Smith-Lemli-Opitz | RSH Syndrome Overview

SLOS Digital Guide TO PRINT

 What is Smith-Lemli-Opitz syndrome (SLOS)?

SLOS is an autosomal recessive disorder, caused by a mutation in the DHCR7 (7-dehydrocholesterol reductase) gene on chromosome 11. This gene codes for DHCR7, an enzyme involved in converting 7-dehydrocholesterol (7-DHC) to cholesterol in the biosynthetic pathway. Disruptions to the activity of DHCR7  can lead to a decrease in cholesterol levels and an accumulation of cholesterol precursor molecules (7-DHC & 8-DHC).

Cholesterol is an essential component of the cell membrane and tissues of the brain. A person who can’t synthesize enough cholesterol will therefore experience poor growth, developmental delays, and mental retardation. SLOS  is characterized by a range of physical malformations, including:

Some children will have only one or two minor malformations, such as webbing of the toes and cleft palate, whereas others will have almost all of the defects listed above. Because of the possibility of internal malformations, patients with SLOS should be evaluated carefully, especially for heart and kidney defects. Often, children with SLOS resemble one another more than they do others in their family.

How do people get SLOS?

SLOS is inherited in an autosomal recessive pattern. Because it is recessive, a child will not have the symptoms of the disorder unless both parents pass on a defective copy of the DHCR7 gene. This can only happen if both parents are carriers. A carrier of SLOS is a person who has one good copy and one mutated copy of the DHCR7 gene, but does not experience any symptoms of the disorder. If both parents are carriers, each of their children will have a 25 percent chance of inheriting SLOS.

SLOS is one of the most common autosomal recessive disorders. Estimates of the incidence vary, but most studies in Europe, the United States, and Canada have found an incidence of 1 in 20,000 births. In some regions, the disorder may occur as often as 1 in 10,000 births. The incidence of SLOS appears to be much lower in Asian and African populations.

How do doctors diagnose SLOS?

Following the discovery of the DHCR7 gene mutation on the long arm of chromosome 11, molecular or DNA testing are now available to aid in carrier determination and future pregnancy testing. An ultrasound (a machine that uses sound waves to look inside a mother’s uterus) can reveal distinct physical deformities before a baby is born and aid in diagnosis. Amniocentesis and chorionic villus sampling (CVS) can also determine whether the baby will be born with SLOS.

After birth, a blood test can determine whether someone has the disorder. The test looks for low levels of cholesterol, as well as elevated levels of cholesterol precursors.

How is SLOS treated?

The major medical problems of children with SLOS are in the areas of feeding, growth, and development. In addition, there may be other serious medical problems caused by one or more malformations, such as heart or kidney defects. The care of these problems often requires the combined efforts of geneticists and specialists.

Even for more mildly affected children, feeding problems are common and require careful management. Special attention must be paid to the frequent problem of limited formula tolerance because of the prevalence of functionally small stomachs and poor gastrointestinal motility in children with SLOS. That children with SLOS have a limited potential for growth is also important to recognize; otherwise, the children are often overfed in an attempt to make them grow faster. Pyloric stenosis, caused by a thickening and spasm of the stomach outlet, is also common in the first weeks or months and often requires surgical correction. Severe liver disease is a rare problem in some of the most severely affected children and may require treatment with special medications.

Current treatment options include:

Cholesterol Supplementation: With the discovery that SLOS children cannot make adequate amounts of cholesterol, the most common form of treatment for SLOS currently involves dietary cholesterol supplementation. Most specialists believe that cholesterol supplementation may result in better growth and overall health. However, dietary cholesterol does not cross the blood-brainbarrier and there is no good evidence that dietary cholesterol will improve behavior or developmental outcomes. Cholesterol supplementation is either achieved by consuming foods that are naturally high in cholesterol (such as egg yolks), or in the form of a synthetic cholesterol compounded by a pharmacy. Any cholesterol supplementation should be recommended and monitored by your child’s physician. More studies are needed to determine the benefits and possible risks of cholesterol supplementation.

Simvastatin Therapy: A placebo controlled study of simvastatin therapy showed a minimal biochemical shift in the 7-DHC to cholesterol ratio. There was also a difference in one of the behavioral scales used to track behavior over the course of the study. This difference was small and unlikely to be of clinical benefit. All of the individual in this study had mild or mild – classical disease and were screened ahead of time with the residual function of their DHCR7 protein to assure that the medication is safe in them. Even though the result in this study were promising, at this point in time simvastatin therapy cannot be recommended. There is the potential of adverse events even in mild to classical cases. A physician should always be involved in prescribing and monitoring side effects of simvastatin.

Antioxidant Supplementation: Antioxidant supplementation has been used since 2008, following studies in an SLOS animal model which showed that abnormalities in eye function could be improved with antioxidant treatment It was then discovered that the precursors 7-DHC and 8-DHC are “oxidized” and turned into substances called oxysterols which are toxic to the brain and the eye. A research protocol was thus developed to give antioxidants in the form of vitamins to help reduce the formation of oxysterols and thus protect the brain and eye from oxysterol toxic side effects. A study looking at retinal and hearing function in patients with SLOS on antioxidants is ongoing. So far there have been no bad side effects of the vitamins, and improvement in special vision tests have been noted.