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Fishing For Answers - Melanin, Mercury and Autism?

Posted Aug 18 2010 12:00am

TConrickpost By Teresa Conrick

Believe it or not, I like FISHING.  It may be from the memories of being a young girl with my family on vacation, the chain of northern, Wisconsin lakes, or the hope that the next one will be "the BIG one."  Autism research on the Internet is very much like fishing for me.  I can throw out all sorts of words (my bait) into Google or Pubmed and hope that I catch a keeper.  Throughout this article, I have bolded my "bait," the words that I have used to investigate more about the possible association between MELANIN, MERCURY and AUTISM.  I hope that this method will help point out any patterns or common factors.

So back I went to the fishing hole of melanin and autism.  I have received lots of feedback since I did my 2 part series on Redheads, Autism and Melanin - here:  Part 1  and Part 2    Some have shared their melanin/autism stories with me, like one mom did, telling me about her daughter who has Neurofibromatosis (NF), a neurocutaneous disease, but she also has autism.

Wikipedia describes NF:  "nerve tissue grows tumors (i.e.,neurofribomas) that may be harmless or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells  ( Schwann cells, melanocytes, endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body forming tumors and the melanocytes function abnormally resulting in disordered skin pigmentation. The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems." [more on neural crest cells as we go] 

As far as its association with autism, here is a brief report:  "A study reviewed neurodevelopment evaluations of 74 patients with Neurofibromatosis Type 1 (NF1) to determine if an association between NF1 and autism exists. Three patients had an additional diagnosis of autism. Findings also showed a high incidence of learning disabilities, speech and language delays, motor deficits, and attention problems in patients." "The Association of Neurofibromatosis Type 1 and Autism"

Having both NF and autism must be extremely challenging.  This ill child, the mother reports, did not meet her milestones on time.  She also has had a history of loss of speech, hypotonia, constipation and cafe au lait spots.  There is always the chance for tumors.  She is very light-skinned yet does not burn.  The mother also shared that there is an older family member with Parkinson's who has a son with Bipolar Disorder.  In addition, the girl's father has had a history of melanoma so again, we see melanin (reading Part 1 and 2 helps illustrate this), or rather, a dysfunction of it, as a common denominator in this family.

Speaking of family, I found this, a pertinent piece of information as I fish around.  It is from the New England Journal of Medicine, called,  "Alzheimer's Disease and Parkinson's Disease"  

It starts with this: "The incidence of many common diseases is increased among the relatives of affected patients, but the pattern of inheritance rarely follows Mendel's laws. Instead, such common diseases are thought to result from a complex interaction among multiple predisposing genes and other factors, including environmental contributions and chance occurrences."

It then ends with this: "The common neurodegenerative diseases are predominantly idiopathic disorders of unknown pathogenesis."

Thus, looking into the environment and common parallels of all of these neurodegenerative disorders may be the fruitful thing to do. If a family has diagnoses that overlap, like Autism, Parkinson's, ALS, Schizophrenia, Dystonia, Alzheimer's, Tourette's or Melanoma, then we need to investigate why that has happened - what the mechanism is that caused these disorders.  Gene hunting is showing very little information.  I do need to point out that I added Melanoma as it seemed to be included in enough families though it is not neurological but more cutaneous. That is another clue.

So, more fishing is good and necessary, and may be the best method to discover the true, root cause to autism because these big gene studies are telling us nothing regarding degeneration or regression.  Another helpful procedure is to actually talk to parents of affected children.  Another mother I spoke with described her son's diagnosis of Urticaria Pigmentosa and autism.  The skin symptoms developed first and the pediatrician assured the mother that her son "would outgrow the pigment issues" but instead, he sadly regressed into autism after his first year.  The mom reported that he had an MMR vaccine on his 1st birthday.  He was sick for a month and continued to have ongoing fevers.  He stopped talking, developed hypotonia and constipation, similar to the girl with NF.  Can anyone wonder why so many parents of affected, autistic children become "warriors" for their child's health?

