From Discovery to Care: Dr. Ellen Elias Sheds Light on Smith-Lemli-Opitz Syndrome
In this exclusive interview, Dr. Ellen Elias, a distinguished clinical geneticist specializing in neurodevelopmental disabilities and pediatrics, provides invaluable insights into Smith-Lemli-Opitz syndrome (SLOS), a condition she played a pivotal role in discovering. With over three decades of experience, Dr. Elias offers a comprehensive overview of SLOS, from its origins and diagnostic intricacies to the latest advances in treatment and ongoing research. Her expertise and dedication in this field, coupled with her role as the director of the largest clinic for patients with complex medical needs and genetic disorders, make this interview an essential resource for medical professionals and families impacted by SLOS.
Can you provide an overview of Smith-Lemli-Opitz syndrome for our audience? What are the key clinical features and symptoms that help in its diagnosis?
Ellen Elias, MD: Smith-Lemli-Opitz syndrome is actually not that rare, a disorder. It was first described in 1964 by those three doctors Smith, Lemli and Opitz, all geneticists. They described three little boys who had unusual facial features, intellectual disability, abnormal genitalia, and poor growth. And then 30 years later, so in 1994, my colleagues and I in Boston at the time working with a group of chemists on the East Coast discovered that Smith-Lemli-Opitz is actually caused by an error in the body’s ability to make cholesterol. That making of cholesterol happens in a person’s liver. So in the final step of this very, very complicated pathway to make cholesterol in your body, there’s an enzyme defect or problem which makes the cholesterol level not able to be manufactured in the normal way, and the cholesterol can be very, very, very low. And when that happens, that leads to all kinds of medical and developmental issues we’re going to talk about in more detail.
The other problem with having the cholesterol level be so low is that the body builds up the compounds, we call them precursors, which are not able to be turned into cholesterol. Those precursors, the main one is called 7-Dehydrocholesterol or 7-DHC for short. And 7-DHC flips back and forth with a very similar compound called 8-Dehydrocholesterol or 8-DHC. So the body of a patient with Smith-Lemli-Opitz has very, very high levels of these 7 and 8-DHC and very, very low levels of cholesterol. And that leads to a number of different medical and developmental concerns. We thought at first that the cholesterol being so low was the main issue, which contributes to problems. But we know now that also having these very, very high levels of seven and 8-DHC leads to additional and what can be very progressive medical problems as well.
So it’s quite a complicated business. A patient usually with Smith-Lemli-Opitz might be identified even before the baby is born based on abnormal ultrasound and prenatal tests because the babies often are very tiny and not growing well in utero and multiple birth defects of almost all the major organs are sometimes found prenatally. And if they haven’t been identified before, the baby’s born in a patient with typical Smith-Lemli-Opitz, they are very obvious right at birth. So unusual facial features, multiple birth defects and growth failure are the main way that this presents. And when a geneticist sees these things altogether, would recommend the specific testing to confirm the diagnosis.
What is the prevalence of SLOS and how does it typically present in pediatric patients? Are there any specific patterns or early signs that doctors should look for during routine examinations?
Ellen Elias, MD: A patient with the sort of garden variety of ops has a very typical facial appearance. The head is small, they can have droopy eyelids, they can often have cleft palate. The ears might be low set in, a little unusual in their shape, and the chin is often very small. So just looking at the facial features, a geneticist can look at that and say, “Oh my gosh, this looks like Smith-Lemli-Opitz.” But a pediatrician, just a regular pediatrician, could see a patient who has what looks like somewhat unusual facial features. The baby is often very tiny, not just the head circumference is small, but the weight and height are small for [inaudible]. But the classic thing is looking at the toes. So there is webbing of the second and third toe in almost every patient. And in the milder patients who might just present with a smallish head and developmental delay and often autism, finding that webbing of the second and third toes should tip off a provider that this could be Smith-Lemli-Opitz and to look and do the specialized test that can be done to confirm a diagnosis.
SLOS is caused by a deficiency in the enzyme 7-Dehydrocholesterol reductase. Could you explain how this deficiency leads to the clinical manifestations observed in patients with SLOS?
Ellen Elias, MD: We didn’t know at first what was going on. So in 1994 is when it was described that this cholesterol problem was associated with Smith-Lemli-Opitz. And interestingly, there was an animal model that was available right away. There were some studies that were looking at medications to try to lower people’s cholesterols. And when you’re trying to develop a new medicine, you first try it out in an animal model. So what was discovered was that rats, pregnant rats treated with a chemical that turns out to directly impact how that enzyme functions, 7-DHC reductase caused little baby rats to have what looks like SLO, very similar birth defects and medical problems.
