The Smith-Lemli-Opitz syndrome and Autism

For all people that think that cholesterol is a bad thing they should take a look at conditions linked to abnormalities in its metabolism such as the Smith-Lemli-Opitz syndrome, Niemann-Pick, Huntington’s and Alzheimer’s disease.

Cholesterol is a fat or lipid molecule that forms part of cell membranes and gives them proper permeability and fluidity.  Cholesterol is especially important to the brain, an organ whose constitution is 12% fat and enjoys the distinction of being the most cholesterol-rich organ of the body.  Abnormalities in the synthesis of cholesterol lead to degeneration of neuronal structures especially those involved in transmitting messages across cells. Unlike what happens in other organs, brain cholesterol is synthesized within the brain itself. This is the case because the blood brain barrier prevents the uptake of cholesterol metabolites from the periphery. Most of the cholesterol within the brain (about 70%) is found in the myelin sheaths that insulate neuronal projections, the rest is found in the membranes of other brain cells such as astrocytes and neurons.

In this blog I will concentrate in describing a particular disorder linked to a defect in cholesterol metabolism: the Smith-Lemli-Opitz syndrome or SLOS. The SLOS is an autosomal recessive disorder caused by a mutation of the 7-dehydrocholesterol reductase gene (DHCR7) located on chromosome 11. Estimated incidence within the general population varies from 1 in 20,000 to 1 in 60,0000.  This condition manifests at term with a very small head (microcephaly) and abnormalities in the facial appearance.  Affected individuals have eyelid drooping, very small jaws and anomalies of their genitalia. Although many patients die during the first year of life (failure to thrive and infections) others survive and, followed over time, they exhibit growth retardation and cognitive defects.


Figure: Facial features and physical findings in SLOS. (ad)  Facial features include small head size, droopy eyelids, broad nasal bridge, upturned nose, and a small jaw.  (e) Limb anomalies include short thumbs and webbing (f) of the second and third toes.

An often quoted study showed that approximately three-fourths of the children with SLOS (71-86% depending on the evaluation method) had an autism spectrum disorder (ASD), about 50% diagnosed with Autistic Disorder and the rest with PDD NOS (Sikora et al., 2006). In common to ASD individuals with SLOS usually suffer from language impairment, self-injurious behaviors, severe sensory hyperreactivity, and sleep-cycle disturbances. Cholesterol supplementation seemingly revereses many symptoms of autism in SLOS.

Neuroimaging and postmortem examination of the brains in SLOS indicate small brain size with enlarged ventricles and reduced size of the fiber bundles linking homologous regions of both hemispheres (the corpus callosum).  At microscopic examination abnormalities of neuronal migration are very common and can be found in both the cerebral hemispheres and cerebellum (e.g. Purkinje cells).

The presence of a deficit in cholesterol synthesis has derailed research into the ASD and SLOS link in favor of trials pursuing dietary cholesterol and even androgenic hormones.  There is even a hypothesis paper regarding the role of sterols in ASD (Lee and Tierney, 2011). However, the search should have been directed at establishing abnormalities of cell migration. These are exceedingly common in SLOS (Sikora et a., 2006). In effect, in SLOS cells have difficulties in migrating out of the germinal zone surrounding the ventricles and remain behind as nodules often protruding to the ventricles (periventricular nodular heterotopias). In addition, cells migrating to the cortex are arrested in their travel forming islands of gray within the white matter (heterotopias).

This is one in a series of blogs where I discuss different conditions manifesting autstic symptomatology of known origin or neuropathology (so-called syndromic autism). The first of these blogs was on tuberous sclerosis ( ), other ones followed on Ehlers-Danlos syndrome ( ) and extreme prematurity ( ). The emphasis in all of these blogs is in the commonality of abnormalities in certain parts of the brain.  It is my belief that in autism there is a common lesion that interferes in some way with the division of germinal cells early during brain development. The end result is abnormalities in cell migration and malformed areas of the cerebral cortex and brainstem. You can find additional information about this process at: and


Lee RWY, Tierney E. The role of sterols in autism spectrum disorder. Autism Research and treatment 2011 ID 653570.

Sikora DM, Pettit-kekel K, Penfield J, Merkens LS, Steiner RD, The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opits syndrome. Am J Med Genet 140(14):1511-8, 2006.

6 responses to “The Smith-Lemli-Opitz syndrome and Autism

  1. Interesting that SLO results in a smaller brain. I thought most post-mortem autopsies and MRI scans showed an enlarged brain in persons with ASD’s. Interesting how problems in germinal cell migration could result in two different brain sizes. I thought that was one argument against the mercury etiology, that mercury poisoning resulted in smaller brains and autism in larger.