Urticaria Pigmentosa needs some clarification as it has some very pertinent pieces.  It actually goes by another name and one that some of you may have read about in the news two years ago -- "Autism is five to seven times higher in patients with a rare disease called mastocytosis, a discovery that may have just uncovered a vital clue to a biological cause that contributes to autism, according to a recent published report authored by a Brookline researcher."   "Brookline Doctor Sees Autism Breakthrough"

This is interesting and important.  Five to seven times is extremely significant.  So what exactly is mastocytosis and what does it have to do with melanin and autism? 

"We report that the apparent prevalence of ASD in patients with mastocytosis, a rare disease occurring in 1/4,000 children and characterized by an increased number of hypersensitive mast cells in many organs, is about 1/10 or 10 times higher than the general population. A child with skin mastocytosis (urticaria pigmentosa), and regressive autism is presented to illustrate the point. Allergic, infectious, neuroimmune and environmental triggers may activate mast cells to release vasoactive, inflammatory and neurotoxic molecules. These could disrupt the gut-blood-brain-barriers, and/or activate susceptibility genes, thus contributing to brain inflammation and ASD."  "Autism spectrum disorders and mastocytosis".

Well that seemed connected so I decided to search a bit more in that area and I should have known.  When you go fishing there is always the chance for -- you guessed it -- mercury:

"Mercury induces inflammatory mediator release from human mast cells"

"Mast cells, by virtue of their location in the skin, respiratory tract, and gastrointestinal system are potential targets for environmental agents with immunotoxic effects [22]. Mast cells are critical not only for allergic reactions, but also important in both innate and acquired immunity [23], as well as in inflammation [24]. In view of the fact that a subgroup of ASD patients have allergy symptoms that do not appear to be triggered by IgE, it is noteworthy that mast cells can be stimulated by non-allergic triggers originating in the gut or the brain.....The results of the present study support the biological plausibility of how mercury could contribute to ASD pathogenesis by inducing VEGF (vascular endothelial growth factor) and IL-6 release from mast cells, and as a result disrupt the BBB and thus permit brain inflammation."

Well, that seemed significant but was a different mechanism to the hypo-melanin from Parts 1 and 2, where mercury was more toxic to less melanin and seemed to correlate with increased numbers of autism.  Could this be the flip side or the other dysfunction of melanin -- the hyper-melanin or hyper-pigmentary issues?  Since children are exposed to mercury in the environment and still in vaccines, especially prenatal and infant flu shots, it is possible that these exposures begin a series of downstream effects.  Now is the time to drink loads of caffeine (or some B12) as I need your full attention as I guide us into the choppy waters of -- neural crest cells>melanocytes>melanin>cytokines>mast cells
"Melanocyte: A pigment-producing cell in the skin, hair and eye that determines their color. The pigment that melanocytes make is called melanin. The major determinant of color is not the number but rather the activity of the melanocytes. Melanin production takes place in unique organelles (tiny structures within the cell) known as melanosomes. Darkly pigmented skin, hair and eyes have melanosomes that contain more melanin.

Embryology: Melanocytes originate in the neural crest and migrate to the basal layer of the epidermis and the hair matrices. These neural crest-derived cells are not confined to the skin and hair. They also migrate to the inner ear, uveal tract in the eye and the leptomeninges, two of the membranes that surround the brain and the spinal cord.

Recent evidence shows that melanocytes have other functions in the skin in addition to their ability to produce melanin. They are able to secrete a wide range of signal molecules, including cytokines, POMC peptides, catecholamines, and NO in response to UV irradiation and other stimuli. Potential targets of these secretory products are keratinocytes, lymphocytes, fibroblasts, mast cells, and endothelial cells, all of which express receptors for these signal molecules.  "Melanocytes"

Off I went looking for how these were all linked together and I found this article about Autism being associated with disorders that have neural crest cells involved:

"To review the association of autism spectrum disorder (ASD) in individuals manifesting thalidomide embryopathy and Möbius sequence and compare them with three new studies in which ASD was also associated with ocular and systemic malformations: Whereas most cases of CHARGE, (Coloboma, Heart, choanal Atresia, developmental or growth Retardation, Genital anomaly, and Ear involvement) are sporadic with unknown etiology, there are some familial cases and some associated with chromosomal anomalies.54–56.  Many features suggest defects in neural crest cell development or migration, which led some investigators to suggest that CHARGE association should be considered in the group of neurocristopathies.(syndromes, tumors, and dimorphologies of neural crest tissue.) 57 Why ASD exists in a significant number of cases is still a mystery." 

