[vc_row el_class=”mr-b-26″][vc_column][vc_column_text single_style=””]<\/p>\n
Table of Contents<\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”6180″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 1. The powerhouse of the cell – the structure of the mitochondrion.<\/strong> Most cells have many mitochondria, which produce ATP as a form of cellular energy.<\/strong> The multifaceted roles of mitochondria in the central nervous system<\/strong> (CNS<\/strong>) – indeed, mitochondria are crucial for various cellular processes, especially in neurons where they support metabolism and calcium homeostasis.<\/strong> Their dynamic nature, including their ability to divide, fuse, and move, ensures they are well-distributed to meet the high energy demands of neurons.<\/strong> Recent advancements in imaging and genetic tools have significantly enhanced our understanding of mitochondrial functions. These techniques have revealed how mitochondria influence axon branching, synaptic function, calcium regulation with the endoplasmic reticulum (ER), glial cell function, neurogenesis, and neuronal repair.<\/em><\/strong> Mitochondrial dysfunction is linked to numerous CNS disorders, from impaired neuronal development to neurodegenerative diseases.<\/u><\/span> Most importantly, understanding the role of mitochondria in ASD<\/u><\/span> could lead to more effective diagnostic and therapeutic strategies, potentially improving the quality of life for those affected.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”introduction”][vc_column][vc_custom_heading text=”Introduction”][vc_single_image image=”6181″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Box-1. Autistic disturbances of affective contact.<\/strong> Dr. Leo Kanner\u2019s observation of regression, a case study. (Kanner, 1943, pp. 225 \u2013 226<\/em><\/span>) [1].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n As the above quote from a parent illustrates observations of regression have been intricately linked with autism from the time of its designation in 1943, when Leo Kanner<\/strong> first published the case histories of eleven children with \u201cautistic disturbances of affective contact\u201d<\/em><\/strong> (see Box-1<\/strong>) [1].<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-1″][vc_column][vc_custom_heading text=”What is Regression?”][vc_column_text single_style=””]<\/p>\n Regression in autism usually occurs within the second year of the life and can happen either abruptly or gradually.<\/strong> The child experiences a stall in skill acquisition or a measurable loss, which usually occurs in the areas of language and\/or social skills,<\/strong> although there are occasional reports of the loss of adaptive and fine motor skills too.<\/strong> Eventually, the regressive period is succeeded by the regaining of skills, although some children may never fully regain the skills they had originally lost [2].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Anywhere between 10 \u2013 50% of children who are diagnosed with autism have experienced regression, with the most common reported figures hovering around one third of cases<\/span>. These estimates probably vary because of differences in criteria used to define \u201cregression.\u201d<\/strong><\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Some studies for instance restrict it to extreme forms of language loss, while others include subtler plateaus in language and social skills. However, estimates also probably vary modestly because the primary means of estimating regression in autism is generally parental report. While parents know their children better than anyone else, especially in those early formative years, human memory is not infallible \u2013 particularly if the regressive losses are subtle and the parent is answering a questionnaire ten years after the fact.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Remarkably, regression appears to be largely unique to autism. When comparing autistic toddlers with other children with various intellectual disabilities, researchers have found that language regression occurs in a large minority of those with autism, however, it is rarely seen in those with intellectual disability alone [2].<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-2″][vc_column][vc_custom_heading text=”Regression in Syndromic Forms of Autism”][vc_column_text single_style=””]<\/p>\n Regression also occurs in some syndromic forms of autism, such as Rett syndrome<\/em><\/strong> and childhood disintegrative disorder<\/em><\/strong> (CDD<\/strong>) (once known as Heller\u2019s syndrome<\/em><\/strong>), both of which had previously been grouped under the DSM-IV\u2019s<\/strong> autism umbrella, Pervasive Developmental Disorders, but have since been removed.