BioCyc]], cholesterol biosynthesis in mice is very similar to that of humans. Most importantly, mice possess both [[7-Dehydrocholesterol reductase|DHCR7]] (the enzyme responsible for SLOS), and [[HMG-CoA reductase]] (the rate limiting step of cholesterol synthesis.<ref name=Biocyc>{{cite journal |doi=10.1093/nar/gki892 |title=Expansion of the BioCyc collection of pathway/genome databases to 160 genomes |year=2005 |last1=Karp |first1=P. D. |journal=Nucleic Acids Research |volume=33 |issue=19 |pages=6083–9 |pmid=16246909 |last2=Ouzounis |first2=CA |last3=Moore-Kochlacs |first3=C |last4=Goldovsky |first4=L |last5=Kaipa |first5=P |last6=Ahrén |first6=D |last7=Tsoka |first7=S |last8=Darzentas |first8=N |last9=Kunin |first9=V |last10=López-Bigas |first10=N |pmc=1266070}}</ref> Rats are similar to mice and have also been used. There are two popular ways in which animal models of SLOS are created. The first is using [[teratology|teratogens]], the second is using genetic manipulations to create mutations in the ''DHCR7'' gene.<ref name="Biochemical, phenotypic and neurophysiological"/>

===Teratogenic models===
[[teratology|Teratogenic]] models are induced by feeding pregnant rats or mice [[enzyme inhibitor|inhibitors]] of DCHR7. Two common inhibitors are BM15766 {{chem name|(4-(2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl)-benzoic acid)}} and AY9944 {{chem name|(trans-l,4-bis(2-chlorobenzylaminomethy1)cyclohexane dihydrochloride)}}. These compounds have different chemical and physical properties, but induce similar effects. AY9944 has been shown to induce [[holoprosencephaly]] and sexual malformations similar to those seen in humans with SLOS.<ref name=ratinhibitor>{{cite journal |last1=Wolf |first1=Claude |first2=Francoise |last2=Chevy |first3=Jacques |last3=Pham |first4=Martine |last4=Kolf-Clauw |first5=Daniele |last5=Citadelle |first6=Nicole |last6=Mulliez |first7=Charles |last7=Roux |title=Changes in serum sterols of rats treated with 7-dehydrocholesterol-Δ7-reductase inhibitors: Comparison to levels in humans with Smith-Lemli-Opitz syndrome |journal=Journal of Lipid Research |year=1996 |volume=37 |pages=1325–33 |pmid=8808767 |url=http://www.jlr.org/cgi/pmidlookup?view=long&pmid=8808767 |issue=6|doi=10.1016/S0022-2275(20)39162-8 |doi-access=free }}</ref> It is also known to cause impairments in the [[5-HT receptor|serotonin receptor]], another defect commonly seen in SLOS patients.<ref name=ratretinal>{{cite journal |doi=10.1016/j.bbalip.2012.03.001 |title=7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome |year=2012 |last1=Xu |first1=Libin |last2=Sheflin |first2=Lowell G. |last3=Porter |first3=Ned A. |last4=Fliesler |first4=Steven J. |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1821 |issue=6 |pages=877–83 |pmid=22425966 |pmc=3340457}}</ref> BM15766 has produced the lack of cholesterol and [[bile acid]] synthesis that is seen in SLOS patients with [[zygosity|homozygous]] mutations. All teratogenic models can be effectively used to study SLOS; however, they present lower levels of 7-DHC and 8-DHC than are seen in humans. This can be explained by the fact that humans experience a permanent block in their DHCR7 activity, where mice and rats treated with inhibitors experience only transient blocks. Furthermore, different species of mice and rats are more [[drug resistance|resistant]] to teratogens, and may be less effective as models of SLOS.<ref name=ratinhibitor /> Teratogenic models are most commonly used to study more long-term effects of SLOS, because they survive longer than genetic models. For example, one study examined the retinal degeneration of SLOS, which in rats does not occur until at least one month after birth.<ref name=ratretinal />

