Vitamin D Newsletter-Autism and Vitamin D 1. June 2008 William Davis (16) Although Dr. John Cannell's most recent Vitamin D Newsletter concerns the connection between autism and vitamin D, and has nothing to do with coronary plaque reversal, this fascinating discussion between a mother of an autistic boy and Dr. Cannell is so enlightening that I thought that it was still worth passing on. I also feel very deeply for parents with autistic children, who I see struggle with the developmental difficulties their children encounter. (I even have several patients who are parents of 2 or 3 autistic children.)As always, Dr. Cannell is at the cutting-edge of converting hard scientific information into practical use. You will note several points or questions raised:1) Dr. Cannell advocates a powdered capsule form of vitamin D. In my experience, most powdered or tablet forms do not work. But some do. He apparently has success with the brand he specifies. 2) Are there vitamin D-receptor (VDR) genotypes that respond differently? Should there be different 25 (OH) vitamin D blood level targets for different VDR genotypes? Nobody knows yet, but it will be an important question to explore in the future.3) Is heavy metal toxicity, at least in its milder forms, a surrogate for vitamin D deficiency? (Are chelationists unwittingly treating vitamin D deficiency?) 4) If this is a genuine association, and vitamin D replenishment exerts profound neurologic effects in autistic children, does a similar, though less marked effect, hold in non-autistic children? Will children perform better, learn more effectively, etc. with vitamin D supplementation to normal levels? 5) Vitamin A--Is vitamin A with vitamin D good or bad? This one I do not have an answer to. Reading the literature Dr. Cannell cites didn't help much. (Dr. BG--Any comments? Dr. BG is a vitamin A advocate.) Perhaps, should the association between autism and vitamin D hold, it raises more questions than it settles. But, true to my experience with vitamin D, every day I stumble on some unique, fascinating effect, all beneficial. We continue to learn new lessons about vitamin D and Dr. Cannell's insights as a practicing psychiatrist deeply concerned with vitamin D issues have helped enormously. (Sorry, but I did not copy the links to the literature Dr. Cannell cites. To obtain the links, go to the original Vitamin D Newsletter.) The Vitamin D NewsletterJune 2008 This month we feature a remarkable series of letters from a mother of an autistic son who treated her child with vitamin D. It is the first case report in the medical literature suggesting vitamin D has a treatment effect in autism. First, a brief case report and then a more detailed exchange of emails between the mother and me. Case Report: John is a seven-year old boy living in the northeastern U.S. with a long-standing diagnosis of autism. Symptoms include temper tantrums, repetitive self-stimulatory behavior, impaired language, mood swings, fear of being alone, toileting problems, dysbacteriosis, and impaired muscle strength. John spends a lot of time outdoors starting in the spring and his mother noticed a distinct seasonal variation in his symptoms in that he improved in the summer and regressed in the winter. A 25-hydroxy-vitamin D in April of 2008 was 25 ng/ml and obtained after John had begun to play outside. Due to the seasonality of John's symptoms the mother consulted me. I advised the mother to stop all products containing vitamin A including cod liver oil and begin John on 5,000 IU of vitamin D3 per day for two weeks followed by 2,000 IU per day in the form of powdered vitamin D dissolved in juice. Within a week of starting the vitamin D, John's language began to return and he was no longer as fearful of being alone. At the end of two weeks his language showed further improvement, he began to toilet himself, counted to 10 and knew the spelling of his name. After three weeks language continued to improve and some improvements were noted in his dysbacteriosis. After four weeks of vitamin D treatment, the mother noted improvements in muscle strength as well as continued improvements in language. A repeat 25-hydroxy-vitamin D is pending while John continues taking 2,000 IU of vitamin D per day. Before you read the series of emails between the mother and me, I'd like to caution that this is only a case report of sorts and does not prove a treatment effect. Spontaneous remissions, while rare in autism, have been reported, thus the supplemental vitamin D may have had nothing to do with his improvement. If the response is due to vitamin D, there is no assurance it will prove lasting. I think it unlikely that older autistic children or individuals with severe autism will show these sorts of apparent improvements. Furthermore, autism is a multifactorial disease with strong genetic roots and it is highly unlikely that treatment of