Mitochondrial Dysfunction in Autism
Introduction
Since Kanner’s original description of autism 70 years ago, the definition of autism, initially described as “autistic disturbances of affective contact,” has undergone a variety of changes and currently refers to a heterogeneous group of disorders. Autism spectrum disorder (ASD) is the broad term encompassing autistic disorder, Asperger disorder or syndrome, and pervasive developmental disorder, not otherwise specified. These disorders share common features of impaired social relationships, impaired communication and language, and stereotypic mannerisms or a narrow range of interests.1
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, has modified the diagnostic criteria.2 The first criteria of deficits of social interaction and communication from the DSM-IV have now been merged into a single criterion of social communication and interaction. The deficits must be clinically significant and persistent and should include the following: (1) marked impairment of both verbal and nonverbal communication used for social interaction, (2) lack of social reciprocity, and (3) a failure to develop peer relationships at the appropriate developmental level. The second criterion consists of restrictive repetitive interests shown by at least 2 of the following: (1) stereotyped motor or verbal behaviors or unusual sensory behaviors, (2) excessive adherence to routines and ritualize patterns of behavior, and (3) restricted, fixated interests. The third criterion states that the symptoms of autism must be present in early childhood (DSM-V).
From a clinical point of view, children who present to a pediatrician should be screened for ASD if they seem excessively shy, are socially awkward, have language impairment, or seem to be obsessed with certain topics of interests. Also, any child who has associated morbidities such as intellectual disability, epilepsy, severe hyperactivity, and obsessive-compulsive behavior should be screened.3
Overall, epidemiologic studies have shown that the prevalence of autism has increased over the past decades not only in the United States but also in other countries in the world.1 In the United States, most studies conducted between 1960 and 1980 reported the prevalence of ASD to be 2-5 per 10,000, whereas studies published in early 2000 reported prevalence ranging from 30-60 per 10,000 individuals.4 The US Department of Developmental Services reported that, between 1991 and 1997, there was a 556% increase in the prevalence of autism in childhood.5 From 1997-2008, the rate of prevalence of autism increased 4-fold from a prevalence of 19 per 10,000 (0.19%) to 74 per 10,000 (0.74%) individuals, respectively.6 A recent study by the US Department of Health and Human Services has reported an astonishing prevalence figure of 200 per 10,000 (2%).7
Although several explanations have been offered for the epidemiologic data mentioned previously, including previous poor diagnosis, screening recommendations by the American Academy of Pediatrics, increased awareness, diagnosis at an earlier age, and change in diagnostic criteria, some authors believe that the higher prevalence of the disease is real.1
Despite many recent scientific advances in the research of autism, its pathogenesis remains elusive. A variety of factors have been implicated, including controversial environmental factors such as exposure to heavy metals like mercury, lead, and immunizations. No scientific data have proved a causal effect of any of these environmental factors.8, 9, 10
Genetic: From studies on twins to the analysis of familial, inherited cases, and genetic investigations (eg, nucleotide polymorphisms, gene defects in autistic syndromes, and specific candidate genes), all of them have demonstrated that genetics is an important factor in the pathogenesis of autism.10, 11, 12
Dysgenetic: Neuroanatomical and neuroimaging studies reveal macrocephaly and abnormalities of cellular configurations in several regions of the brain, including the frontal and temporal lobes and the cerebellum. Very typical is also the presence of cortical minicolumns.10, 13, 14
Immunological: Several studies have demonstrated an activation of the immune system in the cerebrospinal fluid and in the brain of patients with autism, with presence of reactive neuroglia and inflammatory response.10, 13, 15, 16
Metabolic: In experimental models of autism syndromes (eg, Rett syndrome) and in patients with ASD, dysfunction of excitatory (glutamate) and inhibitory (gamma-amino butyric acid or GABA) neurotransmitters has been reported. Other neurotransmitters like serotonin and dopamine may also have abnormal physiological functions.11, 17, 18 Endocrine dysfunction of growth hormone, oxytocin, vasopressin, apelin, and other endocrine factors may also be related to pathogenetic mechanisms or symptoms in patients with ASD.18
Furthermore, some inborn errors of metabolism and genetic metabolic disorders (eg, tuberous sclerosis) have been associated with an ASD-like phenotype.11, 19
