Cholesterol: When Less Is Not Better


Image source:

If, like many Americans, you think that the lower your blood cholesterol, the healthier you would be… think again.  Cholesterol is important for a host of physiological functions in the body described briefly below:

  • Helps build myelin, which is a substance that protects and covers nerve cells so that impulses travel more quickly (Saher, Brugger et al. 2005);
  • Builds and maintains cell membranes, including important signaling areas called “lipid rafts” (Simons and Ehehalt 2002, Korade and Kenworthy 2008);
  • Influences the development and patterning of the central nervous system (see below);
  • Serves as a precursor compound in the production of steroid hormones, bile acids, neuroactive steroids, and vitamins (most notably, Vitamin D) (Porter 2008, Orth and Bellosta 2012).Source: Great Plains Laboratory
cholesterol formation_GreatPlainsLaboratory

Imagine source: Great Plains Laboratory

Low cholesterol is associated with mental health disorders, such as depression, anxiety, suicidal tendencies, impulsivity, and aggressive behavior (Partonen, Haukka et al. 1999).  Importantly, as it relates to this blog, some researchers suspect that abnormal cholesterol and sterol metabolism may also contribute to the development of autism spectrum disorders (Tierney, Bukelis et al. 2006, Lee and Tierney 2011).  It turns out that the prevalence of autism spectrum disorders is relatively high (~50 to 75%) among individuals with a genetic disorder called Smith-Lemli-Opitz syndrome (SLOS) (Tierney, Nwokoro et al. 2000, Sikora, Pettit-Kekel et al. 2006), a disorder which was first described in 1964 by Drs. Smith, Lemli, and Opitz (Smith, Lemli et al. 1964).  Notably, SLOS is characterized by low blood and tissue concentrations of cholesterol (less than 10mg/dL in severe cases) and elevated blood and tissue concentrations of the precursor compound to cholesterol, 7‑dehydrocholesterol (7-DHC) (Tint, Irons et al. 1994).  Individuals with SLOS have characteristic physical malformations, growth problems, and behavioral abnormalities including, but not limited to, the following: failure to thrive (poor weight gain), hypotonia (poor muscle tone), sleep problems, social and language delays, stereotyped behaviors, aggression (such as self-biting and head banging), and some delays in cognitive functioning (Kelley and Hennekam 2000, Tierney, Nwokoro et al. 2001).  Sound familiar?

The prevalence of SLOS and other sterol disorders among individuals with ASD is unknown.  In blood samples from 100 boys and girls with autism, obtained from the Autism Genetic Research Exchange repository, no samples had sterol levels consistent with SLOS, but abnormally low blood cholesterol concentrations (less than 100 mg/dL) were measured in 19 of 100 (19%) samples (Tierney, Bukelis et al. 2006), suggesting that abnormal sterol metabolism is present in at least a subset of individuals with ASD.

Now, let’s review why cholesterol is important.  Listed below are reasons that researchers think low cholesterol may contribute to ASD (Lee and Tierney 2011):

  • Low cholesterol may affect the fate of how brain cells develop and later communicate by impairing sonic hedgehog (SHH) signaling during embryonic development.  SHH helps direct the pattern of the nervous system and limbs during embryonic development.

    lipid raft

    Image source:

  • Low cholesterol may disrupt cell membrane signaling regions by disrupting membrane “lipid rafts” that serve as platforms for cell signaling and direct neuronal networks in the brain.

Anecdotal evidence suggests that cholesterol can improve many areas of functioning in individuals with SLOS (Elias, Irons et al. 1997, Irons, Elias et al. 1997).  However, no relationship between autism behaviors and cholesterol concentration was observed in a group of 14 children (aged 3 to 16 years) with SLOS (Sikora, Pettit-Kekel et al. 2006), nor did long-term dietary cholesterol supplementation improve developmental functioning in this same population (Sikora, Ruggiero et al. 2004).

To further investigate the link between cholesterol and autism, the Eunice Kennedy Shriver National Institute of Child Health and Human Development is sponsoring an ongoing, multicenter (Johns Hopkins, NIH Clinical Center, and Ohio State), randomized, double-blind, placebo-controlled study in 900 children (wow!) with ASD aged 4 to 12 years (“Cholesterol in ASD: Characterization and Treatment”; Identifier: NCT00965068).  As of the time of this post (February 2013), this study was still actively recruiting study participants.  The primary goals of this study are listed below:

  1. Measure and characterize cholesterol concentrations in this large group of children with ASD.
  2. Evaluate the relationship between behavioral symptoms of autism with cholesterol concentrations (low, medium, high).
  3. Determine if adding cholesterol to the diet will improve behavioral and other characteristics in children with ASD who have low cholesterol.

The strength of the study described above is that it meets many of the “gold standard” study design criteria; it is randomized, double-blind, placebo-controlled, and large (900 participants!).  Therefore, the results of this study will hold significant weight with mainstream clinicians and researchers IF the integrity of study conduct is maintained.  Upon completion, the study administration and disposition will be carefully evaluated by asking questions similar to the following:

  • Did the number of participants enrolled into the study meet the target enrollment?
  • How many of the randomized participants completed the study as planned?
  • Did all enrolled participants meet the entrance criteria as planned?
  • Were participants compliant with the study protocol?
  • Was the treatment blind broken for any reason?

The autism community needs more “gold standard” studies.  I wish these investigators luck, because a study of this size with a heterogeneous population of individuals who notoriously have feeding issues will be a lot of work…a common problem for those trying to conduct high-quality studies in the ASD population.


