Deficient Cholesterol: A Common New Factor in Autism

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Dr. William Shaw reports that cholesterol supplementation reverses many symptoms of autism in Smith-Lemli-Opitz syndrome disorder. This deficiency is also common in “regular” autism. The connection between low cholesterol and some cases of autism is encouraging, as it appears to be treatable. The following article contains technical information.

Dr. Richard Kelly, a research physician at John Hopkins University has found, along with his colleagues, that autistic symptoms prevalent in the genetic disorder Smith-Lemli-Opitz syndrome (SLOS) quickly reversed after supplementation with dietary cholesterol.

Some of the many improvements included sleeping through the night, overcoming aberrant behaviors, learning to walk, speaking for the first time, and becoming more responsive and social to family members. In addition, other benefits of cholesterol supplementation included a decreased rate of infections, reduced skin rashes, marked reduction in self-hurtful behaviors, improved muscle tone, decreased tactile defensiveness, more rapid growth, and improved behavior overall. Parents reported their children having significant decreases in autistic behavior. Even some adults, without speech, spoke for the first time — all within days of taking cholesterol supplements. These changes occurred even before cholesterol values had increased in the blood, which indicates that the improvements may be a result of cholesterol forming its derivatives, such as steroid hormones or bile salts.

SLOS and Autism

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic disorder associated with autism, multiple malformations and mental retardation syndrome initially described by Smith Lemli, and Opitz. The syndrome (SLOS) is due to a deficiency of 7-dehydro-cholesterol (7DHC) reductase, the enzyme responsible for catalyzing the final step in cholesterol synthesis. As a result of this enzyme deficiency, 7-dehydro- cholesterol accumulates and the level of cholesterol dramatically decreases. Although some children with SLOS have severe physical abnormalities, many are only mildly affected and autistic behaviors may be their only major abnormality.

Since the biochemical test for this disease is done so rarely, it may be possible that there are many other children with SLOS, with fewer anatomic abnormalities, in which the diagnosis is missed. As a result of this enzyme deficiency, individuals with this disorder have extremely low cholesterol values but extremely high values of 7-dehydrocholesterol. One person with SLOS had the lowest cholesterol value (< 1mg/dL) ever measured in serum while most Americans have values between 150-250 mg/dL. Because cholesterol levels are insufficient in persons with SLOS, virtually none of the normal steroid hormones and bile salts derived from cholesterol can be adequately produced. However, abnormal forms of these hormones derived from 7-DHC can be produced instead. It is important to note that cholesterol is an essential element in myelin, which is the insulating material essential for nerve function (especially in the brain). Persons with SLOS will possess varying degrees of cognitive abilities ranging from borderline intellectual functioning to profound mental retardation. It is common for them to also exhibit sensory hyper-reactivity, irritability, language impairment, sleep cycle disturbance, self-injurious behavior, and autism spectrum behaviors. In one study, nearly 50% of children with SLOS met the DSM-IV criteria for autism. In another study, 86% of children with SLOS had an autistic spectrum disorder. Many of the behavioral abnormalities of SLOS significantly respond to supplementation with cholesterol.

If autism is prevalent in SLOS, and the autistic symptoms improve with cholesterol supplementation, then it is conceivable that any severe biochemical abnormality leading to de-myelination needs to be explored as a possible cause of autism.

Cholesterol Doses to Treat SLOS

Doses of cholesterol used in therapeutic trials have varied from 20-300 mg/Kg body weight/day. In some SLOS treatment studies, supplemental bile acids were also incorporated into the diet. In early studies, 50 mg /Kg of pure crystalline cholesterol was used and showed beneficial results. Other options for cholesterol supplementation include use of egg yolk, whipping cream, and butterfat. A single egg yolk contains about 250 mg of cholesterol. A 100-Kg adult with SLOS would have to consume 40 egg yolks per day to consume enough cholesterol to attain a dose of cholesterol of 100 mg/Kg per day. In addition, organ meats—like liver and kidneys—are particularly rich in this compound. A 3 oz (85 g) serving of beef liver, for example, contains about 372 mg of cholesterol. A similar portion of brain from animal sources has close to triple this amount. In some of the treatment studies, patients with SLOS were dosed with purified cholesterol supplements instead of food sources.

