What is autism?
Autism and ASD are terms that represent a group of complex neurodevelopmental disorders characterized by difficulties in social interaction, including verbal and nonverbal communication, repetitive behaviors, and stereotyped interests and activities. The term ASD signifies that autism is a spectrum disorder, meaning that the onset and nature of signs and symptoms vary among people and can range from mild to severe.
ASD can be classified into three types:
● Autistic disorder (sometimes referred to as classic autism)
● Asperger syndrome (also known as Asperger disorder)
● Pervasive developmental disorder– not otherwise specified (PDD-NOS), also referred to as atypical autism.
Children who meet some but not all of the criteria for autistic disorder
or Asperger syndrome are usually diagnosed with PDD-NOS.
On alert for autism spectrum disorders
Although the pathogenesis of ASD has not yet been elucidated, genetic risk factors are strongly implicated, because the relative risk among siblings is greater than 20, and heritability is estimated to be as high as 38–90%. In contrast, because the concordance rate of identical twins is not 100%, one can infer that environmental factors are also involved, and the recent increase in prevalence also indicates the involvement of various types of “novel environmental exposure”. A debate has arisen over the contribution of vaccination as one environmental trigger of ASD.
The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: The first case–control study in Asia
Development of the vaccine
Measles, mumps, and rubella (MMR) are highly contagious diseases caused by viral pathogens that may result in serious complications, sequelae, serious congenital anomalies (CAs), or death.
The original trivalent M–M–R™ vaccine (measles, mumps, and rubella virus vaccine live) was licensed in 1971. M–M–R™ II was licensed in 1978 with the rubella component of M–M–R™ (HPV-77 DE strain of live attenuated rubella) replaced by the Wistar RA 27/3 live attenuated rubella strain. M–M–R™II has been the only combination measles, mumps, and rubella vaccine used in the United States (US) since 1978 resulting in ≥99% elimination of the three diseases. In 2006, human-derived serum albumin (HSA) was replaced by recombinant human albumin (rHA) in the manufacture of M–M–R™II, eliminating the use of any human-derived substances. This version of the vaccine was licensed in the European Union in 2006 under the name M–M–RVax-PRO™.
Measles, mumps, and rubella virus vaccine (M–M–R™II): A review of 32 years of clinical and post marketing experience
Live, attenuated vaccines light viruses
These vaccines contain a version of the living virus that has been weakened so that it does not cause serious disease in people with healthy immune systems. Because live, attenuated vaccines are the closest thing to a natural infection, they are good teachers for the immune system. Examples of live, attenuated vaccines include measles, mumps, and rubella vaccine (MMR) and varicella (chickenpox) vaccine. Even though these vaccines are very efective, not everyone can receive them. Children with weakened immune systems—for example, those who are undergoing chemotherapy cannot get live vaccines.
Understanding How Vaccines Work
The debate:
In 1998, a British doctor, Andrew Wakefield, and co-authors, published in "Lancet" a study in which he suggested the existence of "a new variant of autism" associated with intestinal inflammation. He proposed the administration of the MMR vaccine as a possible cause of the inflammatory process. The hypothesis suggested by Wakefield led to a drastic drop in vaccination coverage in the UK and to the failure to achieve adequate levels of immunization in many countries, with a consequent increase in the incidence of measles and its complications. Wakefield work stimulated a broad discussion in the scientific community and many studies conducted over the next few years contradicted the research results of the English physician. In 2004, journalist Brian Deer conducted an accurate investigation that revealed how the Wakefield research presented many not regular aspects and was performed with predominantly economic objectives. In 2010, Wakefield was expelled from the General Medical Council, while the "Lancet" retracted the paper. The scientific research conducted in recent years confirm the inconsistency of the relationship between MMR vaccine and autism.
Vaccines and autism
Two Studies proving non-relation between MMR vaccinations and autism:
1^st) Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies
Findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines (thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism or autism spectrum disorder.
Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies
2^nd) The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: The first case–control study in Asia
In this study, there were not any convincing evidences that MMR vaccination and increasing the number of vaccine injections were associated with an increased risk of ASD in a genetically homogeneous population. Therefore, these findings indicate that there is no basis for avoiding vaccination out of concern for ASD.
The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: The first case–control study in Asia
Conclusions
Based on the extensive review presented, GACVS (Global Advisory Committee on Vaccine Safety) concluded that no evidence exists of a causal association between MMR vaccine and autism or autistic disorders. The Committee believes the matter is likely to be clarified by a better understanding of the causes of autism. GACVS also concluded that there is no evidence to support the routine use of monovalent measles, mumps and rubella vaccines over the combined vaccine, a strategy which would put children at increased risk of incomplete immunization. Thus, GACVS recommends that there should be no change in current vaccination practices with MMR.