So there was an animal model right from the start, and then the gene was identified so that people can do a gene test or a biochemical test to look for the elevations in the precursors. And then there was a special genetic knockout mouse that was created that confirmed that the gene causes this. But the big thing, the big discovery was made in the late 1990s when it was determined that cholesterol is critically important for some of the genes in the early fetal life that lead to normal development of your brain, your heart, your kidneys, your limbs, and your genitalia. And that gene has a funny name, it’s called Sonic Hedgehog.
And the person who discovered this in his lab is a very smart scientist named Philip Beachy. They reported this in the late 1990s that this Sonic Hedgehog gene gets activated by adding cholesterol to it. And that activation of hedgehog is essential for this cascade of different developmental genes that is critical for the normal formation of all of these organs that I described. Because initially it was pretty hard to understand why having a real low cholesterol level in the fetus might lead you to have webbing of your second and third toes or having an extra digit, which you can also see in this disease or having all these major birth defects elsewhere that I described. But the reason is really related to this hedgehog pathway and how it can’t even get going and get started because of the very low cholesterol in the fetus. And so we know now that that is the major reason why babies have all of these problems.
And then we’ve also learned more in the last decade, we’ve learned more and more about the role of the precursors and what happens with them. So what has been described is that these seven and 8-Dehydrocholesterol compounds that build up to such a high abnormal level. If you have Smith-Lemli-Opitz syndrome, actually they undergo a chemical reaction called oxidation where they have a change and are turned into these very, very, very toxic substances called oxysterols. And that work is predominantly done by a scientist named Lieben Tsu in Seattle. And Dr. Tsu has identified that these oxysterol compounds build up in all the part of the body, including the brain and the back of the eye, the liver and the skin, and cause significant disease that can be progressive and cause problems that get worse over time. And so now we know this is not just a problem with cholesterol being too low, Sonic Hedgehog not working and leading to all of these embryologic problems, but also there are continuing and progressive problems because of building up of the precursors.
Since SLOS can manifest with a wide range of symptoms and severity, how do you approach the diagnosis? What are the essential diagnostic tests and assessments that help confirm SLOS in patients?
Ellen Elias, MD: The easiest thing to make this diagnosis is to send for a cholesterol level and the precursors, the seven and 8-Dehydrocholesterol cholesterol. And it’s important to know that these have to be done in a very special laboratory, cannot be done by sending a cholesterol test in your own hospital laboratory because the technology for that is not sufficient to distinguish the precursors from cholesterol. And so there’s several labs around the country that do this very specialized test. I send mine to the Kennedy Krieger lab at John Hopkins, so they can tell me the seven and 8-Dehydrocholesterol levels as well as the cholesterol level in a very objective and reproducible way.
The other main way that the diagnosis is made is that many times now genetic tests can be performed to look at gene variants. And so for example, a test called whole exome sequencing that looks at all 23,000 of your genes can identify gene variants in the 7-Dehydrocholesterol reductase gene. And that’s how the diagnosis is made in many patients who are being seen by a neurologist or a geneticist or someone who sends testing to try to figure out why a child has all of these medical problems but also has developmental delay. And so a gene test is the other common way these days. Now that those gene tests are being done more routinely that a patient can have this diagnosis made.
Are there any differential diagnoses that doctors should consider when evaluating patients with suspected SLOS? How do you differentiate between SLOS and other similar conditions?
Ellen Elias, MD: A lot of times in the very beginning, people thought given all of the multiple birth defects and the unusual features and poor growth and developmental delay, that maybe this was a chromosome abnormality. And so in the very beginning, people sent chromosome tests and now the test we do is called microarray, and that test will detect very subtle changes. But this is not a chromosome test, so that will come back negative and not give you your answer. You either have to do the gene test or the biochemical test. Now the target audience to really know this are the obstetricians, the maternal fetal medicine doctors who are looking at the ultrasound of a baby and detecting these multiple birth defects and the slow growth. And then sometimes they’re just sending a chromosome test and that will come back negative and they won’t have their answer.
You can make this diagnosis prenatally by sending either amniotic fluid or chorionic villus sampling to the special lab at Johns Hopkins that I previously mentioned at the Kennedy Krieger Institute. And they can identify prenatally and make this diagnosis. So it’s really important to think outside the box to think this is not just a chromosome test. The other newer testing that is being done is something called whole genome sequencing. And more and more that test is being done in very severely ill newborns who might not survive. And it’s important to try to get a quick diagnosis back so you can give the family some information and figure out how the baby might need to be treated. So more and more these days, whole genome sequencing is also being done even in the newborn period to try to make a clear diagnosis of a very complicated newborn.
As there is no cure for SLOS, what are the current treatment options available? How do you manage the different symptoms and complications associated with the condition?
