Cholesterol in ASD: Characterization and Treatment
Condition: Autism; Asperger Disorder; PDD-NOS
MeSH terms: Autistic Disorder; Autism Spectrum Disorder; Asperger Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      - Autism spectrum disorders (ASD) are developmental disabilities characterized by impaired
      social interaction and repetitive and/or stereotypical behaviors. Research studies suggest
      that some individuals with ASD have very low blood cholesterol levels. This low cholesterol
      level and other abnormal sterol levels may be important markers for

      subtypes of ASD. Providing additional cholesterol to the diets of children with ASD may help
      improve behavior.

      - These findings will guide the medical community in identifying individuals who should be
      tested for sterol disorders. This study will also help researchers learn whether adding extra
      cholesterol to the diet will improve behavioral and other autism spectrum characteristics
      seen in individuals with ASD and low cholesterol.

      Objectives:

        -  To determine cholesterol levels in children with autism spectrum disorders.

        -  To compare behavioral and other characteristics among children who have autism spectrum
           disorders and high, low, or normal cholesterol levels.

        -  To determine whether adding cholesterol to the diet will improve behavioral and other
           characteristics in individuals with ASD and low cholesterol.

      Eligibility:

      - Children between the ages of 4 and 12 who have been diagnosed with an autism spectrum
      disorder.

      Design:

        -  Initial screening study will involve a collection of blood samples (for study purposes
           and cholesterol testing).

        -  Children who have low cholesterol levels will take part in a study in which they will
           receive either cholesterol supplementation or a placebo, and will have detailed physical
           and psychological examinations to measure possible improvement in behavioral or other
           characteristics.

        -  Children who have high or normal cholesterol levels will have further blood samples
           taken, and will undergo an additional set of examinations for comparison purposes.

        -  Researchers may request blood or DNA samples from other family members (parents or
           siblings), which will be collected through blood draws and cheek swabs.
    

Detailed description: 
      Pilot work suggests that some individuals with autism spectrum disorders (ASD) have very low
      blood cholesterol levels. This low cholesterol level and other abnormal sterol levels may be
      important markers for subtypes of ASD. The proposed trial aims to characterize any clinical
      differences between low-cholesterol ASD and normal-or-high-cholesterol ASD and to test the
      response of individuals with ASD and low cholesterol to increased cholesterol in the diet.

      Evidence for the role of low cholesterol in causing ASD in a subgroup of individuals comes
      from five sources. First, half of individuals with Smith-Lemli-Opitz syndrome (SLOS) meet the
      behavioral criteria for autistic disorder (Tierney et al, 2001), and three quarters have some
      type of ASD (Sikora et al, 2006). Second, in individuals with SLOS, the lower the cholesterol
      was in the blood and cerebrospinal fluid, the more severe were the autism and IQ and adaptive
      function deficits. Third, in SLOS, improvement was found in social and communication
      abilities with added dietary cholesterol. Fourth, cholesterol was low in a pilot study of 100
      children with autism of unknown cause (Tierney et al, 2006). Fifth, it is becoming
      increasingly clear that cholesterol plays a pivotal role in several aspects of brain
      development.

      This proposal is designed to 1) determine the prevalence of hypocholesterolemia in ASD
      individuals (ASD+Hypo); 2) determine the prevalence of hypercholesterolemia (in ASD
      individuals (ASD+Hyper); 3) determine the rate of SLOS in the ASD subjects; 4) determine the
      phenotype (physical, behavioral, and developmental) at less than the 5th centile (ASD+Hypo)
      and greater than the 95th centile (ASD+Hyper) individuals and normal cholesterol (ASD+Normal)
      in the ASD subjects; 5) test the efficacy of dietary cholesterol supplementation in ASD
      individuals with hypocholesterolemia; 6) determine whether a raised dose of cholesterol
      supplementation is more effective than a lower dose; and 7) create a repository of
      biomaterial samples from individuals with ASD and their biological family members.

      Three sites (Kennedy Krieger Institute [KKI], Ohio State University [OSU], and the National
      Institutes of Health [NIH]) will collaborate to accomplish the objectives of this study. In
      addition to defining the frequency of altered cholesterol homeostasis in ASD, 60 youths (20
      at each site) with ASD plus hypocholesterolemia will enter a 12-week, double-blind,
      placebo-controlled trial immediately followed by a 12-week open-label cholesterol trial to
      test the efficacy of dietary cholesterol supplementation. Outcome measures will include
      standard tests of behavior, communication, and other autism features.

      These findings will guide the medical community in identifying individuals who should be
      tested for sterol disorders. This study will also help researchers learn whether adding extra
      cholesterol to the diet will improve behavioral and other autism spectrum characteristics
      seen in individuals with ASD and low cholesterol. The results of this study may help
      individuals with hypocholesterolemic ASD by the knowledge of the therapeutic value and safety
      of the use of cholesterol supplementation both biochemically and behaviorally. If improvement
      is demonstrated, it opens a new window to understanding the neurologic mechanisms of ASD.
      This knowledge may also be helpful for hypocholesterolemic individuals with ASD in that this
      newly identified population will benefit from such supplementation. Even if cholesterol
      supplementation is found to not be effective, important behavioral phenotype and
      developmental information will be obtained that might be useful in identifying subjects with
      ASD plus cholesterol abnormalities.
    

Intervention name(s): Cholesterol
Intervention type(s): Other
Allocation: Randomized
Intervention model: Parallel Assignment
Primary purpose: Treatment
Keywords: Autism; Autism Spectrum Disorder; Cholesterol; Smith-Lemli-Opitz Syndrome; ASD; Pervasive Developmental Disorder; PPD-NOS