Medical Breakthroughs on Autism

Mahima Pradhan, Raisa Pawirotareono, Mohamed Afzana Mohamed Ismail

INTRODUCTION

Leo Kanner (Austrian-American psychiatrist and physician) suggested that the mechanism of autism lays in the concept of “refrigerator mothers” – mothers who lack maternal warmth.[1]^,[2]^,[3] The concerning condition is categorized currently in International Statistical Classification of Diseases and Related Health Problems 10 as autism (ICD-10) and in the Diagnostic Statistical Manual of Mental Disorders 5 (DSM 5) it is categorized as autism spectrum disorder (ASD)[4]. ASD is usually first diagnosed in childhood, where one has difficulties in thinking, feeling, language and the ability to relate to others. This disorder is 4 to 5 times more common in males than in females[5]. The prevalence of autism has increased dramatically from 4 to 5 cases per 10,000 in 1966 to 100 per 10,000 today. The cause of ASD is multifactorial, the main cause laying in genetics. Numerous genes on many chromosomes are related to the developments of it. Prenatal causes can be divided into environmental, chemicals, maternal infections during pregnancy, maternal and fetal inflammation and maternal diseases, but many other factors can contribute. Numerous mechanisms for ASD have been proposed. In recent years, studies have offered that ASD is the result of general immune and metabolic disturbances that affect the brain, incl. immune dysregulation with abnormal levels of cytokines, growth factors, fetal and maternal antibodies to brain tissue, microglial activation, abnormal numbers of CD4 and CD8 cells and various antibodies. Other mechanisms related to the brain, have to do with abnormal white matter connectivity and altered synapses. This article focuses on gestational conditions that might be related to the development of ASD and the life expectancy of individuals living with this condition.

CLINICAL MANIFESTATION

Autism spectrum disorder is called so, because of the wide range of symptoms and symptom severity it presents with. The child has obvious difficulty in three areas: (1) social interaction, (2) communication skills and (3) behavior/activities/interests. Based on the level of severity, ASD can be classified into “level 3: requiring very substantial support”, “level 2: requiring substantial support” and “level 1: requiring support”^[6]. The best case scenario for an individual with ASD would be where the person has high-functioning autism. This is an informal way to call someone with ASD, who can speak, write, and handle basic life skills by himself, possibly living independently while the ASD might go unnoticed^[7].

On the other side, ASD is often misperceived as some form of mental retardation/intellectual deficit. Performing an intelligence test and taking conclusions from it, can easily lead to false accusations of the child having low intelligence. In a standard intelligence test the student needs to interact with the tester, answer questions, follow directions, imitate, and identify requested items. Many autistic students of who has been said to have low IQ, simply have not learned the skills yet that were required for them to participate in the test^[8]. If the child would be asked to identify a sheep on a drawing, while he has never before seen a sheep, he might as well point out the cow that was in the picture next to the sheep, because he has also never seen a cow. This point should be taken into consideration when taking intelligence tests. The (autistic) child should be exposed to different experiences in order to get familiarized with the skills necessary in the test.

The absolute indicators which indicate that a child should be evaluated for autism are called “red flags”. If the child shows no joyful expressions, does not share sounds or facial expressions, does not babble or does not wave or point, before the age of 12 months, these can be early signs of autism. Other red flags are when the child is older than 12 months, but does not say any words (at age 16 months), does not say meaningful two-word phrases (by age 24 months), lacks social interaction or shows any behavioral issues^[9].