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n (i) Rett Syndrome<\/strong><\/p>\n Most cases of Rett syndrome<\/em><\/strong> are linked with loss-of-function mutations involving the MECP2<\/strong><\/em> gene, which produces a protein that binds to methylated DNA<\/em><\/strong> and helps to control gene expression. Almost all cases of Rett syndrome are female due to the lethality of the X-linked mutation in males.<\/span> When it does occur in males, this is typically due to something known as somatic mosaicism<\/em><\/strong>, in which the mutation is not present in all cells of the body but only a portion because it has occurred later in embryonic development rather than in the originating germ cells.<\/p>\n [\/vc_column_text][vc_single_image image=”6182″ img_size=”full”][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=””]<\/p>\n Figure 2. Developmental regression onset and key features by condition.<\/strong> Prevalence: autism 1:44 \u2013 100; Rett syndrome 1:10,000 \u2013 15,000; Childhood disintegrative disorder 1.4 \u2013 9.2 per 100,000; Phelan McDermid syndrome 2 \u2013 10 per 1000000; Landau Kleffner syndrome 1 per 1000000. (Green \u2013 regression of developmental skills. Blue \u2013 other typical features may be identified before onset of regression)<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Prior to regression, the majority of girls with Rett\u2019s present with some type of developmental delay. Regression onset then usually occurs between 12 to 18 months of age, with an average of 16 months,<\/em><\/strong> which is slightly younger than the average 20 months in idiopathic autism<\/em><\/strong> (see Figure 2<\/strong>) [2-3].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The most prominent feature in Rett syndrome is a decline in motor skills involving the hands, often leading to the characteristic \u201chand wringing\u201d<\/em><\/strong> feature for which Rett\u2019s is known. However, large numbers of girls also lose language, nonverbal communication and play, and other motor skills<\/em><\/strong> [3].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n (ii) Childhood Disintegrative Disorder (CDD)<\/strong><\/p>\n Unlike Rett syndrome, CDD<\/strong> is a poorly studied and understood condition that occurs more often in boys.<\/em><\/strong> Currently, there are no known mutations associated with CDD, which may reflect the state of our science but may also suggest that, like autism, it is a heterogeneous disorder. Occasional case studies reporting the occurrence of autism and CDD in the same families suggests the latter may also be true [4].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n CDD is typified by normal or near-normal development until at least two years of age,<\/em><\/strong> after which a regression period begins that may be characterized by high levels of anxiety,<\/em><\/strong> followed by a severe decline in skills and the onset of autistic symptomology. Often, language is lost and rarely regained,<\/em><\/strong> as are self-help skills such as appropriate use of the toilet or feeding.<\/em><\/strong> Unfortunately, most children with CDD develop intellectual disability<\/em><\/strong> and are severely affected for the rest of their lives (see Figure 2<\/strong>).<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-3″][vc_column][vc_custom_heading text=”What Causes Regression?”][vc_column_text single_style=””]<\/p>\n Some types of autism have variable hereditary pattern.<\/em><\/strong> For instance, parents of multiplex (multiple incidence) families<\/em><\/strong> often exhibit a broader autism phenotype (BAP<\/strong>) themselves. Meanwhile, parents who have only a single child with autism (simplex cases)<\/em><\/strong> are considerably less likely to have autistic features than multiplex parents.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Although, it may seem surprising given the typical developmental trajectory of children with autistic regression, typified by near-normal development followed by sudden or gradual regression, parents of these children have similar rates of BAP as parents of children without regression. This suggests that regressive autism, on the whole, is as heritable as non-regressive autism.<\/u><\/span><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-4″][vc_column][vc_custom_heading text=”Over-Pruning Hypothesis of Autistic Regression”][vc_column_text single_style=””]<\/p>\n We know that regressive autism may be partly inherited, but what causes it?<\/em><\/strong> One of the more popular current theories is the over-pruning hypothesis of autistic regression<\/em><\/strong> [5]. According to this hypothesis, the loss of neural connectivity<\/strong><\/em> leading to regression is due to overactive pruning of those connections,<\/span> which normally starts to occur in toddlerhood and extends throughout childhood. Curiously, the neurodevelopmental model used to test this hypothesis does seem to support the idea that regression is due to a loss of connectivity \u2013 however, it never proves what causes that loss (e.g., pruning<\/em><\/strong>), merely that there is indeed a loss. (Cf. previous blogs entitled as: \u201cThe Neurotypical Brain versus the Autistic Brain \u2013 Neurotypical Brain Development and Function\u201d<\/a><\/u> & \u201cThe Neurotypical Brian versus the Autistic Brain: Brain Development and Function in ASD\u201d<\/a><\/u>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In addition, the brain in autism is not typified by generalized underconnectivity and in fact has a wealth of short-range connective fibers. Instead, the larger longer fibers of the brain are preferentially depleted.