Benefits of cholesterol feeding in SLOS

Kelley RT. Inborn errors of cholesterol biosynthesis.
Adv Pediatric 2000; 47:1-53

Beginning to walk
Starting to run
Growth improvement
Less infections
Less UV light sensitivity
Increased alertness
Head-banging stops
Decreased tactile defensiveness
Increased sociability
Behavior improves
Talking has started in adults who
were not talking before
Verbal people say they feel better
Many improvements in only a few
days after supplement
Decreased irritability
Increased muscle tone

Cholesterol deficiency: common in regular autism syndrome disorders as well as in SLOS

Dr. Tierney and her colleagues involved in SLOS research wanted to determine if cholesterol deficiency is also common in “ordinary” autism. They investigated the incidence of cholesterol deficiency in blood samples from a group of subjects with autism spectrum disorder (ASD) from families in which more than one individual had ASD, but not SLOS. Using highly accurate gas chromatography /mass spectrometry, cholesterol, 7-DHC and its related molecules were quantified in 100 samples from subjects with ASD. Although no sample had values consistent with SLOS, 19 samples (19%) had total cholesterol levels lower than 100 mg/dl, values that are much lower than those found in normal children of the same age. In addition, these researchers found that cholesterol was low, not as a result of excessive breakdown, but because of reduced production.

Results of Testing at the Great Plaines Laboratory PIC

This work was confirmed at The Great Plains Laboratory which performed cholesterol testing on 40 children with autistic spectrum disorder graph). In this study, as in Dr. Kelly’s study, extremely low cholesterol levels are defined as the lower fifth percentile of normal children (less than 100mg/dL) which was determined in a nationwide study of the Center for Disease Control. The results of the two studies were similar, with The Great Plains Laboratory percentage of extremely low values being 17.5% versus 19% of values being low for the Tierney study. In addition, 57.5% had cholesterol values less than 160 mg/dL.

The National Institutes of Health had concluded in 1990 from a meta-analysis of 19 studies, that men and women (to a lesser extent) with a total serum cholesterol level below 160 mg/dL had approximately a 10% to 20% increased death rate compared with those with a cholesterol level between 160 to 199 mg/dL. Specifically, people with these lower cholesterol levels were more likely to die from cancer (primarily lung and blood), respiratory and digestive disease, violent death (suicide and trauma), and hemorrhagic stroke. It is interesting to note that in The Great Plains Laboratory study, only one child on the autistic spectrum had an extremely high cholesterol level, with a value over 340 mg/dL.

Cholesterol — the good, bad and the ugly

The concept of good and bad for dietary substances depends on the circumstance of the individual person. Much of the information that the public receives is oversimplified. To a person dying of thirst in the desert, any water is very good. To a person who just drank two gallons of water on a dare, another glass of water might be fatal. The concept of good and bad cholesterol is similar to the water analogy.

The type of cholesterol that is associated with high density lipoproteins and helps to remove cholesterol from certain tissues was termed “good” cholesterol or HDL cholesterol (High Density Lipoprotein-associated cholesterol). The type of cholesterol associated with low density lipoproteins and which transports cholesterol to tissues that require it was designated as “bad” cholesterol or LDL cholesterol (Low Density Lipoprotein-associated cholesterol). If, however, the tissues of a certain person have a significant overall deficiency of needed cholesterol, then both LDL and HDL cholesterol are good for that person.

Therefore, a purified cholesterol supplement cannot be inherently “good” or “bad” and the body will distribute it to the locations where it is needed the most. If the person has adequate amounts of cholesterol, however, no additional supplementation would be needed.

Abnormalities in cholesterol metabolism present in SLOS and autism also impair the function of a developmental signaling protein with the bizarre name “Sonic Hedgehog.” Sonic hedgehog (SHH) is named after the character from the popular Sega Genesis video game. The original hedgehog gene was found in the fruit fly Drosophila and was named for the appearance of the mutant fly offspring in which the embryos are covered with pointy spines resembling a hedgehog. The first two types of hedgehog proteins were named after certain species of hedgehogs and the third was named after the video game character.

Cholesterol must covalently bond to SHH before SHH can function properly. In addition, some forms of SHH have both cholesterol and the fatty acid palmitic acid covalently attached to the protein. (Palmitic acid is required for the production of a soluble Hedgehog protein complex and long-range signaling in humans). The attachment of cholesterol activates the sonic hedgehog protein, and without adequate cholesterol, SHH protein function is impaired.