  2. Thank you for the comment. I had not heard from you in some time.

    Abnormalities of migration can result in larger or smaller brains. If germinal cells divide in supernumerary fashion the overall size is likely to increase. If a lesion interferes with cells reaching the cortex then microcephaly is more likely. In autism although on average macrocephaly appears to be common, microcephaly has been reported in a significant number of cases. Microcephaly when it occurs tends to correlate better to seizure disorders. See Fombonne et al. Macrocephaly and mcirocephaly in autism. JADD 29(2): 113-9, 1999.


  3. Pingback: The Smith-Lemli-Opitz syndrome and Autism | IINNUAR Investigación en Neurociencias·

  4. Far too many autism researchers make astonishing claims that they have discovered a single causal mechanism that explains all of autism. There is no single causal mechanism that is predictive of autism.
    There are studies that have questioned the association of macrocephaly with autism. Ghazuddian et al (1999) examined 20 children with autism and 20 children with ADHD only. Of the 20 children with autism, four had macrocephaly, which is 20%, consistent with the findings in most other studies. Of the 20 ADHD controls, five had macrocephaly or 25%. The four autistic children with macrocephaly all were hyperactive and impulsive suggesting the association of macrocephaly in autistic children is with co-occurring ADHD rather than being specific to autism.

    Furthermore twins studies have shown that macrocephaly can be present in an affected twin and an unaffected co-twin.

    Macrocephalus in the Courchesne study is a group average. Other groups confirm that macrocephalus is present in 16% of all autistic children, however microcephalus is also present in 15% of autistic children. Macrocephaly can be familial and can be present in in unaffected sibling or parent

    What about the six cases where autopsy data was available?
    In another article discussing Courchesne’s paper there was dissenting opinions about the meaning of the Courchesne paper and the quality of the autopsy specimens.:

    “I know that sample,” says Lange, who is on the advisory board of the Autism Tissue Program, which manages some of the samples in the study. “It’s of varying quality, from poor to acceptable.”
    Amaral questions the premise that most children with autism have large brains. In an unpublished imaging study of 180 children, including 114 with autism, aged 2 and 3 years, his team has found that only about ten percent have larger-than-normal brains. What’s more, some work suggests that about 15 percent of children with autism have abnormally small brains3
    Red flags have to raised any time an autism researcher makes a claim that he has discovered the mechanism that explains all of autism
    That does not render the Courchesne study meaningless at all. It is an interesting study and may have recognized one of hundreds of risk factors of small effect.


    • Thank you for the comment. Things were quite for a little while on the blog.

      The observation regarding macrocephaly in autism is an interesting one. If true, then the pathology of autism would have to account or provide from a mechanism that involved brain growth. I am hoping to expand on this if one of my manuscripts is soon accepted for publication and published. Given the emphasis on a heterogeneity of autism (with such books as The Autisms and Rethinking Autism) the article will try to explain how a causal mechanism may have a marked spectrum of expression.


  5. Dear Sir,
    I am an RN who cared for a SLO child for 5 years. She was treated by Dr. Irons at Beth Israel Hospital Boston. She was given Cholesterol daily in divided doses per gastrostomy tube. Initially her life expectancy would have been 2 years. Because her mother breast fed her she was 5 to 9 yrs, when I cared for her. To my knowledge she is still living.She was severely effected by SLO with all of the symptoms you describe, Her physiological and motor age was 9 months. Both of her parents carried the recessive gene. She had one sibling without any symptoms, who was to be tested for the gene when she was 16. In order to help her with her decisions.regarding her own personal family decisions about having children when she married.
    Fortunately she was blessed with extremely wonderful devoted parents and sister. many families I worked with divorced due to special needs children and the stress on the family. She received excellent home nursing care, physical therapy, occupational therapy and home school teaching through the school system. The parents had 50 hours a week of nursing care. All of the medical care was provided by the CHIPS program.
    This child needed 24/7 care, and the demands on the family increased as time went by and she grew and gained weight.
    Dr Irons research was significant and many of her articles have been published. Thank you for discussing autism and relationship with cholesterol. The public has not been educated in the need for cholesterol for the proper functioning of the nervous system including and especially the brain, the hormonal system, for motor functioning, balance and locomotion. The importance of the myelin sheath and it’s functioning.
    Most children are not tested for cholesterol and nutrition is not a focus today with disease prevention as much as it should be. I have recently found articles regarding cholesterol and autism. The addition of cholesterol rich foods to their diets improved the symptoms of autism which these children exhibited. Nutrition is crucial in all of these neurologically based disorders with a genetic aspect.
    Thank you for your blog.


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