Autism Research Unit, University of Sunderland, UK
It is universally accepted that there is a considerable genetic element in the incidence of autism. The occurrence of so many families where multi-incidences of autism and related spectral disorders exist is compelling evidence. However, this is probably not the whole story. Even the strongest proponents of genetic research are now beginning to talk in terms of "genetic fragility” or “predisposition". If, as seems highly possible, the incidence of autism is increasing, then factors other than the purely genetic must be implicated. Increasing reported levels of autism have been reported from many parts of the world but, as has been pointed out on a number of occasions, this may reflect no more that increasing awareness of the disorder and changing diagnostic criteria (Gillberg 1998a; Wing 1996).
However, two reports (California, 1999; Taylor et al, 1999) have highlighted what would appear to be very significant increases in the incidence. It must be remarked that the latter was intended to demonstrate that the introduction of the combined Measles, Mumps and Rubella (MMR) vaccine was, in no way, a factor in this increase. Many of those who actually read this paper were unable to reach the same conclusions as the authors but, even so, there was a dramatic (1,700%?) increase of reported incidence between 1979 and 1992 (birth dates). The California (1999) report showed a 273% increase, in the State of California over a similar (but not identical) period of time. Informal and unpublished data from many parts of the UK and other parts of the world are showing similar increases. It is alleged that parallel, staggering increases in incidence are occurring in similar disorders such as dyslexia; Attention Deficit Disorder (ADD) which may be combined with hyperactivity (ADHD). Indeed, reports from the US and Australia suggest that 10% of children of school age are currently taking Ritalin to ameliorate the symptoms of ADHD. In other circumstances, these increases would be regarded as an epidemic and worthy of considerable research but, so far, environmental factors have been completely and utterly ignored by governmentally funded agencies within the UK. If these increases are, indeed, genuine then there must be factors, additional to the purely genetic, which are involved and which may trigger the problems. It may be of interest and relevance to examine other diseases or disorders which have, in comparatively recent history, increased or decreased markedly in incidence. There could be lessons which can be learned and which could be used to explain the apparent upsurge in incidence of the disorders described above.
Some Disorders that have waxed and waned in the past 300 years:
Smallpox, Deficiency Diseases, Infantile Paralysis and Polio, Venereal Diseases ,Measles, Tuberculosis, "Fevers" .
The incidence of these diseases largely reflects the changing social and hygiene systems, which were operating at the time. Until about 300 years ago, the population of the United Kingdom was largely rural and, although often living in poverty, reasonably well fed and not subject to gross overcrowding. Until this time, disorders such as smallpox were not (as is often alleged,) common and were not generally regarded as dangerous. It was only following the overcrowding and under-nourishment arising from industrial revolution that smallpox; tuberculosis and "fevers" became serious infections and that deficiency diseases became common (White 1885). It is more than likely that the two causative elements; under-nourishment and infectious agents combine to increase the risk of serious illness.
Poliomyelitis existed as a fairly mild intestinal disorder until comparatively recently. It was only at the end of the last century, as standards of hygiene improved, that infantile paralysis made its appearance in the homes of the well to do. Before this time, it is hypothesised, the organism would afflict only very young children and was of little consequence. As standards of hygiene improved babies were no longer exposed to the infection and in older children the effects were more serious. In later years (from the 1920s for example) it was young adults who were infected and the disease took the form of the even more serious paralysing poliomyelitis. The incidence, even of this form, is now very much lower than previously and clearly, the use of vaccines played at least a part in this diminution. Similarly the use of antibiotics and education have been significant in the control of venereal diseases of all sorts.
"Fevers" were quoted as the cause of death in numerous instances in the late 18th and early 19th century and it was during this time that deaths through "measles" increased. (White 1885). Deaths in the UK, from measles infections still occur but appear to have reduced to between 5 and 20 a year for the past 50 years. (Whittakers Almanacs 1949 to date).
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Some Disorders that have waned in the past century:
Diphtheria, Tetanus, Whooping Cough, Scarlet Fever, Malaria, Sprue (Coeliac Disease), Rheumatic Fever, Some Zoonoses (from animals), Genetic Disorders? (Down Syndrome; PKU; Fragile X) (Rabies; Hydatid cysts etc.).
In many cases, the actual manifestation of the disease (sprue and PKU) has been ameliorated although the underlying causative condition persists. In other cases (zoonoses and malaria) it is changes in environmental and cultural habits that have brought about the diminution. In the cases of other infectious disorders such as tetanus; whooping cough and diphtheria, although it is fashionable to credit the use of vaccinations for their diminution, it must be recognised that improvements in hygiene and nutritional status were probably more important. This can be seen to be the case with scarlet fever and rheumatic fever for which no vaccines exist. Although we now have therapies for some of these disorders, we must retain vigilance as these diseases may have very serious consequences. Although disorders due to Rubella during pregnancy have not been specifically listed above, it is readily accepted that these have diminished dramatically and that this is most likely due, to a great extent, to the use of preventative vaccination programmes. It is arguable whether or not the incidence of purely genetic disorders has really decreased markedly but the advent of genetic counselling should have resulted in a reduction.
