Smith-Lemli-Opitz syndrome: evolution of research on the condition and how to individualize patient care

Margaret Nowaczyk, MD, professor of pathology and molecular medicine and of pediatrics at McMaster University in Hamilton, Canada, talked about the evolution of research on Smith-Lemli-Opitz syndrome (SLOS) and how individualized care is paramount.

Question:

Can you talk about how the research and understanding of Smith-Lemli-Opitz syndrome (SLOS) have evolved since the condition was discovered

Margaret Nowaczyk, MD:

When I was a fellow was the time when the underlying enzymatic deficiency was discovered by Dr. Mira Irons and Ellen Elias. I still remember the metanoia, the excitement that we all as geneticists felt because Smith-Lemli-Opitz syndrome was the first condition that originally was described as a syndrome of multiple congenital malformations and characteristic facial features. But it was the first condition in which a true biochemical defect was discovered.

Most of the biochemical defects, inborn errors of metabolism, do not have facial features. This was such remarkable discovery that we all kind of stopped, inhaled, and started thinking about things quite differently. Since then, a number of other conditions, especially along the cholesterol or synthetic pathway, have been discovered, and they do have associated physical abnormalities. But Smith-Lemli-Opitz syndrome still remains the paradigm for this particular type of a disorder. That was in 1994.

Shortly thereafter, 2 groups, 1 in Europe and 1 at NIH led by Dr. Danny Porter, discovered the gene, the 7-dehydrocholesterol reductase gene, as being mutated, non-functioning, or hypo-functioning in patients with Smith-Lemli-Opitz syndrome. Then sort going back a little bit when it was discovered that it was the defect in the last step of synthesis of cholesterol, people started wondering whether supplementation with cholesterol would be helpful in patients with this condition.

The other result of this discovery was the realization that cholesterol, far from being the bad guy in terms of coronary artery and vascular disease, was actually very important in the development of the embryonic brain and maturation of the brain. Suddenly, there was a shift in the approach to studies of cholesterol. I remember those things as if it was yesterday, and I became interested in Smith-Lemli-Opitz syndrome at that time.

Since then, there have been a number of studies for cholesterol therapy, which has been found to improve the general health and weight of patients with Smith-Lemli-Opitz syndrome. But unfortunately it did not have many effects on the intellectual disability and behavioral issues that patients with Smith-Lemli-Opitz syndrome present. There were other studies with statins that… Because it was thought that by turning off the cholesterol synthesis in the body, you would decrease the amount of seven-dehydrocholesterol, which was thought to be detrimental. Again, those didn’t quite pan out.

Supplementation with bile acids was tried to improve the absorption of cholesterol from the gut. I think that there’s now a pilot study that shows some benefit in the level of cholesterol in the plasma with bile acid supplementation. But these studies are not completed yet, and there’s no clear-cut evidence whether this is beneficial. Overall, there has been a lot of excitement initially and a lot of studies, but in the end, we still have to fall back on therapies that are not specific to Smith-Lemli-Opitz syndrome, but specific to the symptoms and signs that the patients present.

Question:

Can you talk about the genetic testing and diagnostic component of SLOS? What are the hallmark signs and symptoms of the condition?

Margaret Nowaczyk, MD:

Genetically, Smith-Lemli-Opitz syndrome, just like almost every other inborn error of metabolism, is inherited as an autosomal recessive condition, which means that both parents are carriers for pathogenic variants of the 7-dehydrocholesterol reductase gene. The individual with SLOS inherits both malfunctioning or non-functioning variants and therefore is unable to catalyze the last step of synthesis of cholesterol, leading to cholesterol deficiency.

The genetic testing for SLOS is quite straightforward. There’s only 1 gene associated with a DHCR7 and sequencing of that gene will find the pathogenic variants in both the affected individual and in his or her parents. Genetic testing is relatively straightforward. The question is, whom do we test? How do these individuals present. Smith-Lemli-Opitz syndrome has a huge spectrum from prenatally lethal conditions, conditions that are lethal in the uterus before delivery, such as holoprosencephaly or renal agenesis, all the way to individuals who are very minimally affected, do not have behavioral issues and have very mild, if any, intellectual disability. Their characteristic facial features are almost indistinguishable from the so-called norm.

