Mitochondrial Dysfunction in Autism

https://doi.org/10.1016/j.spen.2013.10.008Get rights and content

Using data of the current prevalence of autism as 200:10,000 and a 1:2000 incidence of definite mitochondrial (mt) disease, if there was no linkage of autism spectrum disorder (ASD) and mt disease, 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 is much higher than these figures, suggesting a possible pathogenetic relationship. Such hypothesis was initially suggested by the presence of biochemical markers of abnormal mt metabolic function in patients with ASD, including elevation of lactate, pyruvate, or alanine levels in blood, cerebrospinal fluid, or brain; carnitine level in plasma; and level of organic acids in urine, and by demonstrating impaired mt fatty acid β-oxidation. More recently, mtDNA genetic mutations or deletions or mutations of nuclear genes regulating mt function have been associated with ASD in patients or in neuropathologic studies on the brains of patients with autism. In addition, the presence of dysfunction of the complexes of the mt respiratory chain or electron transport chain, indicating abnormal oxidative phosphorylation, has been reported in patients with ASD and in the autopsy samples of brains. Possible pathogenetic mechanisms linking mt dysfunction and ASD include mt activation of the immune system, abnormal mt Ca2+ handling, and mt-induced oxidative stress. Genetic and epigenetic regulation of brain development may also be disrupted by mt dysfunction, including mt-induced oxidative stress. The role of the purinergic system linking mt dysfunction and ASD is currently under investigation. In summary, there is genetic and biochemical evidence for a mitochondria (mt) role in the pathogenesis of ASD in a subset of children. To determine the prevalence and type of genetic and biochemical mt defects in ASD, there is a need for further research using the latest genetic technology such as next-generation sequencing, microarrays, bioinformatics, and biochemical assays. Because of the availability of potential therapeutic options for mt disease, successful research results could translate into better treatment and outcome for patients with mt-associated ASD. This requires a high index of suspicion of mt disease in children with autism who are diagnosed early.

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

References (112)

  • R.K. Naviaux

    Mitochondria and autism spectrum disorders

  • A. László et al.

    Serum serotonin, lactate and pyruvate in infantile autistic children

    Clin Chim Acta

    (1994)
  • D.C. Chugani et al.

    Evidence of altered energy metabolism in autistic children

    Prog Neuropsychopharmacol Biol Psychiatry

    (1999)
  • C.M. Sue et al.

    Infantile encephalopathy associated with the MELAS A3243G mutation

    J Pediatr

    (1999)
  • R. Pons et al.

    Mitochondrial DNA abnormalities and autistic spectrum disorders

    J Pediatr

    (2004)
  • W.H. Chien et al.

    Association study of SLC25A12 gene and autism in Ham Chinese in Taiwan

    Prog Neuropsychopharmacol Biol Psychiatry

    (2010)
  • T. Clark-Taylor et al.

    Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial β-oxidation by long chain acyl-CoA dehydrogenase

    Med Hypotheses

    (2004)
  • E. Pastural et al.

    Novel plasma phospholipid biomarkers of autism: Mitochondrial dysfunction as a putative causative mechanism

    Prostaglandins Lekot Essent Fatty Acids

    (2009)
  • M.J. Goldenthal et al.

    Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: Comparison with studies in muscle biopsy

    Mol Genet Metab

    (2012)
  • A.K. Craig et al.

    Dravet syndrome: Patients with co-morbid SCN1A gene mutations and mitochondrial electron transport chain defects

    Seizure

    (2012)
  • G. Tang et al.

    Mitochondrial abnormalities in temporal lobe of autistic brain

    Neurobiol Dis

    (2013)
  • A.M. Psarra et al.

    Glucocorticoid receptors and other transcription factors in mitochondria and possible functions

    Biochim Biophys Acta

    (2009)
  • F.N. Gellerich et al.

    The regulation of OXPHOS by extramitochondrial calcium

    Biochim Biophys Acta

    (2010)
  • N. Demaurex et al.

    Regulation of plasma membrane calcium fluxes by mitochondria

    Biochim Biophys Acta

    (2009)
  • L. Palmieri et al.

    Mitochondrial dysfunction in autism spectrum disorders: Cause or effect?

    Biochim Biophys Acta

    (2010)
  • A. Larbi et al.

    Oxidative stress modulation and T cell activation

    Exp Gerontol

    (2007)
  • J.F. Krey et al.

    Molecular mechanisms of autism: A possible role for Ca2+ signaling

    Curr Opin Neurobiol

    (2007)
  • M. Ristow et al.

    How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)

    Exp Gerontol

    (2010)
  • M.P. Abbracchio et al.

    Purinergic signaling in the nervous system: An overview

    Trends Neurosci

    (2009)
  • E. Ducham et al.

    Epidemiology of autism spectrum disorders

    Pediatr Clin North Am

    (2012)
  • Diagnostic and Statistical Manual of Mental Disorders

    (2013)
  • D. Kogan et al.

    Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007

    Pediatrics

    (2009)
  • E. Stokstad

    Development. New hints into the biological basis of autism

    Science

    (1997)
  • C. Boyle et al.

    Trends in the prevalence of developmental disabilities in US children, 1997-2008

    Pediatrics

    (2011)
  • S.J. Blumberg et al.

    Change in the prevalence of parent-reported autism spectrum disorder in school-aged children: 2007 to 2011-2012

    Natl Health Stat Rep

    (2013)
  • M.D. Lakshmi Priya et al.

    Level of trace elements (copper, zinc, magnesium and selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism

    Biol Trace Elem Res

    (2011)
  • C.J. Clements et al.

    When science is not enough-a risk/benefit profile of thiomersal-containing vaccines

    Expert Opin Drug Saf

    (2006)
  • M.C. Lai et al.

    Autism

    Lancet

    (2013)
  • E. Courchesne et al.

    The autistic brain: Birth through adulthood

    Curr Opin Neurol

    (2004)
  • C.A. Pardo et al.

    Immunity, neuroglia and neuroinflammation in autism

    Int Rev Psychiatry

    (2005)
  • D.C. Chugani

    Neuroimaging and neurochemistry of autism

    Pediatr Clin North Am

    (2012)
  • D.A. Rossignol et al.

    Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis

    Mol Psychiatr

    (2012)
  • S. Dhillon et al.

    Genetic and mitochondrial abnormalities in autism spectrum disorders: A review

    Curr Genomics

    (2011)
  • D.A. Applegarth et al.

    Incidence of inborn errors of metabolism in British Columbia, 1969-1976

    Pediatrics

    (2000)
  • M. Coleman et al.

    Autism and lactic acidosis

    J Autism Dev Disord

    (1985)
  • R.H. Haas

    Autism and mitochondrial disease

    Dev Disabil Res Rev

    (2010)
  • R.E. Frye et al.

    Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders

    Pediatr Res

    (2011)
  • W.D. Graf et al.

    Autism associated with the mitochondrial DNA G8363A transfer RNA (Lys) mutation

    J Child Neurol

    (2000)
  • J.J. Filiano et al.

    Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome

    J Child Neurol

    (2002)
  • J.R. Weissman et al.

    Mitochondrial disease in autism spectrum disorder patients analysis

    PLoS One

    (2008)
  • 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.

    View full text