Statins for Smith-Lemli-Opitz syndrome

Review question

Is statin therapy, either alone or combined with cholesterol therapy, linked to better outcomes (e.g. survival, quality of life, severity or frequency of neurobehavioral abnormalities, changes in growth parameters or biomarker levels) compared to cholesterol therapy alone for people with Smith-Lemli-Opitz syndrome (SLOS), and what are the risks of harmful effects for either option?


Smith-Lemli-Opitz syndrome is a genetic malformation syndrome, which occurs when cholesterol is not able to be produced by the body and there is a build up of several toxic molecules that would, under normal circumstances, go on to become cholesterol, such as 7DHC and 8DHC. This means that people with SLOS may fail to achieve normal physical growth, show various degrees of intellectual disability or developmental delay (or both), and show a range of possible behavioral abnormalities (e.g. irritability, aggressiveness, anxiety, attention-deficit hyperactivity disorder (ADHD), impulsivity and sleep disturbances, among others). It is also notable that SLOS may cause various possible physical abnormalities and disability. There is currently no cure for SLOS, but cholesterol supplementation remains common practice among clinicians caring for people with SLOS. This is based solely on our current understanding of the underlying biochemistry of the disease itself. However, there has been evidence from studies in the laboratory and in single individuals suggesting that statins may be helpful for treating people with SLOS.

Search date

We conducted our latest search on 15 February 2022.

Study characteristics

In this review, we included six studies of different designs that included a total of 61 people with SLOS, mostly males. Five of the studies only included children (18 years old or younger). All studies compared a combination of statin and cholesterol therapy to cholesterol supplementation alone. However, the studies used different doses and formulations of statin or cholesterol therapy (or both), as well as different durations of treatment.

Key results

We found no evidence for the effects of combined statin and cholesterol supplementation, compared to cholesterol supplementation alone, on survival or quality of life in people with SLOS. We are also not sure if combined statin and cholesterol therapy has positive effects on neurobehavioral manifestations or growth in individuals with SLOS compared with cholesterol therapy alone, as we have low confidence in the evidence. We think people with SLOS receiving statin therapy in addition to cholesterol supplementation are more likely to experience adverse events that are usually associated with using statins, compared to those who are only receiving cholesterol supplementation. Finally, we are uncertain about the effects of statin therapy on the levels of various biomarkers usually measured in the blood of people with SLOS.

Authors' conclusions: 

Currently, there is no evidence on the potential effects of statin therapy in people with SLOS regarding survival or QoL, and very limited evidence on the effects on neurobehavioral manifestations. Likewise, current evidence is insufficient and of very low certainty regarding the effects of statins on growth parameters in children with SLOS and plasma or cerebrospinal fluid (CSF) levels of various disease biomarkers. Despite these limitations, current evidence seemingly suggests that statins may increase the risk of adverse reactions in individuals with SLOS receiving statins compared to those who are not. Given the insufficient evidence on potential benefits of statins in individuals with SLOS, and their potential for causing adverse reactions, anyone considering this therapy should take these findings into consideration. Future studies should address the highlighted gaps in evidence on the use of statins in individuals with SLOS by collecting prospective data on survival and performing serial standardized assessments of neurobehavioral features, QoL, anthropometric measures, and plasma and CSF biomarker levels after statin introduction. Future studies should also attempt to use consistent dosages, formulations and durations of cholesterol and statin therapy.

Read the full abstract...

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital malformations syndrome caused by defective cholesterol biosynthesis. Affected individuals show cholesterol deficiency and accumulation of various precursor molecules, mainly 7-dehydrocholesterol and 8-dehydrocholesterol. There is currently no cure for SLOS, with cholesterol supplementation being primarily a biochemical therapy of limited evidence. However, several anecdotal reports and preclinical studies have highlighted statins as a potential therapy for SLOS.


To evaluate the effects of statins, either alone or in combination with other non-statin therapies (e.g. cholesterol, bile acid, or vitamin co-supplementation), compared to cholesterol supplementation alone or in combination with other non-statin therapies (e.g. bile acid or vitamin supplementation) on several important outcomes including overall survival, neurobehavioral features, and adverse effects in individuals with SLOS.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, five other databases and three trials registers on 15 February 2022, together with reference checking, citation searching and contact with study authors to identify additional studies.

Selection criteria: 

Randomized controlled trials (RCTs) and quasi-RCTs with parallel or cross-over designs, and non-randomized studies of interventions (NRSIs) including non-randomized trials, cohort studies, and controlled before-and-after studies, were eligible for inclusion in this review if they met our prespecified inclusion criteria, i.e. involved human participants with biochemically or genetically diagnosed SLOS receiving statin therapy or cholesterol supplementation, or both.

Data collection and analysis: 

Two authors screened titles and abstracts and subsequently full-texts for all potentially-relevant references. Both authors independently extracted relevant data from included studies and assessed the risks of bias. We analyzed the data extracted from the included NRSIs and cohort studies separately from the data extracted from the single included RCT. We used a random-effects model to account for the inherent heterogeneity and methodological variation between these different study designs. We used GRADE to assess the certainty of evidence.

Main results: 

We included six studies (61 participants with SLOS); one RCT (N = 18), three prospective NRSIs (N = 20), and two retrospective NRSIs (N = 22). Five studies included only children, and two limited their participant inclusion by disease severity. Overall, there were nearly twice as many males as females. All six studies compared add-on statin therapy to cholesterol supplementation alone. However, the dosages, formulations, and durations of treatment were highly variable across studies.

We judged the RCT as having a high risk of bias due to missing data and selective reporting. All included NRSIs had a serious or critical overall risk of bias assessed by the Risk Of Bias In Non-randomized Studies of Interventions tool (ROBINS-I).

None of the included studies evaluated survival or reported quality of life (QoL). Only the included RCT formally assessed changes in the neurobehavioral manifestations of SLOS, and we are uncertain whether statin therapy improves this outcome (very low-certainty evidence). We are also uncertain whether the adverse events reported in the RCT were statin-related (very low-certainty evidence). In contrast, the adverse events reported in the NRSIs seem to be possibly due to statin therapy (risk ratio 13.00, 95% confidence interval 1.85 to 91.49; P = 0.01; low-certainty evidence), with only one of the NRSIs retrospectively mentioning changes in the irritability of two of their participants. We are uncertain whether statins affect growth based on the RCT or NRSI results (very low-certainty evidence). The RCT showed that statins may make little or no difference to plasma biomarker levels (low-certainty evidence), while we are uncertain of their effects on such parameters in the NRSIs (very low-certainty evidence).