<\/span><\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Many cases of autistic regression seem to be linked with some kind of stressor or stimulus as reviewed in the following sections in this blog and subsequent ones. Sometimes, that stressor is the onset of an epileptic disorder. Other times, that stimulus is an illness. Sometimes, it is both. Consequently, it implies that regression is the result of excessive or chronic cellular stress, leading to the rapid or slow loss of synapses, neural connections, and sometimes cells themselves.<\/u><\/span><\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n This loss leads to a subsequent loss in skills, such as language and socialization. Sometimes these skills may be regained, especially in smaller neural networks in which regrowth is possible. However, long-range connections are unlikely ever to be recovered owing to the need for specific developmental cues that lead connections along their arduous paths and that are no longer present in the postnatal brain.<\/em><\/u> In this way, coordination amongst disparate functional modules of the brain will be permanently impaired.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”6183″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 3. Exogenous antioxidants.<\/strong> In general, a plant-based diet protects against chronic oxidative stress-related diseases. Dietary plants contain variable chemical families and amounts of antioxidants. It has been hypothesized that plant antioxidants may contribute to the beneficial health effects of dietary plants.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-5″][vc_column][vc_custom_heading text=”Oxidation”][vc_column_text single_style=””]<\/p>\n (i) Free Radicals and Antioxidants<\/strong><\/p>\n Everyone has probably heard the term, antioxidant<\/em><\/strong>, in the context of nutrition. We know that many plant-based foods, such as berries or spices like turmeric, tend to be very high in antioxidants. Meanwhile, animal-based foods such as eggs or fish are generally fairly low (see Figure 3<\/strong>) [6].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Antioxidants help to neutralize free radicals, which are molecules that have unpaired electrons, a state that leaves them chemically unstable<\/em><\/strong> (see Figure 4<\/strong>). In the case of biological systems, we are usually most interested in oxygen-based free radicals known as reactive oxygen species<\/em><\/strong> (ROS<\/strong>), because they are a common metabolic byproduct (see Figure 5<\/strong>).<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”6184″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 4. Free radicals and antioxidants.<\/strong> A free radical, known for stealing electrons from other molecules thereby creating a chain reaction of free radicals. Antioxidants help to neutralize free radicals.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In order to stabilize, free radicals steal electrons from other molecules around them. However, in doing so, whatever molecule has been robbed of its electron typically becomes a free radical itself. This can lead to a long chain of electron thievery, leaving misshapen and poorly functioning molecules in its wake (see Figure 4<\/strong>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Fortunately, the body has a supply of antioxidants that shuts down this runaway reaction, either by donating electrons or degrading the free radical itself. As we mentioned, any of the antioxidants in our bodies are derived from the foods we eat, most of which come from fruits and vegetables and include the vitamins, A, C, and E. However, we also produce antioxidants ourselves, such as glutathione (see Figure 3-4; Figure 6<\/strong>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In fact, the sleep hormone, melatonin, is a very powerful antioxidant.<\/span> Melatonin is mostly produced by the brain\u2019s pineal gland<\/strong>, beginning in the evening hours and reaching its peak at night. Melatonin production is suppressed by exposure to the blue end of the light spectrum, which is why sleep specialists recombined the use of dim yellow lighting in the evenings to mimic effects of the setting sun.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=””]<\/p>\n (ii) Mitochondrial Dysfunction and Reactive Oxygen (ROS)<\/strong><\/p>\n Mitochondria are the powerhouses of the cell.