Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update

Abstract

BackgroundSmith-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.MethodsThis 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.ResultsDevelopmental 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.ConclusionsA 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.Trial registrationClinicalTrials.gov, NCT00001721, NCT00064792Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9145-x) contains supplementary material, which is available to authorized users.

Prevalence of Motor Difficulties in Autism Spectrum Disorder: Analysis of a Population‐Based Cohort

“…The mean standard score for each domain is 100 with a SD of 15. Standard scores are classified as <70 = “low,” 70–84 = “moderately low,” 85–115 = “average,” 116–130 = “above average,” and >130 = “high.” Motor difficulties were defined as a score in the “low” category (≥2 SD below the mean), while those in the “moderately low” category (≥1 SD below the mean) were classified as borderline [Thurm et al, ]. The current study included cases notified to the WA Autism Register between the years 1999 and 2017, which meant that Vineland data were initially from the original Vineland scales [Sparrow et al, ], but then transitioned to the second edition (Vineland‐II, Sparrow et al, ].…”

State of the Field: Differentiating Intellectual Disability From Autism Spectrum Disorder

“…Research on specific genetic conditions associated with ASD has highlighted some of these diagnostic challenges, because ID is much more common when a genetic etiology is identified than in the idiopathic ASD population (46). There are examples from several genetic syndromes, including Fragile X Syndrome (47, 48), Dup15q Syndrome; (49), and Smith–Lemli–Opitz Syndrome (50), wherein lower IQ is associated with increased rates of ASD diagnosis. An exception may be when the ID is so severe that clinicians apparently find it impossible to identify relative deficits in social communication and play, given the extremely low mental age (51).…”

Implication of hypocholesterolemia in autism spectrum disorder and its associated comorbidities: A retrospective case–control study

“…Mutations in the 7‐dehydrocholesterol reductase gene (DHCR7) leads to a defect in cholesterol synthesis followed by a decrease of cholesterol levels in plasma and tissue which overall lead to the onset of the Smith–Lemli–Opitz Syndrome (SLOS) [Hooper & Burnett, ]. Even though assessments of autism in SLOS may be inflated by low level of functioning [Thurm et al, ], autistic symptoms are still the most severe behavior problem found in SLOS and more than three‐fourths of affected children meet the diagnostic criteria of ASD [Sikora, Pettit‐Kekel, Penfield, Merkens, & Steiner, ; Tierney et al, ]. Up‐to‐date, only few studies have reported alterations of cholesterol levels associated with ASD conditions.…”