| Smith–Lemli–Opitz syndrome | |
|---|---|
| Other names | SLOS, or7-dehydrocholesterol reductase deficiency |
 | |
| Child with Smith–Lemli–Opitz syndrome | |
| Specialty | Medical genetics  |
| Usual onset | Present at birth |
| Frequency | 1 in 20,000 to 1 in 60,000 |
Smith–Lemli–Opitz syndrome is aninborn error of cholesterol synthesis.[1] It is anautosomalrecessive, multiple malformation syndrome caused by amutation in theenzyme7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a broad spectrum of effects, ranging from mildintellectual disability and behavioural problems to lethal malformations.[2]
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.[3]
The most common facial features of SLOS includemicrocephaly, bitemporal narrowing (reduced distance between temples),ptosis, a short and upturned nose,micrognathia,epicanthal folds, andcapillary hemangioma of the nose.[3] Other physical characteristics include:[2]
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 andself-injurious behaviours, and sleep disturbances are common.[3] Specific behaviours resembling those of people withautism are often present as well ashyperactivity, 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.[4] Autism is typically diagnosed separately from SLOS using theDSM-V, and approximately 50–75% of SLOS patients meet the criteria for autism.[5]
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.[3]
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,[3] 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 of7-dehydrocholesterol are fairly specific to SLOS.[2]
The gene encodingDHCR7 (labeled asDHCR7) was cloned in 1998, and has been mapped tochromosome 11q12–13.[1] It is 14100base pairs of DNA in length, and contains nineexons,[2] the correspondingmRNA is 2786 base pairs in length (the remaining DNA sequence is intronic). The structure of theDHCR7 rat gene is very similar to the structure of the human gene.[1]
The highest levels ofDHCR7expression have been detected in the adrenal gland, the testis, the liver and in brain tissue. Its expression is induced by decreasedsterol concentrations via sterol regulatory binding proteins (SREBP). There is also evidence that its activity may be regulated by tissue specific transcription, andalternative splicing.[1]
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 ofcytochrome-P450 oxidoreductase. It is also thought to contain iron.[1] DHCR7 is anintegral membrane protein of the endoplasmic reticulum, and computer models have predicted up to ninetransmembrane domains.[2] DHCR7 is most efficient at reducing 7DHC, but it is known to reduce the carbon 7 double bond of other sterols, indicating a range ofsubstratespecificity. The human version of this enzyme is predicted to have amolecular weight of 54,489kDa, and anisoelectric point of 9.05.[1]
Theamino acid sequence that encodes DHCR7 is predicted to contain 475 amino acids, as well as severalprotein 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 potentialprotein kinase C andtyrosine 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.[1]
SLOS is anautosomalrecessive disorder.[6] More than 130 different types of mutations have been identified.[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. 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 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 inspontaneous abortion.[6]
The IVS8-1G>C is the most frequently reported mutation inDHCR7. This disrupts the joining of exons eight and nine, and results in the insertion of 134nucleotides into theDHCR7 transcript. This is a nonsense mutation, thus patients that arehomozygous for this allele are severely affected. It is thought that this mutation first occurred in theBritish Isles, and it has acarrier (those that areheterozygous 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%.[1]
The next most common mutation is 278C>T, and results in athreonine 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.[1]
The third most common mutation is 452G>A. Thisnonsense 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.[1]
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.[1] 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[7]). This number indicates a hypothetical birthincidence 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).[6] 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.[7]
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.[8] It should also be noted that cholesterol cannot pass theblood–brain barrier, thus within the brain, biosynthesis is the only source of cholesterol.[9]
In humans,cholesterol synthesis begins with themevalonate pathway (see diagram), leading to the synthesis offarnesyl pyrophosphate (FPP). This pathway uses twoacetyl-CoA and twoNADPH to makemevalonate, which is metabolized toisopentenyl pyrophosphate (IPP) using threeATP. From there, three IPP are needed to make one FPP. The combination of two FPP leads to the formation ofsqualene; this represents the first committed step towards cholesterol biosynthesis. Squalene leads to the creation oflanosterol, from which there are multiple pathways that lead to cholesterol biosynthesis. The rate limiting step of cholesterol synthesis is the conversion of3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate, this is an early step in the mevalonate pathway catalyzed byHMG-CoA reductase.[10]
Through a complicated series of reactions, lanosterol leads to the formation ofzymosterol. 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.[3] Zymosterol is metabolized to 5α-cholesta-7,24-dien-3β-ol, then tolathosterol, and then to7-dehydrocholesterol, or 7-DHC. 7-DHC is the immediate precursor to cholesterol, and the enzyme DHCR7 is responsible for converting 7-DHC to cholesterol.[1] DHCR7 reduces thedouble bond on carbon 7 of 7-DHC, leading to theunesterified product.[9] 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 of7-Dehydrodesmosterol todesmosterol.[1]
Regulation of cholesterol synthesis is complex and occurs primarily through the enzyme HMG-CoA reductase (catalyst of the rate-limiting step). It involves afeedback loop that is sensitive to cellular levels of cholesterol. The four main steps ofregulation are:[8]