Everyday supplementation with high cholesterol foods, such as egg yolks, might prove to be a useful therapy to try for a few months for children with autism who have cholesterol values that are low (<160 mg/dL). Unfortunately, egg allergy is common in autism and may increase with a steady egg diet, and compliance may be difficult for children who dislike eggs. Although very high blood serum cholesterol values are associated with heart disease, values that are low (below 160 mg/dl) are associated with increased violent behavior, suicide, depression, anxiety, bipolar disorder, Parkinson’s disease, and increased mortality from cancer.

Surprisingly, high cholesterol protects against some infectious diseases like tuberculosis, which has been uncommon in the USA since The Great Depression, during which there was a substantial lack of high cholesterol foods because of financial hardship. Vegetarians have a much higher incidence of tuberculosis than meat eaters. It is possible that the overemphasis on a low cholesterol diet may also be associated with the recent marked increase in cases of tuberculosis. Low cholesterol values are also associated with manganese deficiency, celiac disease, hyperthyroidism, liver disease, malabsorption, and malnutrition. Pregnant women with low cholesterol are twice as likely to have premature babies or babies with small heads.

LDL cholesterol (so-called bad cholesterol) protects humans against infection. Deadly Staphylococcus bacteria produce endotoxins that have the ability to kill human cells, including red blood cells. LDL was found to protect human red blood cells from this toxic effect of endotoxins while HDL was not protective. A study at the University of Pittsburgh found that in young and middle aged men, those that had LDL-cholesterol below 160 mg/dl had a significantly lower number (of total and various types) of white blood cells than men with LDL-cholesterol above 160 mg/l.

Functions of Sonic Hedgehog (SHH):

Plays a central role in developmental patterning, especially of the nervous system and system.
Important in the growth and differentiation of a variety of cell types, including the development of T-cells in the thymus.
Purkinje neurons secrete SHH to sustain the division of granule neuron precursors in granule layer in cerebral development. Abnormal cerebellar development.
As a transcription regulating protein, SHH alters which genes function at a given time.

Testing for cholesterol, cholesterol transport proteins, and homocysteine at The Great Plains Laboratory

The Great Plains Laboratory has developed a special cholesterol- related panel that will help to determine whether cholesterol deficiency or abnormalities in cholesterol transport are present. This panel will include the following markers: Total cholesterol, apolipoprotein A-1, apolipoprotein B, Lipoprotein (a), and homocysteine. Lipoproteins are involved in cholesterol, lipid, and vitamin E transport.

Total cholesterol: Total cholesterol measures all types of cholesterol including esterified and free. Low values (generally values less than 160 mg/dL) are associated with genetic diseases of cholesterol. Low values are more common in hyperthyroidism, liver disease, malabsorption, malnutrition, autism, violent behavior, celiac disease, anxiety, bipolar disease, alcoholism, lung cancer, suicide, depression, and obesity associated with human adenovirus-36 infection. In China, where mean cholesterol is much lower than in the Western world, chronic hepatitis-B virus infection is ubiquitous. Chronic carriers of hepatitis-B, but not individuals with eradicated hepatitis-B, have significantly lower total cholesterol than non-carriers, suggesting a cause-effect relationship. High cholesterol values are associated with atherosclerosis.

Apolipoprotein A-I (Apo A-1): The main protein component of HDL (high density lipoprotein). It accounts for approximately 65% of the total protein content of HDL. Apo A-I activates lecithin cholesterol especially in children.

Apolipoprotein B (Apo B): The main protein component of LDL (low density lipoprotein). It accounts for approximately 95% of the total protein content of LDL. Apolipoprotein B is necessary for the reaction with LDL receptors in the liver and on cell walls and is thus involved in transporting cholesterol from the liver to the cells. Recently the Mind Institute found that low values of Apo B are associated with autism, with the lowest values being found in low-functioning autism. LDL has been found to have protective effects against endotoxins from deadly staphylococcus.

Lipoprotein (a): Consists of two components, the low-density lipoprotein (LDL) and a glycoprotein, which are linked by a disulfide bridge. High values have been implicated as a risk factor for cardiovascular disease, Alzheimer’s disease, Crohn’s disease, and rheumatoid arthritis. Low values have also been found in those with autism who have higher doses of Apolipoprotein E epsilon-4 gene variants that are associated with increased risk of Alzheimer’s disease. Lipoprotein (a) is unrelated to Apolipoprotein A.