<\/em><\/strong> Through complex chain of events known as respiration<\/em><\/strong>, mitochondria take energy from food we eat (e.g., glucose) and the air we breathe (e.g., oxygen) and produce the basic energy currency of the cell, adenosine triphosphate<\/strong> <\/span>(ATP<\/strong>). The cell can the take that ATP and break off phosphate molecules to produce an energy catalyst for processes within the cell (see Figure 1<\/strong>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n ROS are major byproducts of cellular respiration.<\/span> Whenever the cell is overrun by ROS, this leads to oxidative stress, which in turn triggers a host of reactions termed the \u201coxidative response.\u201d<\/em><\/strong> In bacteria, this response is fairly straightforward because they tend to live in environments with fluctuating oxygen levels, therefore the presence of ROS can trigger an oxidative response.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”6185″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 5. Sources of reactive oxygen species generation.<\/strong> Reactive oxygen species (ROS<\/strong>) and their reactivity – indeed, while oxygen is vital for life, its derivatives, particularly ROS, can be quite harmful when present in excess.<\/em><\/strong> ROS are a diverse group of molecules, including both free radicals (like superoxide anion, O2<\/sub>\u2022<\/strong>\u2212, and hydroxyl radical, \u2022<\/strong>OH) and non-radicals (like hydrogen peroxide, H2<\/sub>O2<\/sub>). Free radicals are particularly reactive due to their unpaired electrons,<\/strong> which drive them to \u201csteal<\/strong>\u201d electrons<\/strong> from other molecules, initiating a chain reaction of molecular damage. The production of ROS occurs through various cellular processes, including the one-, two-, and three-electron reductions of molecular oxygen,<\/em><\/strong> leading to the formation of superoxide, hydrogen peroxide, and hydroxyl radicals,<\/em><\/strong> respectively. While superoxide and hydroxyl radicals are highly reactive, hydrogen peroxide is less so but can still contribute to oxidative stress. Cells have evolved sophisticated antioxidant defenses<\/strong> to manage ROS levels and mitigate their potential damage. These defenses include enzymatic antioxidants like superoxide dismutase and catalase, as well as non-enzymatic antioxidants like vitamins C and E6.<\/strong><\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Eukaryotic organisms such as ourselves, however, live in environments in which oxygen levels are indicator of impending damage but a normal part of respiration. Thus, it is the quantity of ROS, not their presence,<\/em><\/strong> which leads to a complicated cascade of events in mammalian cells that help not only to deal with increased ROS load but also repair damage to cellular structures. In some cases, when extreme, these processes may even lead to apoptosis<\/em><\/strong> or cell suicide<\/em><\/strong> [7].<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=””]<\/p>\n (iii) How Oxidative Stress Damages the Brain<\/strong><\/p>\n Because we need oxygen to survive, our cells are constantly bombarded by ROS, leading to perpetual damage of DNA, proteins, and fats<\/strong> that must constantly be repaired (see Figure 5<\/strong>). However, ROS are not only byproducts of cellular metabolism, but they also play important roles in various molecular pathways, such as inflammation, and therefore we are always in a precarious state of balance between having too much and too little ROS. Therefore, it is important to eat antioxidant-rich foods but also not to take excessive amounts of antioxidant supplements because we need some ROS for our cells to work properly (see Figure 6<\/strong>) [8].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Unfortunately, as we age the ability of our tissues to repair themselves following ROS damage declines. The brain is especially vulnerable to oxidative damage because of its high oxygen demands requiring about 20% of the body\u2019s basal consumption.<\/u><\/span> In addition, many things can go wrong in the brain, leading either to increases in ROS or impairments in the mechanism that deal with them.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n For example, excessive availability of the excitatory neurotransmitter glutamate can lead to cell damage or death through \u201cexcitotoxicity\u201d<\/strong> or the excessive stimulation of neurons<\/strong>. Oxidative stress can damage neurons, leading to a release of glutamate into the surrounding space, triggering an excitotoxic domino effect. This excitotoxic storm<\/strong> is one of the major risks following stroke, as cellular damage from the initial ischemic attach release excessive glutamate into the extracellular space, overstimulating intact neurons surrounding the original lesion. Consequently, stroke patients need to be treated rapidly with medications that prevent the spread of excitotoxicity to surround areas of the brain [9].