Cholesterol is an importantlipid involved in metabolism, cell function, and structure. It is a structural component of thecell membrane,[1] such that it provides structure and regulates thefluidity of thephospholipid bilayer. Furthermore, cholesterol is a constituent inlipid rafts. These are congregations ofproteins and lipids (includingsphingolipids 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 affectsignaling pathways. Cholesterol specifically acts as a spacer and a glue for lipid rafts; absence of cholesterol leads to the dissociation of proteins.[11]
Given its prevalence in cell membranes, cholesterol is highly involved in certaintransport processes. It may influence the function ofion channels and other membrane transporters. For example, cholesterol is necessary for theligand binding activity of theserotoninreceptor.[12] In addition, it appears to be very important inexocytosis. Cholesterol modulates the properties of the membrane (such as membrane curvature), and may regulate the fusion ofvesicles with the cell membrane. It may also facilitate the recruitment of complexes necessary for exocytosis. Given thatneurons rely heavily on exocytosis for the transmission ofimpulses, cholesterol is a very important part of thenervous system.[13]
One particularly relevant pathway in which cholesterol takes place is theHedgehog signaling pathway. This pathway is very important duringembryonic 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 cellproliferation anddifferentiation. Cholesterol is important to this pathway because it undergoescovalent bonding to Hedgehog proteins, resulting in their activation. Without cholesterol, the signaling activity is disrupted and cell differentiation may be impaired.[14]
Cholesterol is a precursor for many important molecules. These includebile acids (important in processing dietary fats),oxysterols,neurosteroids (involved in neurotransmission and excitation),glucocorticoids (involved in immune and inflammatory processes),mineralocorticoids (osmotic balance), andsex steroids (i.e.estrogen andtestosterone; wide range of function but involved in genital development prenatally).[1] Finally, cholesterol is a major component ofmyelin, a protective layer around neurons. Myelination occurs most rapidly during prenatal development, meaning that the demand for cholesterol biosynthesis is very high.[9]
Given that the function ofcholesterol 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.[2]
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 ofneurosteroids 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 withnuclear steroid receptors, and bind toneurotransmitter-gated ion channels. Specifically, they modulate the effects ofGABA andNMDA 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.[15]
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 physicalbirth 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.[2] Other hedgehog proteins may be involved in the development of the genital tract and the skeleton.[3]
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 oflipid rafts.[2] Despite their structural similarity, 7DHC is unable to replace cholesterol in lipid rafts.[16] In addition, a lack of cholesterol contributes to the increased fluidity of the cell membrane, and may cause abnormalgranule secretions.[2] All of these changes in the membrane likely contribute to changes in transport functions that are observed in SLOS. They may cause defects inIgE receptor-mediatedmast cell degranulation andcytokine production, which are cells involved in allergic and immune responses.[2] The NMDA receptor is affected, as well as the binding capability of thehippocampalserotonin receptor.[12]Cell to cell interaction, which is very important in development, may be impaired.[3]Exocytosis insynaptic vesicles has been shown to be reduced, likely due to impaired vesicle fusion to the cell membrane, or poor vesicle recycling.[13] Finally, cholesterol is highly prevalent inmyelin, therefore SLOS patients show reduced myelination of thecerebral hemispheres,peripheral nerves, andcranial nerves.[15]
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 impairintracellular 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 noveloxysterol andsteroid derivatives, and many of their functions or effects are yet unknown.[2] A very important finding with respect to 7DHC is that it is the most reactive lipid forlipid peroxidation, and results in systemicoxidative stress. Lipid peroxidation is known to destroy membranes of both cells and membrane-boundorganelles. 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 tocortical neuronal andglial cells, and accelerates theirdifferentiation andarborization.[17] Through oxidative stress, 7DHC is thought to be responsible for the increasedphotosensitivity shown in SLOS patients. NormalUVA 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 ofreactive oxygen species (ROS).[16]
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 andexcretion of toxic metabolites may vary from person to person. Maternalapolipoprotein 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.[6]
The most characteristic biochemical indicator of SLOS is an increased concentration of7DHC (reducedcholesterol 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 inamniotic fluid. The 7DHC:total sterol ratio can be measured at 11–12 weeks ofgestation bychorionic 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.[3]
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.[18] Examining the concentrations ofsterols in maternal urine is one potential way to identify SLOS prenatally. During pregnancy, the fetus is solely responsible for synthesizing the cholesterol needed to produceestriol. 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 reduceddouble 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. 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. Thesepregnadienes originated in the fetus and traveled through theplacenta 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.[18]