"AUTISM WITH OPHTHALMOLOGIC MALFORMATIONS: THE PLOT THICKENS"

Interesting BUT, most autistic children have no physical abnormalities.  Even Dr. Leo Kanner emphasized that the original 11 autistic patients, children of the 1930's, had "strikingly intelligent physiognomy."  The one interesting abnormality was with Frederick, who had a supernumerary nipple in the left axilla.  Supernumerary nipples can be associated with increased melanocytes.
HERE

Note the wording above: "Whereas most cases are sporadic with unknown etiology", referring to strictly CHARGE syndrome and what they consider "genetic" but they are also saying that there are a significant number of ASD cases as well and they are not sure how that happens either.  Is it possible that these neural crest cells can be damaged as they migrate to other areas causing these CHARGE mutations but also make the melanocytes and/or other cells vulnerable for a later time?   Back I went fishing that neural crest/melanocyte/mercury area "Spontaneous calcium transients are required for neuronal differentiation of murine neural crest."

"We have shown that cultured mouse neural crest (NC) cells exhibit transient increases in intracellular calcium. Up to 50% of the cultured NC-derived cells exhibited calcium transients during the period of neuronal differentiation. Thimerosal increased the frequency of oscillations in active NC-derived cells and induced them in a subpopulation of quiescent cells."
Well that's not good and describes a possible role for future neural crest cell problems, ie- melanocytes. Here too is another example of what mercury can do to melanocytes "Mercury accumulation in the squirrel monkey eye after mercury vapour exposure"

"Squirrel monkeys were exposed to mercury vapour at different concentrations and for different numbers of days....The pigmented epithelium of the pars plicata of the ciliary body and of the retina contained a considerable amount of mercury. This finding indicates that mercury is trapped within the melanocytes.

This final example of neural crest cell/melanocyte damage describes types of insults that can happen.  Note: These are not Neural Tube Defects but cells that migrate around the body. Migration is the word used to explain their departure or poor ability to do that:

"Migration anomalies are congenital anomalies caused by genetic (neurofibromatosis type 1, trisomy 13), vascular, or environmental insults to migrating neuroblasts. Exposure to ionizing radiation, excessive levels of alcohol (fetal alcohol syndrome), anticonvulsants (phenytoin, barbiturates),or toxic materials (methyl mercury poisoning) may be associated with abnormal neural cell migration."

  "A Rare Expression of Neural Crest Disorders: An Intrasphenoidal Development of the Anterior Pituitary Gland"

So again, mercury is being named as an exposure that can cause abnormal neural cells which then can lead to disorders.  Is it possible for them to migrate normally but to not show or not succumb to a "disorder" until some future time?

This is a good spot to see how melanoma seems to be connected to this hypothesis about melanin being involved in autism.   Since a good number of parents have shared that melanoma is in their family in addition to autism, that seemed to be another area to investigate and a possible clue to an upstream mechanism.  So hold on as this gets even more interesting:

" ScienceDaily (July 1, 2010) — Scientists at the Stanford University School of Medicine have identified a cancer-initiating cell in human melanomas. ....He found that one protein, called CD271, was always expressed on only a fraction of the cells in the human melanoma samples tested...This was interesting because CD271 was previously identified as a marker that identifies a group of cells called the neural crest stem cells. These cells are unique in that they are a multipotent, migratory cell population that becomes many cell types during development including melanocytes (cells responsible for skin pigmentation), bone, smooth muscle, neurons, and cartilage in the head and face. When Boiko transplanted the melanoma cells from nine human samples into laboratory mice with severely compromised immune systems, he found that the cells expressing CD271 on their surface were much more likely to cause cancers in the recipients than those from the same tumor that didn't express the marker.  "Melanoma-Initiating Cell Identified"
 
