Smith–Lemli–Opitz syndrome
Smith–Lemli–Opitz syndrome | |
---|---|
Other names | SLOS, or 7-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 an
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.[3]
Physical characteristics
The most common facial features of SLOS include microcephaly, bitemporal narrowing (reduced distance between temples), ptosis, a short and upturned nose, micrognathia, epicanthal folds, and capillary hemangioma of the nose.[3] Other physical characteristics include:[2]
- low-set and posteriorly rotated ears
- high-arched, narrow, hard palate
- cleft lip/palate
- agenesis or hypoplasia of the corpus callosum
- cerebellar hypoplasia
- increased 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
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]
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 (
Genetics
DHCR7
The gene encoding DHCR7 (labeled as DHCR7) was cloned in 1998, and has been mapped to chromosome 11q12-13.[1] It is 14100 base pairs of DNA in length, and contains nine exons,[2] the corresponding 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.[1]
The highest levels of DHCR7 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.[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 of
The amino acid sequence that encodes DHCR7 is predicted to contain 475 amino acids, as well as several 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.[1]
Mutations and incidence
SLOS is an
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
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.[1]
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.[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 birth 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).[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 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.[8] It should also be noted that cholesterol cannot pass the blood–brain barrier, thus within the brain, biosynthesis is the only source of cholesterol.[9]
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 NADPH to make mevalonate, which is metabolized to isopentenyl pyrophosphate (IPP) using three 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 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate, this is an early step in the mevalonate pathway catalyzed by HMG-CoA reductase.[10]
Through a complicated series of reactions, lanosterol leads to the formation of
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 are:[8]
- The synthesis of the enzyme HMG-CoA reductase is controlled by sterol regulatory element binding protein (SREBP). This is a transcription of the HMG-CoA reductase gene.
- The 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 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,[1] such that it provides structure and regulates the fluidity of the phospholipid bilayer. Furthermore, cholesterol is a constituent in lipid rafts. These are congregations of proteins and lipids (including sphingolipids 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 signaling 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 certain transport processes. It may influence the function of ion channels and other membrane transporters. For example, cholesterol is necessary for the ligand binding activity of the serotonin receptor.[12] 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 vesicles with the cell membrane. It may also facilitate the recruitment of complexes necessary for exocytosis. Given that neurons rely heavily on exocytosis for the transmission of impulses, cholesterol is a very important part of the nervous system.[13]
One particularly relevant pathway in which cholesterol takes place is the
Cholesterol is a precursor for many important molecules. These include
Pathogenesis
Given that the function of cholesterol encompasses a very wide range, it is unlikely that the symptoms of SLOS are due to a single molecular mechanism. Some of the molecular effects are yet unknown, but could be extrapolated based on the role of cholesterol. In general, the negative effects are due to decreased levels of cholesterol and increased levels of cholesterol precursors-most notably, 7DHC. Although 7DHC is structurally similar to cholesterol, and could potentially act as a substitute, the effects of this are still being studied.[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 of
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
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
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
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.[6]
Screening and diagnosis
Prenatally
The most characteristic biochemical indicator of SLOS is an increased concentration of
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 of sterols 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.[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. These pregnadienes 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.[18]
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
There are many different ways of detecting 7DHC levels in blood plasma, one way is using the Liebermann–Burchard (LB) reagent. This is a simple 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.[20]
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.[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.[20]
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.[7] Other treatments have yet to be proven successful in randomized studies, however anecdotally they appear to cause improvements.[22]
Cholesterol supplementation
Currently, the most common form of treatment for SLOS involves
Simvastatin therapy
Antioxidant supplementation
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 the 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 oxysterols 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]
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.[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]
Research
The most common animal used to study SLOS is the mouse. According to BioCyc, cholesterol biosynthesis in mice is very similar to that of humans. Most importantly, mice possess both DHCR7 (the enzyme responsible for SLOS), and HMG-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 using teratogens, the second is using genetic manipulations to create mutations in the DHCR7 gene.[28]
Teratogenic models
Teratogenic models are induced by feeding pregnant rats or mice inhibitors 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 induce holoprosencephaly and sexual malformations similar to those seen in humans with SLOS.[29] It is also known to cause impairments in the serotonin receptor, another defect commonly seen in SLOS patients.[30] BM15766 has produced the lack of cholesterol and bile acid synthesis that is seen in SLOS patients with 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 resistant 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
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
Eponym
It is named after David Weyhe Smith (1926–1981), an American pediatrician; Luc Lemli (1935–), a Belgian physician; and John Marius Opitz (1935–2023), a German-American physician. These are the researchers who first described the symptoms of SLOS.[35]
See also
- List of syndromes
- Toxidrome
- Symptom
- Sequence (medicine)
- Characteristics of syndromic ASD conditions
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This article incorporates public domain material from Genetics Home Reference. United States National Library of Medicine.