If SLOS goes undetected until after birth, diagnosis may be based on the characteristic physical features as well as finding increased plasma levels of7DHC.[20]
There are many different ways of detecting 7DHC levels in blood plasma, one way is using theLiebermann–Burchard (LB) reagent. This is a simplecolorimetric 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.[20]
Another way of detecting 7DHC is throughgas chromatography, a technique used to separate and analyze compounds. Selected ionmonitoring gas chromatography/mass-spectrometry (SIM-GC/MS) is a very sensitive version of gas chromatography, and permits detection of even mild cases of SLOS.[21] Other methods includetime-of-flight mass spectrometry,particle-beam LC/MS,electrospray tandem MS, andultraviolet 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.[20]
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.[7] Other treatments have yet to be proven successful in randomized studies, however anecdotally they appear to cause improvements.[22]
Currently, the most common form of treatment for SLOS involvesdietary cholesterol supplementation.[23] Anecdotal reports indicate that this has some benefits; it may result in increased growth, lowerirritability, improved sociability, lessself-injurious behaviour, lesstactile defensiveness, fewerinfections, more muscle tone, lessphotosensitivity and fewerautistic behaviours.[24] Cholesterol supplementation begins at a dose of 40–50 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.[3] However, dietary cholesterol does not reduce the levels of 7DHC, cannot cross theblood–brain barrier, and does not appear to improve developmental outcomes.[24] One empirical study found that cholesterol supplementation did not improvedevelopmental 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.[25]
HMG-CoA reductaseinhibitors have been examined as treatment for SLOS. Given that thiscatalyzes the rate-limiting step in cholesterol synthesis, inhibiting it would reduce the buildup of toxic metabolites such as 7DHC.[23]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 of7DHC, as well as increase the levels ofcholesterol.[24] The increased cholesterol levels are due to simvastatin's effect on the expression of different genes. Simvastatin increases theexpression ofDHCR7, 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 thosehomozygous for null alleles or mutations, simvastatin therapy may actually be toxic.[23] This highlights the importance of identifying the specificgenotype of the SLOS patient before administering treatment. It is still unknown if simvastatin will improve the behavioural or learning deficits in SLOS.[24]
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 theperoxidation 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 ofoxidative 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 ofoxysterols 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.[26]
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.[23] 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.[23]
The most common animal used to study SLOS is themouse. According toBioCyc, cholesterol biosynthesis in mice is very similar to that of humans. Most importantly, mice possess bothDHCR7 (the enzyme responsible for SLOS), andHMG-CoA reductase (the rate limiting step of cholesterol synthesis.[27] 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 usingteratogens, the second is using genetic manipulations to create mutations in theDHCR7 gene.[28]
Teratogenic models are induced by feeding pregnant rats or miceinhibitors of DCHR7. Two common inhibitors are BM15766 (4-(2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl)-benzoic acid) and AY9944 (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 induceholoprosencephaly and sexual malformations similar to those seen in humans with SLOS.[29] It is also known to cause impairments in theserotonin receptor, another defect commonly seen in SLOS patients.[30] BM15766 has produced the lack of cholesterol andbile acid synthesis that is seen in SLOS patients withhomozygous 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 moreresistant to teratogens, and may be less effective as models of SLOS.[29] 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.[30]
Genetic models of SLOS are created byknocking out theDHCR7 gene. One study usedhomologous recombination to disruptDCHR7 in mouseembryonic stem cells. Similar to what is found in humans, heterozygous mice (having only one mutated allele) werephentoypically 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, hadcraniofacial malformations, and less movement. Many also had acleft palate, and decreased neuronal responses toglutamate. Overall however, the pups had fewer dysmorphic features than human patients with SLOS; they did not present limb, renal, adrenal orcentral nervous system malformations. This is explained by the fact that in rodents, maternal cholesterol can cross theplacenta, 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, thegenetic mouse model is helpful to explain the neuropathophysiology of SLOS.[28]
Many discoveries in SLOS research have been made using animal models. They have been used to study different treatment techniques, including the effectiveness ofsimvastatin therapy.[24] Other studies have examined behavioural characteristics while attempting to explain their underlying pathogenesis.[31] A common finding is that mouse models of SLOS show abnormalserotonergic development, which may be at least partially responsible for theautistic behaviours seen in SLOS.[32] Mouse models have also been used to develop diagnostic techniques; multiple studies have examinedbiomarkers that result from theoxidation of 7DHC, such as DHCEO.[17][33] It is likely that as animal models are improved, they will lead to many more discoveries in SLOS research.[34]
It is named afterDavid Weyhe Smith (1926–1981), an American pediatrician; Luc Lemli (born 1935), a Belgian physician; andJohn Marius Opitz (1935–2023), a German-American physician. These are the researchers who first described the symptoms of SLOS.[35]
This article incorporatespublic domain material fromGenetics Home Reference.United States National Library of Medicine.