Ellen Elias, MD: For 30 years now, since 1993, I have been giving patients cholesterol because their cholesterol levels are super low. And you know that you can raise your cholesterol level by what you eat. Yeah? A lot of adults struggle in the opposite direction where their cholesterol levels are too high. So I’ve been giving cholesterol to my patients now for the last 30 years, and there are various ways to do that, to try to raise a patient’s cholesterol level. For the more mild patients who are able to eat, they can eat high cholesterol foods. So egg yolks are the main food that has a lot of cholesterol in it. There are 200 milligrams approximately of cholesterol in every egg yolk. So I have some patients who can eat a lot of eggs. The problem with that is patients with Smith-Lemli-Opitz, especially the more severe ones, have significant feeding problems and they are not able to eat by mouth and they’re not able to eat regular food.
And so many of them have feeding gastrostomy tubes. And the formulas that are used to treat patients like that who are tube fed on special formulas have very, very, very little cholesterol in them. And that was the main reason that I invented a cholesterol medicine. I invented this in 1993, 1994, and it’s a medication that has to be made by a compounding pharmacy. It’s made by adding pure pharmaceutical grade cholesterol powder to oil such as soy oil, and if a patient is allergic to soy, we can put it in another kind of oil. And it’s a mixed up to be very concentrated 200 milligrams of cholesterol per ml, so the same as one egg yolk per ml. So a teaspoon has the equivalent of five eggs in it. And that’s pretty nice because it’s pretty hard to get lots of eggs into a child, especially who has feeding and GI issues, which many of these kids do.
You can now purchase on Amazon online. There are other cholesterol powders that are now available. And you can also buy egg yolk online. If you’re just doing raw eggs, that’s a little trickier because sometimes raw eggs can be contaminated with bacteria. And so what I taught a lot of my patients to do back in the day was to sort of soft boil eggs so that the white part is harder and you can remove the egg from it and the egg but is still liquid, so you can scoop it out the yolk and add it to formula. And a lot of my patients are still doing that. So that is the way you can get cholesterol. In what other ways do we need to treat these kids because they’re very medically complicated kids. So there are other medicines that can help a child who has severe feeding problems, and I work fairly closely with my GI partners in that regard.
There are medicines that can help your appetite increase or that can help some of the symptoms that look like reflux and things like that. So we use a lot of those medications. I also closely follow nutritional labs, things like iron, things like vitamin D, and just to make sure that the child with a severe feeding disorder is getting everything that they need to optimize their growth. A second thing that I’ve been doing on a research level is to add special vitamins called antioxidants. And that is to try to inhibit the formation of these very toxic oxysterols that I mentioned earlier that have a bad effect on the back of the eye particularly is what I study, the retina. And so I do this on a research protocol basis and I give patients these special medicines that are supplied by my research pharmacy in my hospital and mailed to the families.
And then once a year they come and we look at their retina, we look at their hearing pathway, which can be impacted and do a lot of the labs I mentioned to look at their nutritional status, their special cholesterol and precursor levels. And I have a student with me now trying to pull all of that data together to show that treating with antioxidants is impactful and seems to help.
Some patients with this disease have severe liver problems and liver abnormalities. And for those patients, especially the more severe patients, their bodies are not able to make compounds called bile acids that are normally made by cholesterol, and you need bile acids in your intestines to absorb nutrients. So just recently, it got COVID canceled for a while, but we were able to show with a very small pilot study that a certain bile acid, which is now available again, can be helpful for patients with SLO. And we’re in the process of publishing that pilot study. And once we do that, we hope to do a larger study to prove the benefit of giving bile acids in addition to cholesterol for this patient. But that is still a work in progress.
What challenges do patients with SLOS and their families typically face in managing the condition and how can a multidisciplinary approach improve patient outcomes?
Ellen Elias, MD: That’s a really good question. Because these are complicated patients, they have multiple medical problems. Some of my patients, many of them are followed by a pediatric gastroenterologist along with me because of their liver disease and their feeding issues. Some of these patients have kidney problems too. They may have malformations of their kidneys that are followed by a nephrologist. Developmental pediatricians and neurologists are often involved because these patients can have very low muscle tone and significant developmental delay, and so they often need developmental services including different therapies to help make them get better. I’d say the most challenging aspect for some of my patients is the behavioral problem. So many of these patients, well more than half have autism. And so their behaviors can be very, very, very challenging. They may be aggressive, they may have self-injurious behaviors. They are sometimes so severely involved, they’re nonverbal, they may be in a wheelchair.