PATHOGENESIS

Under normal conditions, inflammation is controlled by various homeostatic processes that limit or counteract inflammation once it has been induced by a stimuli. It also ensures eradication of pathogen and contributes to tissue repair and wound healing. Dysfunction of such surveillance mechanisms would result in inappropriate release of inflammatory cytokines which results in tissue damage. Maternal immune activation and cytokine dysregulation may be a mediator in pshychiatric behaviour observed in autism. Among the maternal diseases in pregnancy associated with ASD are pre-gestational diabetes mellitus and gestational diabetes mellitus, maternal infections(CMV, rubella), prolonged fever, drugs (valproic acid, thalidomide, misoprostol etc) ethanol, heavy metals such as mercury, folic acid deficiency etc; causes enhanced expression of pro-inflammatory cytokines and other mediators of inflammation in the maternal, fetal and neonatal compartments may interfere with brain development, thereby increasing the risk for long-term brain dysfunction later in life. Additionally, one case -control study conducted within a cohort of infants born in california (between 1995-1999), examined the association of “immune -related conditions” and reported that maternal autoimmune diseases during the second trimester of pregnancy correlated with a two-fold increase of ASD in their children mainly because of an over-active immune system [10].An inflammatory response in ASD is supported by a number of facts like TNF increased almost 50 times in CSF[11], and IL-6 gene expression was increased in brain of ASD children. CSF and microglia of ASD patients also had increased amounts of MCP-1 which is a potent chemo attractant for mast cells[12], who have an active role in allergic response. Apart, from IgE stimulation various environmental factors , brain and intestinal peptides trigger mast cell activation and release of selective mediators even without degranulation .For example, neurotensin (NT) was reported recently found to be increased in the serum of young children with autism[13] which inturn causes brain and gut inflammation additionally increasing vascular permeability due to acute stress. Monocyte Chemotactic Protein-1 (MCP-1), is believed to play an important role in the maturation of cerebellar Purkinje cells, and may serve as a useful marker of abnormal neuronal development. Genetic mutations in mTOR gene[14] and negative control of Rten activity seen in ASD patients[15] also induce mast cell proliferation supporting the research.

SCHIZOPHRENIA AND AUTISM

Acute neuro inflammation during early fetal brain development may negatively affect ongoing neurodevelopmental processes such as neuronal/glial cell differentiation, proliferation, migration, and survival[16][17]. It is proposed that acute fetal neuro inflammation, together with its effects on early neurodevelopmental processes, may facilitate the development of psychopathological and neuropathological phenotypes shared by schizophrenia and autism. Upon the initiation of acute prenatal inflammation, the maternal and/or fetal system may then either be driven into persistent inflammation or gain control over the inflammatory processes. The former may be related to a failure in the homeostatic control of inflammation, and may eventually result in chronic inflammation persisting into late fetal and neonatal periods. By contrast, mounting sufficient anti-inflammatory and/or immunosuppressive activity in the maternal and/or fetal system may dampen the acute fetal inflammatory response. Still, the developing organism might sustain latent immune abnormalities that may not become relevant until exposure to specific environmental stimuli over the postnatal life span. Prenatal inflammation-induced behavioral manifestations are accompanied by neuroanatomical and neurochemical abnormalities are common in both schizophrenia and autism, including neuromorphological alterations in cerebellum, basal ganglia and amygdala, deficient Reelin expression in hippocampus and prefrontal cortex, and alterations in serotonin synthesis and metabolism. Despite, that apparent similarities between schizophrenic and autistic disease, a plethora of distinctive neuropathological and psychopathological characteristics allow to distinguish the two disorders. One example is that autism has generally been associated with excessive brain growth (macrocephaly) [18]involving thickening of cortex, increased gray and white matter, and lack of gray matter loss , while schizophrenia seems to be associated with microcephaly involving thinner cortical areas, reduced gray and white matter, and accelerated gray matter loss[19]. Moreover, the induction of persistent inflammation may be more relevant for the etiopathogenesis of autism by contributing to phenotypic abnormalities specifically seen in this disorder. By contrast, latent immune inflammation may be essential to the pathogenesis of schizophrenia-specific brain and behavioral abnormalities.[20]

VITAMIN D DEFICIENCY AND ASD

It is not unknown that vitamin D plays a big role in the development of the fetal brain, the regulation of calcium and phosphate concentrations, suspected anti-inflammatory effect and more. For more than a decade, scientists have been trying to find out the importance of studies that link vitamin D deficiency with increased brain size and enlarged ventricles – characteristics similar to those found in children with ASD^[21]. Scientists have started to find a connection between vitamin D deficiency and traits found in ASD.