vitamin D deficiency in all autistic children will result in similar improvements. Finally, I did not examine this child, and I am relying on the child's mother to report both his condition and his apparent response to vitamin D treatment. However, the mother agreed to speak with the press about her son and allow for independent confirmation of the apparent treatment response. Below are the emails, edited for brevity, clarity, and confidentiality. Dear Dr. Cannell: I am writing because I believe my son John is strongly affected by vitamin D and I need some advice. John is seven and autistic and weighs 50 pounds. We live in the northeastern part of the United States . He starts spending lots of time outside in May and continues until September. Every year, like clockwork, he has the same patterns of behavior and ability. After about six weeks of sun exposure, every July, he begins feeling much better, seems to be comfortable in his skin, does not have as much self-stimulatory behavior, can eat a variety of foods and has language. This past summer, he was using 14-word sentences. By the end of November, he can't even ask you for a cup of juice. He becomes more exclusive, has emotional highs and lows, has tantrums and is easily frustrated. His 25(OH)D level on April 15th was 25 ng/ml but he had already been going out in the sun so his level must have been lower in the winter. I have had his genetics tested (Nutrigenomic) and he has mutations in his vitamin D receptors: VDR Bsm/Taq ++VDR Fok --VDR Taq ++ My first question, does it sound like the changes in his behaviors and abilities could be caused by lack of vitamin D? Could you elaborate on the time it would take to get adequate amounts of vitamin D to start seeing positive results? For example, even if he starts going out in the sun in May, it's usually not until July that I see positive changes. Then would it take a month or two to go back to being deficient, thus explaining his 'regression' by the time November comes around. Secondly, I am looking at different forms of vitamin D therapy: a vitamin D lamp, vitamin D3 cream, or oral vitamin D. Can you tell me what might be the best form during the winter months? Thank you very much for your time and attention. Jane, Boston MA Dear Jane: Yes, it is possible your son's autism is related to vitamin D. Such seasonality has been reported before in autism, both in an individual and in autistic children at a summer camp. Although suggestive, such seasonality does not prove a vitamin D connection. Sun exposure, unless it is full body, takes several months to get vitamin D levels up. If sunblock or clothes are worn sun exposure will not get 25(OH)D levels much above 30 ng/ml. As far as the "mutations" you list, they are actually vitamin D receptor (VDR) polymorphisms and not referred to as mutations although all such changes occurred through mutations at some time in the past. VDR polymorphisms are simply the different structures of the vitamin D receptor that different people have and they are widely distributed. A pilot study of actual VDR receptor mutations did not detect VDR mutations in 24 autistic individuals but they did not assess for VDR polymorphisms. However, a highly significant association exists between one VDR polymorphism and larger head size. Mean head circumference is larger in autism. Yan J, et al. Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases. Neurosci Lett 2005;380(1-2):37-41. Handoko HY, et al. Polymorphisms in the vitamin D receptor and their associations with risk of schizophrenia and selected anthropometric measures. Am J Hum Biol 2006;18(3):415-7. Lainhart JE, et al. Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism. Am J Med Genet A 2006;140(21):2257-74. Lainhart JE, et al. Macrocephaly in children and adults with autism. J Am Acad Child Adolesc Psychiatry 1997;36(2):282-90. I emailed the world's foremost expert on VDR polymorphisms asking him about your son's polymorphisms and his reply, quite technical, is below. Dear John: I apologize for the delay in getting back to you regarding VDR polymorphisms. Initial studies by Eisman and coworkers many years ago suggested that several of the polymorphs identified above in the VDR gene (Bsm/Tag) correlated strongly with osteoporosis. Despite the hoopla, subsequent analyses by many different investigators did not really confirm these results, i.e. only a very modest (3%) correlation. This spawned multiple studies searching for correlations between VDR polymorph's and cancer, autoimmune disease and so forth. It is fair to say from all of these studies that the correlation is at best weak, and in most cases non-existent. Part of this may be due to the fact that the Bsm and Taq polymorphs are located in VDR gene introns and as a first approximation cannot affect the VDR protein's function. This is not an absolute statement, however, as our work is now