MMR and autism
Biochemical hypothesis: thimerosal
What is thiomersal?
Thiomersal (also known as thimerosal, mercurothiolate and sodium 2-ethylmercuriothio-benzoate) is a mercury compound used to prevent bacterial and fungal growth in some vaccines during storage, and especially during use of opened multi-dose vials. It has also been used during vaccine production both to inactivate certain organisms and toxins and to maintain a sterile production line.
Thiomersal and vaccines: questions and answers
Can thimerosal cause adverse effect on the neurodevelopment?
Thimerosal contains 49.5% ethylmercury. It can be converted to ethylmercury and accumulate in the brain. Under normal conditions, intracellular glutathione has a role in detoxifying ethylmercury, and high levels of ethylmercury can deplete the available glutathione. Thus, cytotoxicity can result from excess ethylmercury. Therefore we hypothesized that a higher dose of thimerosal would induce neurological alterations in the premature rats, and the results of our study were consistent with this hypothesis.
Effect of thimerosal on the neurodevelopment of premature rats
Some people are at higher risk:
The reduced form of glutathione (GSH) is the most important cell antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from l-arginine. Reduced levels of GSH, due both to a hyperglycemia increase of free radical production and to a decrease of NADPH levels [like in diabetes mellitus (DM)], can hamper the endothelial cell functions. This condition may play an important role in the aetiology of some clinical signs, like erectile dysfunction (ED).
Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus
We find that ethylmercury not only inhibits mitochondrial respiration leading to a drop in the steady state membrane potential, but also concurrent with these phenomena increases the formation of superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated hydroxyl radical.
These oxidants increase the levels of cellular aldehyde/ketones. Additionally, we find a five-fold increase in the levels of oxidant damaged mitochondrial DNA bases and increases in the levels of mtDNA nicks and blunt-ended breaks. Highly damaged mitochondria are characterized by having very low membrane potentials, increased superoxide/hydrogen peroxide production, and extensively damaged mtDNA and proteins. These mitochondria appear to have undergone a permeability transition, an observation supported by the five-fold increase in Caspase-3 activity observed after Thimerosal treatment.
Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA
a) As a lipophilic cation, ethylmercury will become concentrated inside astrocytes, following the plasma membrane potential of 45mV , by a factor of 5.6 fold, and cytosolic ethlymercury will partition into the mitochondria by a factor of 1,000 fold, its accumulation driven by the approximate 180mV mitochondrial membrane potential .
b) Inside the mitochondria ethylmercury will react and cap thiols/selenols, including the cysteine residues of iron-sulfur centers. The formation of ethylmercuricthiol adducts will not only cause enzyme inhibition, but also increase the levels of free iron inside the mitochondria.
c) The release of iron catalyzes Fenton/Haber-Weiss chemistry leading to the formation of the highly oxidizing HO•. HO• has multiple targets, including sensors of the permeability transition complex and also mtDNA. High levels of HO• cause Mitoposis, leading to cytochrome c release from the mitochondria and the initiation of apoptosis.
Proposed mechanism for the toxicity of organomercury.
● Thimerosal and DRD4
Expression of DRD4 and 5-HT2AR and learning function decreased, and apoptosis increased significantly in the 131.2 μg/kg group. Memory function was significantly impaired by 65.6, 98.4 and 131.2 μg/kg.
Effect of thimerosal on the neurodevelopment of premature rats.
The DRD4 7-repeat allele may increase the risk for clinically elevated autistic symptoms in children and adolescents with ADHD. Further studies are needed to confirm this finding and explore the role of specific gene-gene and gene-environment interactions in the development of autistic symptoms and other co-occurring psychopathology among individuals with ADHD.
Association between DRD4 genotype and Autistic Symptoms in DSM-IV ADHD
Other hypothesis: Aluminium adjuvants
Exposure to high levels of aluminum leads to neurodegeneration, which may be mediated through over-generation of free radicals.
The obtained results indicated that Al induced oxidative stress through induction of free radical production and inhibition of activity and expression of the antioxidant enzymes catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx); and at the same time induced superoxide dismutase (SOD) activity and gene expression
Quercetin and Omega 3 Ameliorate Oxidative Stress Induced by Aluminium Chloride in the Brain.
Our previous ecological studies of autism spectrum disorder (ASD) has demonstrated a correlation between increasing ASD rates and aluminium (Al) adjuvants in common use in paediatric vaccines in several Western countries. The correlation between ASD rate and Al adjuvant amounts appears to be dose-dependent and satisfies 8 of 9 Hill criteria for causality.
Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes.
Enrico Trogolo, Serena Viale