Some disorders which have "appeared" or increased in prominence in the past 40 years:
Autism, Dyslexia, ADD/ADHD, SIDS (Sudden Infant Death Syndrome), Crohn's Disease, CFS/ME, Irritable Bowel Syndrome.
Ulcerative Colitis, Gulf War Syndrome, Asthma, "Heart Disease" , Hay Fever and other allergies, Depression.
Hypersensitivities (eg Nut Allergies), Diabetes (all types), "Cancers" , Sheep Dipper Syndrome, BSE/CJD, HIV/AIDS, Meningitis.
Many of these disorders (such as HIV/AIDS and hypersensitivities) have only come to prominence in the past few years whilst others (such as Hay Fever and Ulcerative Colitis) have existed as unusual disorders for many years but the incidence has increased hugely in recent years and to such an extent that it is forgotten that these are comparatively new disorders. Until very recently, few had heard, for example, of "peanut allergy" in which the merest contact from protein from peanut can be fatal to afflicted individuals. Nowadays, most people know someone who needs to carry antidote, in the form of adrenaline injection, at all times. It is accepted that peanut consumption may have increased but, clearly, other factors are involved.
In many of the conditions described above, (diabetes and the bowel disorders for example) there is a clear auto-immune element. Many infections, such as measles and pertussis (as well as HIV) are known to have serious effects upon the immune system. Together with the chemically induced effects, the effects upon the immune system could, in the more genetically susceptible individuals, be very dramatic.
There may be genetic elements, genetic fragilities, involved in all of these situations but the fact that the increases have been dramatic must point to environmental factors. We would, therefore, see autism within this context. We would, therefore, suggest that it should be examined within the context of this group of disorders in which "environmental factors" are involved.
There are numerous environmental factors, which have changed over the past 20 years in the UK. The use of lead paints has decreased dramatically as has the use of mercury in pesticides and dental fillings. Asbestos has been largely removed from the environment but there are increasing levels of Aluminium in water and potentially toxic fumes and radiation from television sets and computers. Naturally occurring infections such as measles and mumps have diminished markedly whilst the incidence of meningitis appears to have increased dramatically. The use of attenuated strains of many of these diseases, introduced in the form of vaccines, has increased. The older Organo-Chlorine (OC) insecticides have been replaced by those based upon Organo-Phosphorus (OP) compounds. Thus, there are many potentially significant elements which have resulted from a changed environment. It is difficult to consider each element in isolation in a system in which so many factors are changing and in which the interplay between these factors is so complex. Even the requirements of television viewing may have an effect. Programmes presented to children seem designed to train them to have a very limited attention span and train towards ADD type behaviours.
The two main factors, which are considered here are infectious agents and environmental chemicals and their effects upon the immune system. It is, perhaps, inappropriate to study factors in isolation but the attempt will be made here. This report will focus on just two, the effects of the introduction of the combined Measles, Mumps and Rubella (MMR) vaccine and the wholesale use of Organo-Phosphorus pesticides. These involvements must be seen as relevant in the context of the opioid excess theory of autism, which we have discussed many times before. (See Shattock 1997.)
This is, of course, a highly contentious area and contributions to the debate have, unfortunately, been polarised. Apart from the Wakefield study (Wakefield 1998), all of the other heavily quoted contributions to the debate (Taylor (1999); Peltola (1998); Gillberg (1998 c)); have sought to rely upon the manipulation of epidemiological data or, as in the case of Fombonne (1998) and Afzal (1998) are of no relevance to the situation. Other papers (e.g. Chadwick (1998)) have been interpreted in a way, which may well have surprised the authors.
We have reviewed our records on this issue and reported them only last year (Shattock 1998). In this presentation we attempted to demonstrate that those children who (according to parents) showed dramatic and rapid behavioural regression within a very short period of receiving the combined MMR vaccine within formed a separate subgroup within the autistic spectrum and we outlined certain clinical characteristics which, we felt, could be useful in defining this group. Additionally, our evidence would suggest that the urinary peptide profiles we obtain, from the majority of this group at least, differ significantly from those obtained from subjects suffering from more typical forms of autism. This information has now been tightened up and prepared for formal publication (Shattock 1999).
We are of the opinion that there exists a group of children, diagnosed with some form of autism, whose clinical history and current clinical presentation differ significantly from that seen in more typical forms. The work of Wakefield (1998) clearly suggests an identifiable biological differences. As further studies of these subjects occur, it is possible that other differences will be found.