showing that regulatory regions that control the VDR's expression are located within introns as well as upstream. Therefore the possibility exists that these polymorphs could affect expression, although we have not found these regions to contain enhancers yet. This is clearly where gene and disease studies are going. The only polymorph that could affect function is the Fok1 site, which we identified many years ago following our initial cloning and structural analysis of the human VDR gene. The presence of this site leads to the expression of a shorter VDR protein (424 aa) that is purported to have a slight increase in transcriptional activity (10%?) vs the large protein (427 aa). The above analysis suggests that this polymorph is absent, leading to production of the larger perhaps less active protein. On a single patient basis, it is really difficult to conclude anything regarding this finding. Indeed, despite large numbers of patients, the VDR polymorph have not really revealed any significant insight. Given the summer correlations, it is probably more likely that the individual is low in vitamin D3 in winter. Sincerely, Professor John Doe Thus, one of your son's polymorphisms may have less functionality but that should be easily overcome by higher vitamin D levels. The first thing to do is stop all vitamin A, multivitamins containing vitamin A, or cod liver oil and start vitamin D. As you will see below, vitamin A antagonizes the action of vitamin D and he should have plenty of vitamin A if he eats colorful vegetables, colorful fruit, eggs and fortified oatmeal. As far as vitamin D, I think the easiest way to give vitamin D is powdered capsules, not a cream. You can open the capsule and put the powder in about anything, such as juice. To buy the capsules, go toBio Tech Pharmacal and buy both a bottle of the 5,000 and the 1,000 IU capsules. He should take one 5,000 IU capsule a day for two weeks then take 2,000 IU per day. After a month, go to the doctor and have another 25-hydroxy-vitamin D blood test. Do not let your doctor order a 1,25-dihydroxy-vitamin D as it will give you and your doctor false information about your son's vitamin D status. The other option is buying a Sperti vitamin D light. Daily use of the light on both sides of his trunk will raise levels fairly quickly but he should still have a 25(OH)D blood test every month to assure his levels rise to the mid level of normal ranges, about 70 ng/ml. Vitamin D is very safe. Your son would have to take more than 10,000 IU a day for more than a year to have any risk of toxicity. If he improves and his level is 50 ng/ml, the next question is would he improve even more if his level was 70 ng/ml? Some lifeguards have levels of 80-100 ng/ml; normal ranges in the labs in the USA are 30 -100 ng/ml (ideal ranges are 50 -100 ng/ml.) If you have any more questions, let me know. I certainly want to know how he is doing. Sincerely, John Cannell Dear Dr. Cannell: It has been one week on 5,000 IUs of vitamin D3 daily and already we're getting some language back! We haven't had original language since probably around the end of November. The only language we have had in the past five months has been verbal scripting. Today John has already told me "turn off the TV" and "clean up the water". This is all very exciting. Will it last? I will continue to keep you updated on progress and change in behavior. One more thing, all winter long he was afraid to be by himself anywhere. Now he is starting to be able to be in another room or outside by himself. Thanks so much, Jane Dear Jane: I can't tell you how happy I am for you. I suspect John will continue to improve. Do you have any parent rating scales or does his treating pediatrician have any objective rating scales? If you have before and after rating scales or his treating doctor does then it becomes important to track his progress on an objective measure. Jane, if you are a member of any autism discussion groups, you should post about this, including doses used. If your son's case is typical, then hundreds of thousands of autistic children may be helped with vitamin D. John Cannell Dear Dr. Cannell: It has been two weeks on 5,000 IU per day and I want to inform you that we are having continued success with language. Continued in the sense that it is consistent, it wasn't just a one day fluke. In addition, he is taking himself to the bathroom; this is another thing that goes away in winter months. I usually have to catch him holding it in and then suggest he go, but now he is going completely by himself. In therapy last week, he started drawing again. He drew a bee and then ran around the room buzzing. His toileting is consistent with his therapists, not just mommy. Last night, I asked him to count to 10 for me and he did - quite enthusiastically. Then I said what does J-O-H-N spell? It took him a bit but then he said "John." Unfortunately, the