Homocysteine: A sulfur-containing amino acid that can be converted to methionine by methionine synthetase or by betaine methyl transferase. The role of homocysteine in atherosclerosis gained attention after finding massive atherosclerosis in young people with the genetic disorder homocystinuria. Methionine synthetase requires the folic acid derivative 5- methyl tetrahydrofolate. Abnormally high values have been reported in autism. All of the Great Plains testing for the cholesterol panel is done with FDA- approved diagnostic laboratory reagents.

Why the brain needs cholesterol

There is a direct correlation between the concentration of cholesterol in the brain, particularly in the myelin, and how well the brain functions.
The brain is the most cholesterol-rich organ in the body.
In the central nervous system (CNS), essentially all (99.5%) cholesterol is the free or unesterified form (unattached to fatty acids).
The majority (70%) of cholesterol present in the CNS is believed to reside in the myelin (the material that insulates the nerve fibers) sheaths and the plasma membranes of astrocytes (brain support cells) and neurons.
Half of the white matter, which contains the nerve axons that allow for transmission of brain signals, may be composed of cholesterol-rich myelin.

Paulina’s Story and Cholesterol

The cholesterol story really made an impact on me because of my stepdaughter Paulina, a delightful 18-year old girl with severe autism. Biomedical treatment including the gluten-free, casein-free diet, antifungal therapy, control of Clostridia, and heavy metal chelation had been successful in controlling severe hyperactivity, abnormal sleep patterns, and self-abusive behavior. However, Paulina still had very little use of the hands, had lost all speech at the age of four, and had a physical abnormality in which her fourth toe was much smaller than the fifth. All of these symptoms led to her diagnosis of the genetic disease Rett’s syndrome at the local children’s hospital, but her DNA test was inconsistent with Rhett’s.

Paulina was always energetic and would sometimes burst into a run when going for a walk. At the beginning of the school year, we were receiving unfavorable school reports (which were unusual) indicating that she was losing interest in participating in school activities and was becoming increasingly withdrawn. She was even falling asleep in class after a full night’s sleep. At home, she was becoming more and more withdrawn as well and overall, more “autistic.” The notes from school became more and more disturbing, and Paulina was obviously not the same happy person that she used to be. She began wanting to go to bed earlier and earlier until she was going to sleep immediately after arriving home at 3:00 pm. Even after sleeping 15 hours at night, she was still falling asleep in school. Thyroid tests, an obvious abnormality associated with low energy, were normal.

One morning my wife burst into tears at the breakfast table and sobbed to me,” I think Paulina is dying.”

I decided to review all of Paulina’s test results and treatments but the only thing I could find was the egg allergy. “When did you take the eggs out of Pauina’s diet?” I asked my wife. “At the beginning of the school year,” she responded. That was exactly the timeframe when we started getting unfavorable reports from the school noticing her regression. I realized it was the eggs! The lack of eggs and cholesterol! “Paulina has cholesterol deficiency and we need to give her eggs again.”

(Please note that Paulina had IgG egg allergy. A child with IgE egg allergy might have an anaphylactic reaction to eggs and should not eat eggs at all.) Paulina’s cholesterol was 142 mg/dL, a very low value. Within a few days of giving two eggs for breakfast every day, the smiling, happy, alert, and energetic (but still autistic) Paulina had returned. Once again, she was smiling, full of energy, and difficult to get into bed before 11 pm in the evening. Glowing reports from the teacher became common again. Even though the eggs upset her stomach as a result of the allergy, the cholesterol from the eggs had proven to be essential for her well-being. After six months on the egg-enriched diet, Paulina’s cholesterol had increased to 157 mg/dL, indicating how slowly cholesterol increases. With the arrival of the purified cholesterol supplement from New Beginnings Nutritionals, we are now able to give her the much needed cholesterol her body needs without giving her eggs.

Editor’s Note: Dr. Shaw developed New Beginnings Nutritionals to offer high quality supplements designed for adults and children with special needs and allergies. This includes the product called Sonic Cholesterol – a pure and potent nutritional supplement designed to correct cholesterol deficiency mentioned above in the story about his step-daughter. For information on these products see www.nbus.com.

Please see the Great Plains Laboratory website for extensive references on cholesterol.

For more information or to request test kits, contact: Great Plains Laboratory www.greatplainslaboratory.com