The Anatomic Severity Scale Correlates with Level of Impairment On Measurements of Autism and Intellectual Disability in Children with Smith-Lemli-Opitz Syndrome (SLOS)

Background: SLOS is an autosomal recessive, multiple malformation syndrome caused by an inborn error of cholesterol biosynthesis (Tint, 1994). Mutations in the gene encoding 7-dehydrocholesterol reductase (DHCR7) impairs conversion of 7-dehydrocholesterol (7DHC) to cholesterol, resulting in low cholesterol and elevated concentrations of abnormal sterols in tissues and blood. A pilot study showed significant hypocholesterolemia in a subpopulation of children with autism (Tierney, 2006). Autism is commonly found in SLOS (Tierney, 2001). Studies demonstrate cholesterol has multiple biologic functions as a structural component of myelin and lipid rafts, synaptogenesis, formation of bile acids and neurosteroids, and hedgehog signaling (Fantini, 2009). A clinical scoring system that measures the involvement of multiple organ systems has been confirmed in SLOS cases (Kelley, 2000; Bailer, 1987). Further studies are required to elucidate the role of impaired cholesterol biosynthesis in autism. Objectives: This study hypothesizes that the anatomic severity scale correlates with severity of impairment on measurements of autism, IQ, adaptive function, and sterol levels. Methods: 23 subjects with SLOS between the ages of 4 years and 18 years received the ADI-R, ADOS, Vineland adaptive behavioral scales (VABS), Stanford-Binet-IV, and Mullen Scales. Plasma 7DHC and 8DHC levels were acquired by GC-MS. Anatomic severity scores were obtained by a blinded physician examiner. Simple and multiple regression analyses were used. Results: Significant correlations were found between severity score and ADI-R-social (p=0.02), ADI-R-verbal communication (p=0.02), ADI-R-non-verbal communication (p=<0.01), ADOS-play (p=0.02), VABS (p=<0.01), VABS-social (p=0.02), VABS-motor (p=0.01), VABS-daily living (p=0.01), full scale IQ (FSIQ) (p=<0.01), non-verbal IQ (p=<0.01), verbal IQ (p=0.01), plasma 7DHC (p=0.01), and plasma 8DHC (p=<0.01). Multiple regression showed FSIQ was the primary predictive factor in social but not communicative ADI-R. Conclusions: These findings suggest that higher anatomic severity scores correlate with increased scores on autism measures in children with SLOS, but this is likely mediated by intelligence. Higher severity scores correlate with sterol levels in children with SLOS. Further studies investigating the neurologic underpinnings of behavioral phenotypes and anatomic malformations within SLOS and other neurogenetic syndromes, may lead to new diagnostic and therapeutic strategies for autism and other neurodevelopmental disabilities.