last scale taken was when he was 3 when he had his first developmental evaluation. But we do track behavior and language on a weekly basis. The forms we fill out give a good indication as to how he is doing. I belong to a parent forum. It was created by a doctor named Amy Yasko. She's a PhD, a researcher, not a medical doctor. It was through her that I got John's genetics tested. She advocates vitamin D as being very crucial. I will post something on her forum for the parents there. However, if the parents on the forum are following her recommendations, they should be taking it already - 2000 IUs in winter and 1000 IUs in summer is her recommendation. I will post something on the forum to really emphasize how important vitamin D is. Jane Dear Jane: I'm glad the improvements are continuing. I see Dr. Yasko recommends 10,000 IU of vitamin A/day as well as cod liver oil. I strongly disagree. Make sure your son is taking neither vitamin A nor cod liver oil. Rather, make sure he eats colored fruits and vegetables as well as fortified oatmeal. Vitamin A interferes with vitamin D's function, especially at the doses Dr. Yasko recommends. Vitamin A antagonizes the action of vitamin D. In humans, even the vitamin A in a single serving of liver impairs vitamin D’s rapid intestinal calcium response. Furthermore, the consumption of preformed retinols, even in amounts consumed by many Americans in both multivitamins and cod liver oil appears to be causing low-grade, but widespread, bone toxicity, perhaps through its antagonism of vitamin D. In a recent dietary intake study, Kyungwon et al found high retinol intake completely thwarted vitamin D’s otherwise protective effect on distal colorectal adenoma and they found a clear relationship between vitamin D and vitamin A intakes as the women in the highest quintile of vitamin D intake also ingested almost 10,000 IU of retinols/day. As early as 1933, Hess et al warned about vitamin A consumption, concluding, “as to a requirement of thousands of units of vitamin A daily, the unquestionable answer is that this constitutes therapeutic absurdity, which, happily, will prove to be only a passing fad.” Rohde CM, Deluca HF. All-trans retinoic acid antagonizes the action of calciferol and its active metabolite, 1,25-dihydroxycholecalciferol, in rats. J Nutr. 2005;135(7):1647-1652. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001;16(10):1899-1905. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83(2):191-201. Oh K, Willett WC, Wu K, Fuchs CS, Giovannucci EL. Calcium and vitamin D intakes in relation to risk of distal colorectal adenoma in women. Am J Epidemiol. 2007;165(10):1178-1186. Hess AF, Lewis JM, Barenberg LH. Does our dietary require vitamin A supplement? JAMA. 1933;101:657-663. Unfortunately, Hess’s prophecy of a passing fad proved premature and many Americans continue to consume “absurd” and dangerous quantities of vitamin A. For example, multivitamins, until recently, had small amounts of vitamin D (200 to 400 IU) but high amounts of preformed retinols (5,000 to 10,000 IU). This pales in comparison to a tablespoon of modern cod liver oil, which contains sub-physiological amounts of vitamin D (400 to 1200 IU) but supra-physiological amounts of completely preformed retinols (5,000 to 15,000 IU or in some cases 30,000 IU). John Cannell Dear Dr. Cannell: It has been three weeks and he went from 5,000 IU of vitamin D per day to 2,000 IU per day a week ago. His language is increasing. He's now back to saying the things he wants with some prompting. He also has gut dysbiosis and I'm sure the D is helping with microbes in his gut. He has a lot of problems with his immune system and bacteria and viruses. Also, doesn't vitamin D aid in the production of glutathione? I feel that could be a big part of his increased language. Jane Dear Jane: Yes, abnormal immune responses are associated with both autism and vitamin D deficiency. For example, autistic individuals have immune abnormalities that show a striking similarity to the immune functions affected by vitamin D. Animal evidence indicates some vitamin D deficiency induced brain damage may be malleable, that is, vitamin D may partially reverse the brain damage, if given early enough. These studies offer hope that sunlight or oral vitamin D, especially in young autistic children, may have a treatment effect. Ashwood P, et al. The immune response in autism: a new frontier for autism research. J Leukoc Biol 2006;80(1):1-15. Cantorna MT, et al. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004;80(6 Suppl):1717S-20S. Burne TH, et al. Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle. Physiol Behav 2004;81(4):651-5. Both the brain and the blood of autistic individuals show evidence of ongoing chronic inflammation and oxidative stress. That is, the disease process is probably increasingly destructive. Further hope for a treatment effect rests in activated vitamin D's powerful anti-inflammatory properties. Its administration reduces production of inflammatory cytokines in the brain, which have consistently been associated with cognitive impairment. Furthermore, activated vitamin D is remarkably neuroprotective by stimulating neurotropin release, reducing toxic cellular calcium levels in the brain, inhibiting the production of nitrous oxide, and by its immunomodulating properties, especially in reducing inflammatory cytokines and by increasing brain glutathione. Moore ME, Piazza A, McCartney Y, Lynch MA. Evidence that vitamin D3 reverses age-related inflammatory changes in the rat hippocampus. Biochem Soc Trans 2005;33(Pt 4):573-7. Cohen-Lahav M, Shany S, Tobvin D, Chaimovitz C, Douvdevani A. Vitamin D decreases NFkappaB activity by increasing IkappaBalpha levels. Nephrol Dial Transplant 2006;21(4):889-97 Kalueff AV, Eremin KO, Tuohimaa P. Mechanisms of neuroprotective action of vitamin d(3). Biochemistry (Mosc) 2004;69(7):738-41. This last function of vitamin D, increasing cellular levels of glutathione, may explain the purported link between heavy metals, oxidative stress, and autism. For example, activated vitamin D reduces iron-induced and zinc-induced oxidative injuries in rat brain. The primary route for the neurotoxicity of most heavy metals is through depletion of glutathione and subsequent generation of reactive oxygen and nitrogen species. Besides its function as a master antioxidant, glutathione acts as a chelating (binding) agent to remove heavy metals. Several studies indicate autistic individuals have difficulty excreting heavy metals, especially mercury. If vitamin D deficient brains are unable to utilize glutathione properly, and thus unable to remove heavy metals, they may be oxidatively damaged by heavy metal loads normal children easily excrete. The amount of activated vitamin D in the brain directly depends on how much vitamin D is made in the skin or put in the mouth. Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab 2002;13(3):100-5. Chen KB, Lin AM, Chiu TH. Systemic vitamin D3 attenuated oxidative injuries in the locus coeruleus of rat brain. Ann N Y Acad Sci 2003;993:313-24. Lin AM, Chen KB, Chao PL. Antioxidative effect of vitamin D3 on zinc-induced oxidative stress in CNS. Ann N Y Acad Sci 2005;1053:319-29. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005;12(10):1161-208 Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev 2006;9(6):485-99. Sincerely, John Cannell Dear Dr. Cannell: It has been a month now and John's Improvements are continuing. In the last week, he has been using his muscles more, he goes on the swing outside and lifts his legs and bends in ways that take core muscle strength. This is yet another skill or interest that left and is returning. I will report more next week.Jane Conclusion: It is too early to say vitamin D has a treatment effect in autism. However, a simple risk/benefit analysis suggests that autistic children should be diagnosed and aggressively treated for vitamin D deficiency. If readers want to learn more about vitamin D and autism, they can obtain the entire paper on the link below. Unfortunately, Elsevier charges $31.50 to download it. You can read a similar document for free on the website, where we first published the theory a year ago. Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9.http://vitamindcouncil.org/newsletter/2007-may.shtml In summation, autistic children should be given enough vitamin D to get their 25(OH)D levels up to the mid to high range of normals, that is, 70 ng/ml (175 nmol/L in countries that use the metric system). In the absence of sun exposure, this usually requires long-term administration of about 1,000 IU/day per 20 pounds of body weight with a loading dose of 2,000 IU of vitamin D/day for every 20 pounds of body weight for the first two weeks. As individual variation in response is very high, they should have 25(OH)D blood tests every month until their level has stabilized around 70 ng/ml. They should stop all products containing preformed retinols (vitamin A), especially cod liver oil. John Cannell, MDThe Vitamin D Council This is a periodic newsletter from the Vitamin D Council, a non-profit trying to end the epidemic of vitamin D deficiency. If you don't want to get the newsletter, please hit reply and let us know. As we are a 501(3)(c) non-profit corporation, dedicated to ending vitamin D deficiency and not making money, the Vitamin D Council does not copyright this newsletter. Please reproduce it and post it on Internet sites. If this newsletter proves useful to a child you know with autism, the Vitamin D Council asks for a donation as we have not been able to secure a grant and our bank account balance is again below $5,000. Send your tax-deductible contributions to: The Vitamin D Council9100 San Gregorio RoadAtascadero, CA 93422