Abstract
PURPOSE: This study investigates receptive and expressive language abilities in individuals with Smith-Lemli-Opitz syndrome (SLOS) and examines how these are associated with intellectual functioning, sex, autism spectrum disorder (ASD) diagnosis, and biochemical markers of cholesterol metabolism. METHODS: Participants (ages 4-18) with mild to classic SLOS were enrolled from a double-blind, placebo-controlled simvastatin trial. Receptive and expressive language scores were assessed using the Peabody Picture Vocabulary Test, Third Edition (PPVT-3), the Expressive One-Word Picture Vocabulary Test, 2000 Edition (EOWPVT-2000), and the MacArthur Communicative Developmental Inventories (MCDI). Intellectual ability and adaptive functioning were measured using the Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) and Vineland Adaptive Behavior Scales, Third Edition (VABS-3). The SLOS Severity Scale (SSS) quantified disease severity. Associations with plasma and CSF sterol biomarkers (cholesterol, 7-dehydrocholesterol [7-DHC], 8-dehydrocholesterol [8-DHC]) were examined using nonparametric statistics with correction for multiple comparisons. RESULTS: Twenty-one participants (mean age 7.85 years) had complete data; 71.4% had a diagnosis of ASD. Receptive and expressive language scores correlated with IQ and adaptive functioning. Receptive vocabulary scores were significantly negatively associated with disease severity, plasma 7-DHC and 8-DHC, and CSF 7-DHC. Expressive vocabulary scores also declined with increasing disease severity, but associations with sterol biomarkers were not significant. ASD was linked to higher rates of non-scorable assessments, though did not fully explain floor effects. No sex differences were found. CONCLUSIONS: Language impairment in SLOS reflects contributions from disease severity, disrupted cholesterol metabolism, and ASD. Receptive language showed stronger biomarker associations, while expressive impairments were more pervasive. Integrating clinical, biochemical, and caregiver-report tools is critical for comprehensive assessment of individuals with SLOS.