In between, there’s the classic Smith-Lemli-Opitz syndrome, which presents with the facial differences with short eye openings, small eyes, epicanthal folds, short and upturned nose. Often, these patients have small jaw with cleft palate. They may have extra fingers and toes, they may have webbed toes, and the characteristic webbing of the toes is between the second and third toe and it gives a little bit of a little fork or a little Y kind of so that the 2 toes starts from one stem and then they separate. That’s a very characteristic finding.

Then in terms of internal anomalies, they may have gut malformations, they may have heart malformations, they may have renal malformations. But altogether, geneticists recognize the pattern, the pattern in which these malformations fall and the characteristic facial features and the extra fingers and toes and the webbed toes, and geneticists with experience will be able to recognize this patient as having Smith-Lemli-Opitz syndrome and order both biochemical testing, which is the level of plasma cholesterol and the level of 7 DHC in plasma, which is diagnostic of Smith-Lemli-Opitz syndrome. Following that, molecular testing is also available, and as I said is pretty straightforward.

Question:

What are treatment and management options for patients living with SLOS?

Margaret Nowaczyk, MD:

The management of a patient with Smith-Lemli-Opitz syndrome is symptomatic. If they have a cleft palate, you are referred to an ENT specialist for cleft palate surgery. If they have Hirschsprung’s disease, you refer to general surgeon for management of that condition. If they have a heart defective, a cardiologist. You manage what they have. You don’t manage the underlying condition. You manage what manifestations they have. When they’re little, they frequently have feeding intolerance. Some food allergies that need to be managed.

They may need supplementation. Many of the children have oral aversion and they do not eat very well by mouth. They need tube feeding, usually by a gastrostomy tube directly into the stomach. That’s how we also administer cholesterol supplementation. If they eat orally, they can take the cholesterol orally, either as a form of a cholesterol preparation or egg yolk. What you manage is you manage the patient. You don’t manage the underlying biochemical defect because we can’t. But you have to holistically approach all of the complications, all of the manifestations of it.

Feeding and general health management of birth differences that require surgery as they get older. They have issues with behavioral, managing sometimes pharmacologically managing the behavioral difficulties. Individuals with Smith-Lemli-Opitz syndrome have tremendous sleep abnormalities. Some of them don’t sleep at all and parents experience 2, 3 years of sleepless nights. Sometimes we manage that with medication, like melatonin, or sometimes stronger medication for that to help them establish a sleep pattern. You manage general wellbeing of the patient. You manage the surgical issues. Once the surgical issues are corrected in infancy, they usually are not an issue. They’re fixed, so to speak.

You manage the feeding, you manage their food intolerances, you manage their food allergies. Just like any child, they are allowed to get an ear infection. You treat that. They’re allowed to get a stomach flu, you treat that. You treat the whole patient. Then for the less severely affected intellectually patients, at school, you manage their behaviors, you manage the learning programs. They get individual educational plans and supports, aids. For nonverbal patients, you use communication aids. Again, it’s a global approach to everything. They all need to have their immunizations. There’s no reason for them not to get immunized. To prevent other illnesses, serious illnesses like measles or diphtheria, so immunizations. Then just general wellbeing.

Question:

What are the continued unmet needs patients with SLOS face? What research is needed to continue to move the needle on the care and management of these patients?

Margaret Nowaczyk, MD:

I think over the last 25 years or however long it’s been, we’ve done a lot of different research in terms of addressing specific needs of individuals with Smith-Lemli-Opitz syndrome. Right now, I know that there’s a pilot study for cholic acid supplementation with Dr. Ellen Elias. I am interested in knowing what the results of that study are. But in terms of management, I think we have made all the gains over the last few years and it’s just day-to-day management. Weight, feeding, general well-being, learning resources, supports to the parents and siblings, which are very important.