Simvastatin: a new therapeutic approach for Smith-Lemli-Opitz syndrome

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is caused by deficient ⌬ 7 -dehydrocholesterol reductase, which catalyzes the final step of the cholesterol biosynthetic pathway, resulting in low cholesterol and high concentrations of its direct precursors 7-dehydrocholesterol (7DHC) and 8DHC. We hypothesized that i ) 7DHC and 8DHC accumulation contributes to the poor outcome of SLOS patients and ii ) blood exchange transfusions with hydroxymethylglutaryl (HMG)-CoA reductase inhibition would improve the precursor-to-cholesterol ratio and may improve the clinical outcome of SLO patients. First, an in vitro study was performed to study sterol exchange between plasma and erythrocyte membranes. Second, several exchange transfusions were carried out in vivo in two SLOS patients. Third, simvastatin was given for 23 and 14 months to two patients. The in vitro results illustrated rapid sterol exchange between plasma and erythrocyte membranes. The effect of exchange transfusion was impressive and prompt but the effect on plasma sterol levels lasted only for 3 days. In contrast, simvastatin treatment for several months demonstrated a lasting improvement of the precursor-to-cholesterol ratio in plasma, erythrocyte membranes, and cerebrospinal fluid (CSF). Plasma precursor concentrations decreased to 28 and 33% of the initial level, respectively, whereas the cholesterol concentration normalized by a more than twofold increase. During the follow-up period all morphometric parameters improved. The therapy was well tolerated and no unwanted clinical side effects occurred. This is the first study in which the blood cholesterol level in SLOS patients is normalized with a simultaneous significant decrease in precursor levels. There was a lasting biochemical improvement with encouraging clinical improvement. Statin therapy is a promising novel approach in SLOS that deserves further studies in larger series of patients.

7‐Dehydrocholesterol (7‐DHC), But Not Cholesterol, Causes Suppression of Canonical TGF‐β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD)

“…Therapeutic trials using dietary supplementation of cholesterol have been shown to increase plasma cholesterol levels in some SLOS patients but have thus far failed to alter plasma levels of 7‐DHC in the patients. Therapeutic trials in SLOS with simvastatin, which inhibits biosynthesis of both 7‐DHC and cholesterol, have been shown to decrease 7‐DHC plasma levels, with variable clinical improvement [Jira et al, ]. Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS have been recently evaluated in a randomized, double‐blind, placebo‐controlled trial.…”

Dysregulation of Neuronal Nicotinic Acetylcholine Receptor–Cholesterol Crosstalk in Autism Spectrum Disorder

“…Cholesterol supplementation results in only slight improvements in SLOS symptoms and does not appear to be an effective treatment for SLOS. The lack of demonstrable effects may be due to the fact that dietary cholesterol, according to currently accepted evidence, does not cross the BBB (Jira et al, 2000;Björkhem and Meaney, 2004). Thus, more randomized controlled trials with standardized cholesterol dosing, laboratory monitoring of sterol levels, and well-defined outcome measures are required for a more objective assessment of the potential role of cholesterol as an effective palliative treatment for SLOS patients.…”

Apolipoproteins, Triglycerides and Cholesterol

“…Glycation of HDL in vitro reduces its capacity to mediate cholesterol efflux from THP-1 macrophages, and incubation High-Density Lipoprotein: From Biological Functions to Clinical Perspectives DOI: http://dx.doi.org/10.5772/intechopen.91136 with glycation inhibitors (metformin and aminoguanidine) restores HDL-mediated cholesterol efflux [124,125]. HDL from diabetic subjects reduces the abilities of anti-oxidation and anti-apoptosis as well as the capacities to mediate cholesterol efflux from THP-1 macrophages, which result from depleting HDL-associated apoA-I level and PON1 activity and elevating SAA concentration [126][127][128]. Both glycated HDL in vitro and diabetic HDL lose their protective effects on inhibition of cytokine release against LPS in macrophages [129].…”

“…The subcellular element (SCE) modeling approach has been successful in modeling mechanical properties of individual cells as well as their components and determining individual cell impact on the emerging properties of growing multicellular tissue as well as describing cellular interactions with mediums such as the extracellular matrix and fluids [76,84,86,89,90,95,96,111,117,120,122,[124][125][126][127]. The general modeling framework was initially developed by Newman et al [89] for simulating the detailed dynamics of cell shapes as an emergent response to mechanical stimuli.…”

“…Current treatment protocols for SLOS usually involve endogenous cholesterol supplementation with or without adjunct therapies such as simvastatin [126]. There is broad anecdotal evidence throughout the literature as to the positive benefit of cholesterol supplementation for patient growth, overall health (including improved photosensitivity and response to infection) and behaviour, as well as measurable changes towards typical plasma sterols [127][128][129].…”