Among the metabolic diseases, mitochondrial (mt) disorders have recently been considered as possibly related to ASD. The mt are intracellular organelles that play a crucial role in adenosine 5′-triphosphate (ATP) production through oxidative phosphorylation (OXPHOS). The latter process is carried out by the electron transport chain (ETC) made up of complex I (nicotinamide adenine dinucleotide [NAD] + hydrogen [H]: ubiquinone oxidoreductase or dehydrogenase), complex II (succinate: ubiquinone oxidoreductase), complex III (coenzyme Q: cytochrome-c reductase or cytochrome bc complex), complex IV (cytochrome-c oxidase), and complex V (ATP synthase). The ETC is situated in the inner membrane of the mt and contains proteins encoded by both nuclear and mtDNA. About 100 proteins coded by nuclear genes are required for assembly of the complexes of the respiratory chain.20, 21, 22
The epidemiology of mt disease has evolved rapidly over the past 15 years. The first estimates of its prevalence were as low as 1:33,000.23 More recent figures available are that 1 in 2000 children born each year in the United States would develop definite mt disease in their lifetimes.24 However, when Elliott et al25 studied the frequency of 10 mtDNA point mutations in 3168 neonatal cord blood samples, they found that at least 1 in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers; the most common was the MELAS A3243G mutation. Approximately, 15% of pediatric mt disease is caused by mtDNA mutations and 85% is caused by nuclear DNA mutations that are inherited in a Mendelian fashion.26
A possible relationship between mt disease and autism was initially suggested by findings of elevation in the levels of lactate and pyruvate in the plasma27, 28, 29, 30, 31 or in the brain, which was measured with magnetic resonance spectroscopy,29 a sign of mt dysfunction in patients with ASD. Furthermore, Sue et al32 in 1999 and Graf et al33 in 2000 were the first ones to report 2 patients with ASD and a mtDNA mutation thought to be causing the ASD clinical picture. Since then, other similar cases have been reported and research on mt gene mutations and mt metabolism (OXPHOS) has been developed, the results suggest a possible pathogenetic link between mt dysfunction and autism.21, 26, 32, 33 Using data of the current prevalence of autism and a 1:2000 incidence of definite mt disease, if there was no linkage of ASD and mt disease, then it would be expected that 1 in 110 subjects with mt disease would have ASD and 1 in 2000 individuals with ASD would have mt disease. The co-occurrence of autism and mt disease appears to be much higher than these figures would suggest, again supporting a possible pathogenetic relationship.21, 30, 31 The relative proportions and overlaps between children with autism and mt disease are displayed in Fig. 1.26, 30 In this article, we review the current evidence linking mt dysfunction and ASD.
Section snippets
Peripheral Studies
During the past decade and a half, several cases and series of children with autism and genetic abnormalities have been reported. Specifically, mtDNA mutations or chromosome anomalies involving nuclear genes that regulate mt OXPHOS function have been described.32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47
Mitochondrial DNA Gene Defects
As indicated before, the first evidence of a mtDNA mutation that could cause ASD was published in 1999 and 2000.32, 33 Sue et al32 reported 3 children with infantile
Metabolic Evidence of a Link Between Mitochondrial Dysfunction and Autism
Multiple metabolic abnormalities, indicating dysfunction of mt, have been described in children with ASD. They include elevation in levels of lactate, pyruvate, or alanine in blood, cerebrospinal, or brain21, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 41, 54, 55; decreased levels of plasma carnitine21, 41; abnormal levels of urine organic acids36, 55; and impaired mt fatty acid β-oxidation.56, 57
As indicated previously, the most important metabolic role of mt, though, is the production of
Pathogenetic Mechanisms Underlying the Relationship of Mitochondria and Autism
In spite of the genetic and biochemical findings presented previously, suggesting a relationship between ASD and mt, it is not clear whether mt dysfunction contributes to the development or pathogenesis of ASD or whether it is merely an epiphenomenon of ASD.21 Several metabolic abnormalities or exposures to environmental toxic substances could result in secondary mt dysfunction in children with ASD. Alternatively, these factors could worsen mild mt dysfunction in some children, transforming it
Abnormal Neuroimmune Response
This immune-mediated mechanism could characterize a large subgroup of patients with ASD. An abnormal neuroimmune response would be the primary trigger in causing an increase in intracellular Ca2+ levels, producing mt dysfunction and, as a consequence, abnormal energy metabolism and stimulation of OS. Prenatally, deranging neurodevelopment would occur, affecting cell proliferation and migration, which ultimately would cause abnormal wiring, functional disconnection in association cortices, and
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Cited by (0)
This work was in part supported by grants from the St. Christopher's Foundation (St. Christopher's Hospital for Children), PHEC (Philadelphia Health Education Corporation), and DUCOM (Drexel University College of Medicine), Philadelphia, PA.