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Metal ions,<\/strong> such as iron, can also act as free radicals and are released into the extracellular space following neuronal damage. Unfortunately, because the brain has little iron-binding capacity, the presence of these metal ions can persist for long periods of time, triggering oxidative stress until they are finally flushed from the cerebral spinal fluid<\/strong> (CSF<\/strong>).<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”6186″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 6. Impacts of oxidant and antioxidant imbalance on oxidative stress outcome.<\/strong> Reactive oxygen species (ROS<\/strong>) and oxidative stress \u2013 indeed, ROS are a double-edged sword in cellular biology.<\/u> While they play crucial roles in cell signaling<\/strong> and homeostasis<\/strong>, their overproduction can lead to oxidative stress<\/strong>, causing significant damage to cellular components like DNA, proteins, and lipids<\/strong>. Oxidative stress is implicated in the pathogenesis of numerous diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders such as Alzheimer\u2019s and Parkinson\u2019s.<\/em> The body employs a variety of antioxidant defenses, both enzymatic<\/em><\/strong> (e.g., superoxide dismutase, catalase) and non-enzymatic<\/em><\/strong> (e.g., vitamins C and E, glutathione), to counteract the harmful effects of ROS.<\/em><\/strong> The balance between ROS production and antioxidant defenses is crucial. When this balance tips in favor of ROS, oxidative stress occurs, leading to cellular damage and contributing to aging and various diseases. Cells have evolved numerous stress response mechanisms to manage oxidative stress, including pathways that promote cell survival or, in some cases, cell death, depending on the context.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The fatty membranes of neurons are also common targets of oxidation in a process known as \u201clipid peroxidation.<\/em><\/strong>\u201d When lipid peroxidation occurs in excess, the membranes of cells can become more permeable, allowing in toxic agents that damage the cell.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The functions of ion channels and receptors<\/strong> within the membrane can also be irreparably damaged, ultimately leading to cell death and many of the processes mentioned above (e.g., release of glutamate and metal ions into the surround tissue).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In contrast to much of the rest of the body, antioxidant defense is comparatively modest in the brain. Considering the communicative roles some ROS play in brain function, such as nitric oxide,<\/span> this may well be an adaptive evolutionary strategy. However, with such benefits come risks, notably increased oxidative stress over time.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n With time also come mutations.<\/strong> Not only do we house DNA within the nucleus of our cells, but our mitochondria also contain their own small genomes<\/span>, which, like nuclear DNA, acquire more and more mutations over time that affect the mitochondria\u2019s capacity to function properly. Because mitochondria produce a lot of ROS, many of these mutations are like the result of oxidative damage. Impaired mitochondrial function can lead to excessive ROS production and further oxidative stress, resulting in a positive feedback loop (see Figure 5<\/strong>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Finally, inflammation also drives oxidative stress. Astrocytes, <\/strong>a type of glial (helper) cell, produce inflammatory molecules such as various cytokines. These cytokines then stimulate immune cells within the brain known as microglia<\/strong>. These microglia release more inflammatory molecules, as well as various ROS, as part of their inflammatory response [8; 10]. If this type of reaction occurs chronically, it can lead to progressive damage as seen in some types of neurodegenerative disorders.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n There are many more ways in which ROS can damage the cell. However, the majority of these mechanism feed into one another, leading or progressive damage regardless of which pathway is stimulated first. All of these processes together lead to aging of the brain and, in those vulnerable individuals, play pivotal roles in the development of senile neurodegeneration. However, as we will discuss in the next section, they may play important roles in neurodevelopmental conditions such as autism as well.<\/u><\/span><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=””]<\/p>\n (iv) Mitochondrial Diseases and Dysfunction in Autism<\/strong><\/p>\n More than three decades ago, researchers realized that the mitochondrion, the powerhouse of cell (see Figure 1<\/strong>), may play a role in autism susceptibility. We now know that \n