Thank you, Laurette for sending that my way.  Here was evidence that neural crest cells expressing this specific protein, CD271,+gave rise to cancerous cells and tumors (tumors are involved in Neurofibromatosis, too).  Another comment in the study, "CD271+ melanoma cells lacked expression of TYR."  TYR is Tyrosine,  the precursor to the pigment melanin, which I discussed in Part 1 and 2.   Could this then be a key to more doors of discovery as it shows how these cells connect Autism children to their Melanoma parents and possibly more?  One is not born with Melanoma but like Autism, a person can manifest (regress) into that illness. Excessive UV light can do that with Melanoma but what else?

http://tinyurl.com/2fj2kuq
book - "Skin Cancer'
Keyvan Nouri - 2007

"Metal exposure may be quite important in the development of melanoma and has been very little studied. Occupational arsenic and mercury exposure have been associated with an increased risk for cutaneous melanoma among Swedish women who were members of an occupational cohort."

"Cutaneous melanoma in Swedish women: Occupational risks by anatomic site."
"Accordingly, our aim was to identify occupations with higher risk of cutaneous melanoma, overall and by site, in Swedish female workers. RESULTS: High risks were observed among educators, bank tellers, dental nurses, librarians/archivists/curators, horticultural workers, and hatmakers/milliners. Some occupations with possible exposure to arsenic/mercury displayed increased risk."

This may show that mercury can affect these neural crest skin cells way beyond migration, so how does this all relate to our quest for answers about Autism?  This recent study about neurogenesis and neuronal migration may illustrate again that there are common factors in these diseases of the body and brain.  Mercury seems to be a connection and needs further investigations.  That should not be gene or epidemiological studies but with research on autopsies and labs from children with an autism diagnosis.
"The Neuropathology Of Autism: Defects Of Neurogenesis And Neuronal Migration, And Dysplastic Changes."  "The Neuropathology Of Autism: Defects Of Neurogenesis And Neuronal Migration, And Dysplastic Changes."    (Dysplasia- Abnormal development or growth of tissues, organs, or cells.)

"The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism..... Formalin-fixed brain hemispheres of 13 autistic (4-60 years of age) .....  (31%) reflect abnormal neuronal migration...Cerebellar flocculonodular dysplasia detected in  (46%)... local failure of cerebellar development in 62% of autistic subjects."

Then this-

http://tinyurl.com/2ahmrdn  
"Human Embryology" - book
Philip R. Brauer - 2003 -

"Cerebellar dysplasia (an abnormal number of cerebellar neurons) may or may not produce symptoms, depending on its extent. When it does, patients usually exhibit abnormal coordination of movement and speech.  Cerebellar dysplasia is associated with elevated exposure to mercury; chromosomal anomalies, including trisomy 13, 18, or 21; or chromosomal deletions."  In case you didn't know, trisomy 21 is the textbook way of saying Down's Syndrome, and since "exposure to mercury" seems to share this same cerebellar dysplasia, then that seems important to mention.

...and this as well:

"Low Dose Mercury Toxicity and Human Health"  
The neuropathological examination of brains of children prenatally exposed to organic mercury reveals dysplasiaof cerebral and cerebellar cortexes, neuronal ectopia and several other developmental disturbances (Geelen and Dormans, 1990).

I'll conclude this fishing trip with a plea for more research in this area.  I am definitely not an expert but there are many patterns here and coincidences that need to be examined. The topic of mercury and its connection to so many illnesses has had my interest for quite awhile.  Stay tuned for Dan and Mark's book which is fascinating and reads like a baffling mystery that is solved.  Going back in time often helps us figure out the mysteries here and now so stay tuned for more fishing excursions.
--
Teresa Conrick is a Contributing Editor of Age of Autism.

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