And so having the services of a psychiatrist who can prescribe certain psychiatric medications to help with some of the behaviors is often very, very helpful. As well as developmental services, both for the little kids up to age three through early intervention. And then in older patients, they get their developmental services often through the school to try to address their developmental disabilities. So it takes a village because these are very, very complicated patients. I mentioned that I’m studying the retina, but some patients with SLO have developed progressive retinal abnormalities and have gone blind actually in their late teens and early twenties and show my research treatment with antioxidants is trying to prevent that from happening in patients now. And there’s an association with hearing loss, and so many of these patients are followed by ENT and audiology as well.
Given the complexities of SLOS, what role does genetic counseling play in the management and support of families affected by the syndrome?
Ellen Elias, MD: So this is a genetic disorder. It’s inherited in an autosomal recessive pattern. So both parents are carriers for change in the gene, but the parents have one normal gene and one changed gene. There’s a one in four chance with every pregnancy in parents who are both carriers that they’re going to have an affected child with this condition. You can do prenatal diagnosis, you can do it with chorionic villus sampling, can do it with amniocentesis. And so it’s possible to let families know who are at risk, have that 25% recurrence risk, can do prenatal testing and let them know if they have an affected child. And if it’s a very severely affected impacted child, you could offer the family pregnancy termination. But there’s no prenatal intervention that would fix this, just like there’s no cure once the baby’s born.
Are there any ongoing research or clinical trials focusing on SLOS treatment or understanding the underlying mechanisms of the condition?
Ellen Elias, MD: I already mentioned my study with antioxidants. There are other studies around the country. There’s a group at the NIH that is studying the natural history. They did a trial of simvastatin, which really didn’t seem to help. Simvastatin is a medicine used to lower cholesterol, and the hope was that it would lower the making of precursors, but the problem is the only place that the cholesterol that you need in your brain is manufactured in is in your brain, and the cholesterol that you give to a patient’s by mouth or through their G-tubes does not cross the blood brain barrier and get into the brain.
But simvastatin does cross the blood-brain barrier and get into the brain. So I’ve never used it in severe patients because if you shut off their ability to make whatever tiny amount of cholesterol they’re making in the brain by giving them simvastatin and you can’t get any more cholesterol into the brain, I just was worried that would not be helpful. As I mentioned a minute ago, we’re going to be starting a colic acid trial to show that that will be helpful in having the patients be able to absorb whatever cholesterol they’re getting in their diet.
As a clinician with experience in treating patients with SLOS, what advice would you give to other doctors in providing comprehensive care to these patients while also supporting their families?
Ellen Elias, MD: Well, I think it’s really important for specialists to be involved in these patients. They’re very complicated. A regular pediatrician and practice is not going to have the time to manage all of these different issues that are involved. So sending the patient to specialists who are knowledgeable about this will help make sure that the patients get the help that they need. The Smith-Lemli-Opitz Family Support Group and Foundation is a very, very helpful support group. You can find them online and they are enormously helpful for families. They have good information on their website. They help hook families up with other families and other providers in their area. So that has been a very, very, very helpful group for our patients. And they really, they’re very careful. They try to vet all the information they’re giving to families. They have a good medical board that helps give them advice. So I think that that is an enormously important resource.
In your experience, what are some common misconceptions or myths about SLOS among medical professionals and how can we address and overcome these misconceptions?
Ellen Elias, MD: I think the biggest one in my experience as a geneticist and a developmental pediatrician is really encouraging people to do genetic testing and to make a diagnosis in patients that are being seen with autism and who are on the more mild end of the spectrum. Because honestly, what is very, very sad is if you have a genetic diagnosis that’s been missed or not looked for, and then the family goes ahead and has another affected child. And I’ve seen that happen with many, many families. The important thing is to get to people who are caring for patients with developmental delay and autism and make them aware that the testing for this. It has to go to a special lab and maybe a little tricky to get insurance to pay for genetic testing sometimes. But it’s really critically important for these families because you want these children to get the right intervention and the right treatment and the parents to get the correct genetic information about that 25% recurrence risk. And it’s a true, true tragedy that patients are often not diagnosed until after they’ve had another affected child.
For doctors who may not encounter SLOS frequently in their practice, what resources or educational materials would you recommend to help them stay informed and up to date about the latest developments in the field?
Ellen Elias, MD: The carrier rate in Caucasians is actually quite high. It may be as high as one in 30 Caucasians. We see Smith-Lemli-Opitz in other ethnic groups too, and the carrier rate is probably a little bit lower in Asians and people who are Native American and black. But we do see this in Hispanics and Caucasians, and we see it in people who are at risk for having autosomal recessive disorders such as Ashkenazi Jewish people and people from French Canadian background and so on who have a higher chance of recessive disorders. So I think making sure that people who fall in those groups, if there’s any family history, they should be referred for genetic counseling and testing so that the parents can know if they’re carriers and we can really try to educate the population. There’s good information about this, not just from the SLO website, but from genetic resources too online. And I think it’s really important for people to get as much information as possible and be informed.