===Genetic models===
[[Animal model|Genetic models]] of SLOS are created by [[gene knockout|knocking out]] the ''DHCR7'' gene. One study used [[homologous recombination]] to disrupt ''DCHR7'' in mouse [[embryonic stem cell]]s. Similar to what is found in humans, heterozygous mice (having only one mutated allele) were [[phenotype|phentoypically]] normal, and were crossed to produce pups (young mice) homozygous for the mutated allele. Although these pups died within the first day of life due to their inability to feed, they showed characteristics similar to humans with SLOS. They had decreased levels of cholesterol, increased levels of 7- and 8DHC, showed less growth and smaller birth weights, had [[craniofacial]] malformations, and less movement. Many also had a [[cleft lip and palate|cleft palate]], and decreased neuronal responses to [[glutamic acid|glutamate]]. 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. In humans, very little maternal cholesterol is transferred to the fetus. In sum, the [[model organism|genetic mouse model]] is helpful to explain the neuropathophysiology of SLOS.<ref name="Biochemical, phenotypic and neurophysiological">{{cite journal |doi=10.1093/hmg/10.6.555 |title=Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome |year=2001 |last1=Wassif |first1=C. A. |journal=Human Molecular Genetics |volume=10 |issue=6 |pages=555–64 |pmid=11230174 |last2=Zhu |first2=P |last3=Kratz |first3=L |last4=Krakowiak |first4=PA |last5=Battaile |first5=KP |last6=Weight |first6=FF |last7=Grinberg |first7=A |last8=Steiner |first8=RD |last9=Nwokoro |first9=NA |last10=Kelley |first10=RI |last11=Stewart |first11=RR |last12=Porter |first12=FD|doi-access=free }}</ref>

===Discoveries===
Many discoveries in SLOS research have been made using animal models. They have been used to study different treatment techniques, including the effectiveness of [[simvastatin]] therapy.<ref name=mousesimvastatin /> Other studies have examined behavioural characteristics while attempting to explain their underlying pathogenesis.<ref>{{cite journal |doi=10.1016/j.pbb.2013.03.007 |title=Behavioral and serotonergic response changes in the Dhcr7-HET mouse model of Smith–Lemli–Opitz syndrome |year=2013 |last1=Korade |first1=Z. |last2=Folkes |first2=O.M. |last3=Harrison |first3=F.E. |journal=Pharmacology Biochemistry and Behavior |volume=106 |pages=101–8 |pmid=23541496|s2cid=38380298 }}</ref> A common finding is that mouse models of SLOS show abnormal [[Serotonin|serotonergic]] development, which may be at least partially responsible for the [[autism|autistic]] behaviours seen in SLOS.<ref>{{cite journal |doi=10.1016/j.ijdevneu.2003.09.002 |title=Abnormal serotonergic development in a mouse model for the Smith–Lemli–Opitz syndrome: Implications for autism |year=2003 |last1=Waage-Baudet |first1=H |last2=Lauder |first2=J.M |last3=Dehart |first3=D.B |last4=Kluckman |first4=K |last5=Hiller |first5=S |last6=Tint |first6=G.S |last7=Sulik |first7=K.K |journal=International Journal of Developmental Neuroscience |volume=21 |issue=8 |pages=451–9 |pmid=14659996|s2cid=42098029 }}</ref> Mouse models have also been used to develop diagnostic techniques; multiple studies have examined [[biomarker]]s that result from the [[lipid peroxidation|oxidation]] of 7DHC, such as DHCEO.<ref name=biomarker /><ref>{{cite journal |doi=10.1194/jlr.M014498  |doi-access=free |title=An oxysterol biomarker for 7-dehydrocholesterol oxidation in cell/mouse models for Smith-Lemli-Opitz syndrome |year=2011 |last1=Xu |first1=L. |last2=Korade |first2=Z. |last3=Rosado |first3=D. A. |last4=Liu |first4=W. |last5=Lamberson |first5=C. R. |last6=Porter |first6=N. A. |journal=The Journal of Lipid Research |volume=52 |issue=6 |pages=1222–33 |pmid=21402677 |pmc=3090243}}</ref> It is likely that as animal models are improved, they will lead to many more discoveries in SLOS research.<ref name="DeBarber Eroglu Merkens Pappu 2011 p. ">{{cite journal | last1=DeBarber | first1=Andrea E. | last2=Eroglu | first2=Yasemen | last3=Merkens | first3=Louise S. | last4=Pappu | first4=Anuradha S. | last5=Steiner | first5=Robert D. | title=Smith–Lemli–Opitz syndrome | journal=Expert Reviews in Molecular Medicine | publisher=Cambridge University Press (CUP) | volume=13 | year=2011 | pages=e24 | issn=1462-3994 | doi=10.1017/s146239941100189x | pmid=21777499 | pmc=3366105 }}</ref>