  1. Compagnone, N. A. and S. H. Mellon (2000). “Neurosteroids: biosynthesis and function of these novel neuromodulators.” Front Neuroendocrinol 21(1): 1-56.
  2. Elias, E. R., M. B. Irons, A. D. Hurley, G. S. Tint and G. Salen (1997). “Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS).” Am J Med Genet 68(3): 305-310.
  3. Irons, M., E. R. Elias, D. Abuelo, M. J. Bull, C. L. Greene, V. P. Johnson, L. Keppen, C. Schanen, G. S. Tint and G. Salen (1997). “Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial.” Am J Med Genet 68(3): 311-314.
  4. Kelley, R. I. and R. C. Hennekam (2000). “The Smith-Lemli-Opitz syndrome.” J Med Genet 37(5): 321-335.
  5. Korade, Z. and A. K. Kenworthy (2008). “Lipid rafts, cholesterol, and the brain.” Neuropharmacology 55(8): 1265-1273.
  6. Lee, R. W. and E. Tierney (2011). “Hypothesis: the role of sterols in autism spectrum disorder.” Autism Res Treat 2011: 653570.
  7. Majewska, M. D. (1992). “Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance.” Prog Neurobiol 38(4): 379-395.
  8. Nishimori, K., Y. Takayanagi, M. Yoshida, Y. Kasahara, L. J. Young and M. Kawamata (2008). “New aspects of oxytocin receptor function revealed by knockout mice: sociosexual behaviour and control of energy balance.” Prog Brain Res 170: 79-90.
  9. Orth, M. and S. Bellosta (2012). “Cholesterol: its regulation and role in central nervous system disorders.” Cholesterol 2012: 292598.
  10. Partonen, T., J. Haukka, J. Virtamo, P. R. Taylor and J. Lonnqvist (1999). “Association of low serum total cholesterol with major depression and suicide.” Br J Psychiatry 175: 259-262.
  11. Paul, S. M. and R. H. Purdy (1992). “Neuroactive steroids.” FASEB J 6(6): 2311-2322.
  12. Porter, F. D. (2008). “Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management.” Eur J Hum Genet 16(5): 535-541.
  13. Reversi, A., V. Rimoldi, S. Brambillasca and B. Chini (2006). “Effects of cholesterol manipulation on the signaling of the human oxytocin receptor.” Am J Physiol Regul Integr Comp Physiol 291(4): R861-869.
  14. Saher, G., B. Brugger, C. Lappe-Siefke, W. Mobius, R. Tozawa, M. C. Wehr, F. Wieland, S. Ishibashi and K. A. Nave (2005). “High cholesterol level is essential for myelin membrane growth.” Nat Neurosci 8(4): 468-475.
  15. Sikora, D. M., K. Pettit-Kekel, J. Penfield, L. S. Merkens and R. D. Steiner (2006). “The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome.” Am J Med Genet A 140(14): 1511-1518.
  16. Sikora, D. M., M. Ruggiero, K. Petit-Kekel, L. S. Merkens, W. E. Connor and R. D. Steiner (2004). “Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome.” J Pediatr 144(6): 783-791.
  17. Simons, K. and R. Ehehalt (2002). “Cholesterol, lipid rafts, and disease.” J Clin Invest 110(5): 597-603.
  18. Smith, D. W., L. Lemli and J. M. Opitz (1964). “A newly recognized syndrome of multiple congenital anomalies.” J Pedatrics 64: 210-217.
  19. Tierney, E., I. Bukelis, R. E. Thompson, K. Ahmed, A. Aneja, L. Kratz and R. I. Kelley (2006). “Abnormalities of cholesterol metabolism in autism spectrum disorders.” Am J Med Genet B Neuropsychiatr Genet 141B(6): 666-668.
  20. Tierney, E., N. A. Nwokoro and R. I. Kelley (2000). “Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome.” Ment Retard Dev Disabil Res Rev 6(2): 131-134.
  21. Tierney, E., N. A. Nwokoro, F. D. Porter, L. S. Freund, J. K. Ghuman and R. I. Kelley (2001). “Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome.” Am J Med Genet 98(2): 191-200.
  22. Tint, G. S., M. Irons, E. R. Elias, A. K. Batta, R. Frieden, T. S. Chen and G. Salen (1994). “Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome.” N Engl J Med 330(2): 107-113.

About EstherAsplund

Freelance regulatory writer, runner, mother. "Life is not about what I produce, it is who I become." - Fr. Keller
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2 Responses to Cholesterol: When Less Is Not Better

  1. Liv says:

    Hi Esther

    My daugther 7 years old with asd has really low cholesterol(3,6). This have been a problem for many years. We have tried to give cholesterol supplements(sonic) and give eggs and high-cholesterol food. I have been trying many interventions(biomediacal) and she gets ABA at school.But she dont progress much like many others do. I am so tired, but offcourse I wont give up…
    She can speak some phrases and know many words. But mostly just ask for food and basic things. She dont care much about her classmates.
    I love her so much and have hope, but it is very difficult. She is very hyperactive also.

    I am glad to read about your son!

    All the best Liv from Norway

    • Hi Liv,

      Thanks for viewing my blog and sharing your story. I’m sorry that your daughter has not greatly benefited from some of the less invasive interventions that work for others. I think that is the most frustrating thing for parents, doctors, and researchers in this field. Simply, we don’t understand all the underlying reasons that a child eventually develops an ASD phenotype. It’s not so simple as one solution or a one-size-fits-all solution. For example, are you aware of the possible defect in the branched chain amino acids? See link:

      Cholesterol may be one of those interventions that help during pregnancy or in those early years when those brain connections are being patterned. Reading the SLOS papers, cholesterol supplementation didn’t resolve 100% of the abnormalities. So, it may be that there is a critical time period for cholesterol supplementation or that the buildup of the 7-DHC is also playing a role (most likely, both contribute).

      It sounds like you are a dedicated mother and I wish you and your daughter the best!


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