A large population-based cohort study was done of mothers and their children from fetal life onward, based in the Netherlands, by Vinkhuyzen et al ^[22]. The scientists looked into the association between gestational 25-hydroxyvitamin D (25OHD – sum of type D₂and D₃) and the measurement of the Social Responsive Scale (SRS) at age six. The vitamin D concentrations were taken at two time points: (1) midgestation ~ 21 weeks from maternal serum and (2) at birth (from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol/L. Vitamin D sufficiency was defined as concentrations more than 50 nmol/L. The SRS is a questionnaire for teachers/parents measuring children’s social impairments in naturalistic social situations. The SRS assesses social awareness, social information processing, capacity for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. This was taken when the same children were six years old. This study had ultimately shown that the mother-infant pairs who had low vitamin D concentration in both time-points (1) and (2) had higher scores on the SRS (higher scores are associated with more/stronger autistic traits). This suggested that infants exposed to persistent low vitamin D from mid-gestation until birth, may be at risk for autism-related traits.

Other researchers have been investigating this matter as well in different animal studies, and have also speculated that decreased vitamin D is associated with more autistic traits^[23]^,[24].

Neonatal vitamin D deficiency has actually been associated with increased risk of schizophrenia as well^[25]. With this information it seems highly useful and attainable to make vitamin D supplements accessible to at-risk groups, to reduce the prevalence of this risk factor. Just as folate supplementation has reduced the incidence of spina bifida, vitamin D supplementation may reduce the incidence of ASD.

LIFE SPAN

It is said that autistic people have an overall risk of early mortality twice as high than that of the general population^[26]. On average, individuals with ASD die substantially earlier than people who are not autistic. People with ASD die on average 18 years before the general population. Individuals with both ASD and an intellectual disability die even younger, about 30 years earlier than those without. The increased risk of dying is basically for any cause of death.

The main causes of early death in autism are epilepsy and suicide. Epilepsy in these people usually starts in the teenage years and increases in rate as age becomes higher. Suicide is the leading cause of early death among autistic individuals without learning disability. Other causes include cardiovascular disease, diabetes, stroke and respiratory disorders. An explanation behind all this is not fully available, but both social and biological factors tend to play a role. Autistic people have a more restricted diet, limited access to exercise and use a lot of medication. Often they have to cope with social and cultural pressures such as bullying, and social isolation. Not to mention, depression, anxiety and sensory overload.

These numbers of early death are unfavorable, thus should not be overlooked.

CONCLUSION

It is yet unknown whether the increase in the incidence of ASD in the last decades is mainly due to better ascertainment or is a reflection of a real increase in the occurrence of ASD. It is assumed that it stems mainly from prenatal causes as a result of significant changes in our surrounding environment and life habits. Autistic children have vast range of signs and symptoms also requiring intense observation while assessing intelligence test. The association between maternal infection during pregnancy and ASD is apparently linked to maternal inflammatory process; hence maternal immune-activation may play a major role in neuro-developmental perturbation. It is proposed that perinatal mast cell activation by environmental, infectious, neurohormonal and immune triggers could adversely affect neurodevelopment, disrupt the gut-blood–brain barriers, and contribute to focal brain inflammation and ASD. Prenatal infection and inflammatory responses appear to play a significant role in the etiology of both schizophrenia and autism while subsequent latent versus persistent inflammation may lead to phenotypic characteristics of schizophrenia versus autism, respectively. Vitamin D deficiency is common in children with ASD recent studies proposed that maternal vitamin D defi ciency during pregnancy may also increase the risk for ASD in children. Autistic people have shorter life expectancy, epilepsy and suicide being the major cause of death and are most likely to face more societal pressures and depression.