==Eponym==
It is named after [[David Weyhe Smith]] (1926–1981), an American pediatrician; Luc Lemli (1935–), a Belgian physician; and [[John M. Opitz|John Marius Opitz]] (1935–2023), a German-American physician. These are the researchers who first described the symptoms of SLOS.<ref>{{cite journal |doi=10.1016/S0022-3476(64)80264-X |title=A newly recognized syndrome of multiple congenital anomalies |year=1964 |last1=Smith |first1=David W. |last2=Lemli |first2=Luc |last3=Opitz |first3=John M. |journal=The Journal of Pediatrics |volume=64 |issue=2 |pages=210–7 |pmid=14119520}}</ref>

==See also==
* [[List of syndromes]]
* [[Toxidrome]]
* [[Symptom]]
* [[Sequence (medicine)]]
* [[Characteristics of syndromic ASD conditions]]

==References==
{{Reflist}}
{{GHR}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=slo  GeneReview/UW/NIH on Smith–Lemli–Opitz syndrome]

{{Medical resources
| ICD11           = <!-- {{ICD11|5C52.10}} -->
| ICD10           = <!-- {{ICD10|Q87.1}} -->
| ICD10CM         = <!-- {{ICD10CM|E78.72}} -->
| ICD9            = <!-- {{ICD9|759.89}} -->
| ICDO            =
| OMIM            = 270400
| MeshID          = D019082
| DiseasesDB      = 12223
| SNOMED CT       = 43929004
| Curlie          = Health/Conditions_and_Diseases/Nutritional_and_Metabolic_Disorders/Inherited/Smith_Lemli_Opitz_Syndrome/
| MedlinePlus     =
| eMedicineSubj   = article
| eMedicineTopic  = 949125
| PatientUK       =
| NCI             =
| GeneReviewsNBK  = NBK1143
| GeneReviewsName = Smith-Lemli-Opitz Syndrome
| NORD            = Smith-Lemli-Opitz Syndrome
| GARDNum         = 5683
| GARDName        = Smith-Lemli-Opitz syndrome
| RP              = 12335
| AO              =
| WO              =
| OrthoInfo       =
| Orphanet        = 818
| Scholia         = Q998273
| OB              =
}}

{{Autism spectrum}}
{{Phakomatoses and other congenital malformations not elsewhere classified}}
{{Defects of steroid metabolism}}

{{DEFAULTSORT:Smith-Lemli-Opitz syndrome}}
[[Category:Autosomal recessive disorders]]
[[Category:Cholesterol and steroid metabolism disorders]]
[[Category:Genodermatoses]]
[[Category:Rare diseases]]
[[Category:Syndromes with microcephaly]]
[[Category:Syndromes affecting the nervous system]]
[[Category:Syndromes with short stature]]
[[Category:Syndromic autism]]