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. (a–d) 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 (http://bit.ly/17ExHYt ), other ones followed on Ehlers-Danlos syndrome (http://bit.ly/167eZuR ) and extreme prematurity (http://bit.ly/1ddJuVk ). 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: http://bit.ly/1aM5KFu and http://bit.ly/136db0t
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.