title: Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update.
abstract: BACKGROUND
  Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive inborn error of cholesterol metabolism syndrome with neurocognitive manifestations. SLOS is the result of mutations in the gene encoding the 7-dehydrocholesterol reductase, which results in the elevation of the cholesterol precursor 7-dehydrocholesterol (7-DHC). Previous reports indicate that intellectual disability, behavioral disturbances, and autism symptoms are frequently part of the SLOS behavioral phenotype. In the current study, we characterize the developmental history and current behavior of 33 individuals with SLOS aged 4 to 23 years and report on biomarkers 7-DHC and 8-DHC in relation to cognition and behavior.
  
  
  METHODS
  This was an observational case series, wherein participants with SLOS underwent extensive behavioral evaluation of cognitive function, adaptive function, autism symptoms, and problem behaviors, in addition to parent report of developmental milestones. Serum and CSF were contemporaneously obtained from the majority of participants.
  
  
  RESULTS
  Developmental milestones such as walking, talking, and toileting were uniformly delayed. Overall levels of cognitive and adaptive functioning were low; no participant received adaptive behavior scores in the average range, and the mean level of cognitive functioning in the full sample was in the moderate range of impairment. Aggressive behavior was present in nearly half of participants. Although the majority of participants had elevated scores on the gold standard autism diagnostic instruments, only about half of participants received a clinical diagnosis of autism spectrum disorder. Finally, while CSF cholesterol was not found to correlate with cognitive or adaptive functioning, both serum and CSF 7-DHC and 8-DHC (and their ratios with cholesterol) were moderately and negatively correlated with functioning in this group.
  
  
  CONCLUSIONS
  A history of developmental delay, followed by intellectual disability, is common in individuals with SLOS. Although autism spectrum disorder appears to be a frequent diagnosis in this population, it is apparent that the low level of functioning observed in SLOS may artificially inflate scores on standard autism assessments. Our findings further support that cholesterol precursors 7-DHC and 8-DHC are important biomarkers of the level of functioning in SLOS, especially regarding cognitive abilities, and thus may be to explore as mediators within the context of treatment trials.
  
  
  BACKGROUND
  ClinicalTrials.gov, NCT00001721, NCT00064792.
authors.affiliation: Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892 USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Thurm
authors.affiliation: Kennedy Krieger Institute, 716 N. Broadway, Baltimore, MD 21205 USA ; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tierney
authors.affiliation: Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892 USA.
authors.forename: Cristan
authors.initials: C
authors.lastname: Farmer
authors.affiliation: Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892 USA.
authors.forename: Phebe
authors.initials: P
authors.lastname: Albert
authors.affiliation: Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892 USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Joseph
authors.affiliation: Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892 USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Swedo
authors.affiliation: Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892 USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Bianconi
authors.affiliation: Kennedy Krieger Institute, 716 N. Broadway, Baltimore, MD 21205 USA.
authors.forename: Irena
authors.initials: I
authors.lastname: Bukelis
authors.affiliation: Kennedy Krieger Institute, 716 N. Broadway, Baltimore, MD 21205 USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Wheeler
authors.affiliation: Kennedy Krieger Institute, 716 N. Broadway, Baltimore, MD 21205 USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Sarphare
authors.affiliation: Kennedy Krieger Institute, 716 N. Broadway, Baltimore, MD 21205 USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Lanham
authors.affiliation: Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892 USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.affiliation: Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892 USA.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
keywords: Autism; Developmental delay; Smith-Lemli-Opitz; Sterols