Indolyl Acryloyl Glycine (IAG) and Organo-Phosphorus (OP) Pesticides?
We have reported, on a number of occasions, on the increased levels of IAG in the urine samples obtained from the majority of subjects (say 80%) diagnosed with autism and related disorders. The nature of the relationship is unclear but there are reasons to suspect that the relationship may be causative rather than casual. This must, for the time being at least, remain a speculation rather than accepted fact.
The source of the IAG is unclear but, as far as we are aware, the only source so far identified is as an abnormal metabolite of the amino-acid tryptophan. Table 1 shows the basic elements of biosynthetic pathway by which tryptophan may be converted to IAG. In the case of Hartnup Disease, the initial stages of the transformation of tryptophan to IAG are performed by intestinal bacteria and it is likely, but not certain, that the similar situation will pertain here.
So far, there is no published evidence that IAG has any marked physiological activity (although this possibility is being investigated in our laboratories). Given its size and structure (planar and rather reactive), it would appear highly likely that the only known precursor for IAG, that is Indolyl Acrylic Acid (IAcrA), would possess considerable potential for activity.
In particular, it "could" become involved in the structure of the lipid elements of cell membranes thereby greatly increasing their permeability to other molecules. As far as autism is concerned, of particular interest would be the effect of IAcrA on the permeability of the intestinal wall and of the blood-brain barrier. Increased permeability would permit the increased translocation of peptides, with biological activity, from the intestines to the CNS.
In the case of Hartnup Disease and PKU the reasons for the increased levels of IAG in the urine are believed to be purely genetic but there could be other reasons. Through our associated studies, we have become aware of what would appear to be elevated levels of IAG in certain other conditions. These results will be reported in due course. In particular, we have found elevated levels in subjects who are experiencing symptoms described as of "Gulf War Syndrome"
We are speculating and investigating the possibility that Organo-Phosphorus based pesticides could be responsible, to some extent, for these abnormally elevated levels. Certainly the US and UK forces deployed in the Gulf would have been treated with such compounds as would those suffering from "Sheep Dippers' Syndrome" ("Fruit Pickers' Syndrome" in the US). All of these groups experience marked psychological as well as physical effects. Organo-Phosphorus compounds were developed as agents of war ("nerve gases") and insecticides on account of their ability to cause paralysis by inhibiting certain enzyme systems and, in particular, those involving anti-cholinesterases. Such compounds tend to be fairly non-specific in their actions and could affect other enzyme systems. Of particular interest in this respect would be the effects upon the enzymes involved in the metabolism of tryptophan. It has been reported (Sieffert 1992; 1993) that Diazinon (an OP pesticide) will seriously interfere with the metabolism of tryptophan via the kynurenine pathways. This, in itself, could be sufficient to force tryptophan metabolism towards the IAG route. If, additionally, there are effects upon the enzyme tryptophan hydroxylase (and this we are currently investigating) then there will be added impetus towards this abnormal route.
Thus increasing levels of OP compounds in the environment would, through a sequence of stages, result in increasing permeability of membranes of the intestines and blood brain barrier as well as other membranes such as those lining the respiratory organs. The increased permeability of membranes would permit increased passage, not only of peptides, but of slightly larger polypeptides or even protein material. These could be large enough and present in sufficient quantities to result in the production of antibodies, which could generate allergies or hypersensitivities. Thus, we could anticipate increased incidences of autism and its associated disorders, as well as of hay fevers; hypersensitivities and afflictions of the intestinal tract. Even BSE/CJD could be explained in this way. Cattle have been consuming ground up sheep (the alleged source of the infectious agent, the prions, causative of the condition) since the 1920s without developing "mad cow disease".
It was soon after the switch from the older Organo-Chlorine Insecticides (such as BHC) to OPs (such as Diazinon) that these problems arose. The switch occurred largely between 1979 and 1982 and "mad cow disease" made its first appearance in 1984-86 followed by "New Variant" CJD (the human form) a couple of years later. Interestingly, it is reported that the first subjects to experience the New Variant form were farmers. Perhaps, as reported, this was on account of their proximity to afflicted cattle but it could also be a consequence of their intimate and frequent contact with OP pesticides and the consequent facilitation of transport of the previously excluded prions from affected meat.
There would appear to be an increase in the incidence in autism and related disorders and of many other disorders, which, at first sight, would appear to be unrelated. These increases would appear to be real and notmerely the consequence of better diagnoses. Thus environmental factors must be involved. There are many possible factors but two important aspects would appear to be the changing patterns of infections and especially those introduced by vaccination programmes and the wholesale use of Organo-Phosphorus insecticides.
The long-term effects of these elements do not appear to have adequately considered before their acceptance and wholesale introduction.
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