Hypocholesterolemia in Autism Spectrum Disorder

Background: Studies of metabolic function (metabolomic studies) in fragile X syndrome and Rett syndrome have been helpful in understanding cellular dysfunction that leads to autism spectrum disorder (ASD) profiles.  Studies have extended to Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive disorder due to an inborn error of cholesterol metabolism that is caused by mutations of the 7-dehydrocholesterol reductase gene (DHCR7) encoded on chromosome 11q12-13. SLOS has an estimated incidence among individuals of European ancestry of 1 in 20,000 to 1 in 60,000 births and a carrier frequency of 1%.  In SLOS, insufficient cholesterol is synthesized and the precursor sterols 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) accumulate.  Approximately 50% of individuals with SLOS met the diagnostic criteria for autism (Tierney 2001, Sikora 2006) and approximately three-fourths met criteria for ASD, suggesting a consistent relationship with ASD and SLOS (Sikora 2006). In Autism Genetic Resources Exchange (AGRE) multiplex families, a high degree of hypocholesterolemia was detected (Tierney 2006) and hypocholesterolemia occurs at 10 times the expected rate. Cholesterol has multiple biological functions, some of which could plausibly contribute to ASD. Cholesterol is an important building block for the body’s cell membranes and myelination of the central nervous system, is a major component of lipid rafts, modulates oxytocin receptor function, modulates ligand binding activity and G-protein coupling of the serotonin1A (5-HT1A) receptor, and is the precursor for neurosteroid production.

Objectives: To determine the relationship of both physical and behavioral phenotype to plasma and cerebral spinal fluid (CSF) sterol levels in individuals with SLOS.

Methods: Autism features, cognitive abilities, adaptive skills, and anatomical severity in 23 individuals with mild to moderate SLOS were correlated with plasma and CSF sterols.

Results: In SLOS, 56% had autism and 70% had ASD. Regression analyses with sterol levels and the scores of Autism Diagnostic Interview-Revised, IQ, adaptive behavior, and anatomical severity demonstrated that plasma and CSF 7DHC levels were the most significant correlates of social and nonverbal autistic symptom characteristics and that sterol ratios (7DHC+8DHC/ total sterols) were the most significant correlates of anatomical severity.

Conclusions: Using clinical assessment tools and metabolomic studies, we have been able to distinguish distinct neurobehavioral phenotypes among young persons with SLOS, and determined that ASD related behaviors in SLOS may be a functional consequence of the abnormal biochemistry in the brain and specifically due to the accumulation of 7DHC.  Thus, in SLOS and non-SLOS hypocholesterolemic ASD, autistic symptoms may be potentially amendable to therapeutic interventions that increase cholesterol and reduce 7DHC levels. A study is being performed with AGRE multiplex non-SLOS hypocholesterolemic individuals to determine if there is a distinct physical and behavioral phenotype that represents an etiologically independent subgroup (endophenotype).  In a community sample of mostly simplex families, a study is being performed to behaviorally characterize the hypocholesterolemic individuals and determine if cholesterol supplementation is safe and helpful for ASD-related behaviors.