title: A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome.
abstract: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood-brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles.
  
  
  
  Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period.
  
  
  
  No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin.
  
  
  
  This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol-to-total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.Genet Med 19 3, 297-305.
authors: Section on Molecular Dysmorphology, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors: Christopher A
authors: 0000-0002-2524-1420
authors: CA
authors: Wassif
authors: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.
authors: Lisa
authors: L
authors: Kratz
authors: Section on Molecular Dysmorphology, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.|Current affiliation: Sanofi Genzyme, Cambridge, Massachusetts, USA.
authors: Susan E
authors: SE
authors: Sparks
authors: Department of Psychiatry, Kennedy Krieger Institute, Baltimore, Maryland, USA.
authors: Courtney
authors: 0000-0002-8349-8080
authors: C
authors: Wheeler
authors: Section on Molecular Dysmorphology, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors: Simona
authors: 0000-0003-1005-4152
authors: S
authors: Bianconi
authors: Department of Neurology, Children's National Medical Center, Center for Neuroscience and Behavioral Medicine, Washington, DC, USA.
authors: Andrea
authors: 0000-0002-2106-6776
authors: A
authors: Gropman
authors: Office of the Clinical Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors: Karim A
authors: KA
authors: Calis
authors: Department of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
authors: Richard I
authors: 0000-0002-5508-7145
authors: RI
authors: Kelley
authors: Department of Psychiatry, Kennedy Krieger Institute, Baltimore, Maryland, USA.
authors: Elaine
authors: 0000-0002-8546-3383
authors: E
authors: Tierney
authors: Section on Molecular Dysmorphology, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors: Forbes D
authors: 0000-0001-9397-0046
authors: FD
authors: Porter
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol; D018592:Cross-Over Studies; D003684:Dehydrocholesterols / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000134:cerebrospinal fluid / Q000235:genetics; D010919:Placebos; D019821:Simvastatin / Q000009:adverse effects / Q000627:therapeutic use*; D019082:Smith-Lemli-Opitz Syndrome / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000235:genetics
chemical_list: D003684:Dehydrocholesterols; D010919:Placebos; D002784:Cholesterol; D019821:Simvastatin; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase