Abstract
Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder. Over the past decade, evidence has emerged that some children with ASD suffer from undiagnosed comorbid medical conditions. One of the medical disorders that has been consistently associated with ASD is mitochondrial dysfunction. Individuals with mitochondrial disorders without concomitant ASD manifest dysfunction in multiple high-energy organ systems, such as the central nervous, muscular, and gastrointestinal (GI) systems. Interestingly, these are the identical organ systems affected in a significant number of children with ASD. This finding increases the possibility that mitochondrial dysfunction may be one of the keys that explains the many diverse symptoms observed in some children with ASD. This article will review the importance of mitochondria in human health and disease, the evidence for mitochondrial dysfunction in ASD, the potential role of mitochondrial dysfunction in the comorbid medical conditions associated with ASD, and how mitochondrial dysfunction can bridge the gap for understanding how these seemingly disparate medical conditions are related. We also review the limitations of this evidence and other possible explanations for these findings. This new understanding of ASD should provide researchers a pathway for understanding the etiopathogenesis of ASD and clinicians the potential to develop medical therapies.
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Abbreviations
- ASD:
-
autism spectrum disorder
- GI:
-
gastrointestinal
- MDC:
-
mitochondrial disease criteria
- PDD-NOS:
-
pervasive developmental disorder-not otherwise specified
- ROS:
-
reactive oxygen species
REFERENCES
Rice C for the Autism and Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal Investigators, Centers for Disease Control and Prevention (CDC) 2009 Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill Summ 58: 1–20
Schaefer GB, Mendelsohn NJ 2008 Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med 10: 4–12
Xue Ming, Brimacombe M, Chaaban J, Zimmerman-Bier B, Wagner GC 2008 Autism spectrum disorders: concurrent clinical disorders. J Child Neurol 23: 6–13
Rossignol DA 2009 Novel and emerging treatments for autism spectrum disorders: a systematic review. Ann Clin Psychiatry 21: 213–236
Rossignol DA, Frye RE 2011 Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry, in press
Cornford ME, Philippart M, Jacobs B, Scheibel AB, Vinters HV 1994 Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain. J Child Neurol 9: 424–431
Su H, Fan W, Coskun PE, Vesa J, Gold JA, Jiang YH, Potluri P, Procaccio V, Acab A, Weiss JH, Wallace DC, Kimonis VE 2011 Mitochondrial dysfunction in CA1 hippocampal neurons of the UBE3A deficient mouse model for Angelman syndrome. Neurosci Lett 487: 129–133
Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Cohen BH 2007 Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 120: 1326–1333
Coleman M, Blass JP 1985 Autism and lactic acidosis. J Autism Dev Disord 15: 1–8
Lombard J 1998 Autism: a mitochondrial disorder?. Med Hypotheses 50: 497–500
Oliveira G, Diogo L, Grazina M, Garcia P, Ataide A, Marques C, Miguel T, Borges L, Vicente AM, Oliveira CR 2005 Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol 47: 185–189
Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN 2010 Mitochondrial dysfunction in autism. JAMA 304: 2389–2396
Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, Mitchell RL, Kern RL, Natowicz MR 2008 Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS ONE 3: e3815
Zeviani M, Bertagnolio B, Uziel G 1996 Neurological presentations of mitochondrial diseases. J Inherit Metab Dis 19: 504–520
Skladal D, Halliday J, Thorburn DR 2003 Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126: 1905–1912
Trushina E, McMurray CT 2007 Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 145: 1233–1248
Martin LJ 2006 Mitochondriopathy in Parkinson disease and amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 65: 1103–1110
Roberts RA, Laskin DL, Smith CV, Robertson FM, Allen EM, Doorn JA, Slikker W 2009 Nitrative and oxidative stress in toxicology and disease. Toxicol Sci 112: 4–16
Anderson MP, Hooker BS, Herbert MR 2008 Bridging from cells to cognition in autism pathophysiology: biological pathways to defective brain function and plasticity. Am J Biochem Biotechnol 4: 167–176
Morava E, van den Heuvel L, Hol F, de Vries MC, Hogeveen M, Rodenburg RJ, Smeitink JA 2006 Mitochondrial disease criteria: diagnostic applications in children. Neurology 67: 1823–1826
Stefanatos GA 2008 Regression in autistic spectrum disorders. Neuropsychol Rev 18: 305–319
Fernell E, Hedvall A, Norrelgen F, Eriksson M, Hoglund-Carlsson L, Barnevik-Olsson M, Svensson L, Holm A, Westerlund J, Gillberg C 2010 Developmental profiles in preschool children with autism spectrum disorders referred for intervention. Res Dev Disabil 31: 790–799
Chen CY, Chen KH, Liu CY, Huang SL, Lin KM 2009 Increased risks of congenital, neurologic, and endocrine disorders associated with autism in preschool children: cognitive ability differences. J Pediatr 154: 345–350
Volkmar FR, Nelson DS 1990 Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 29: 127–129
Hara H 2007 Autism and epilepsy: a retrospective follow-up study. Brain Dev 29: 486–490
Buie T, Campbell DB, Fuchs GJ III, Furuta GT, Levy J, Vandewater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H 2010 Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125: S1–S18
Buie T, Fuchs GJ III, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H 2010 Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics 125: S19–S29
Fukumoto A, Hashimoto T, Mori K, Tsuda Y, Arisawa K, Kagami S 2010 Head circumference and body growth in autism spectrum disorders. Brain Dev, in press
Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P 2010 Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry 167: 1349–1356
Connolly BS, Feigenbaum AS, Robinson BH, Dipchand AI, Simon DK, Tarnopolsky MA 2010 MELAS syndrome, cardiomyopathy, rhabdomyolysis, and autism associated with the A3260G mitochondrial DNA mutation. Biochem Biophys Res Commun 402: 443–447
Nasrallah F, Feki M, Kaabachi N 2010 Creatine and creatine deficiency syndromes: biochemical and clinical aspects. Pediatr Neurol 42: 163–171
Karakaya P, Yis U, Kurul SH, Turkmen MA 2010 Rhabdomyolysis associated with olanzapine treatment in a child with Autism. Pediatr Emerg Care 26: 41–42
Correia CT, Almeida JP, Santos PE, Sequeira AF, Marques CE, Miguel TS, Abreu RL, Oliveira GG, Vicente AM 2010 Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J 10: 418–430
Mouridsen SE, Rich B, Isager T 2010 A longitudinal study of epilepsy and other central nervous system diseases in individuals with and without a history of infantile autism. Brain Dev, in press
Johansson M, Gillberg C, Rastam M 2010 Autism spectrum conditions in individuals with Mobius sequence, CHARGE syndrome and oculo-auriculo-vertebral spectrum: diagnostic aspects. Res Dev Disabil 31: 9–24
Correia C, Coutinho AM, Diogo L, Grazina M, Marques C, Miguel T, Ataide A, Almeida J, Borges L, Oliveira C, Oliveira G, Vicente AM 2006 Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene. J Autism Dev Disord 36: 1137–1140
Germanò E, Gagliano A, Magazù A, Calarese T, Calabrò ME, Bonsignore M, Tortorella G, Calamoneri F 2006 [Neurobiology of autism: study of a sample of autistic children]. Minerva Pediatr 58: 109–120
László A, Horváth E, Eck E, Fekete M 1994 Serum serotonin, lactate and pyruvate levels in infantile autistic children. Clin Chim Acta 229: 205–207
Moreno H, Borjas L, Arrieta A, Sáez L, Prassad A, Estévez J, Bonilla E 1992 [Clinical heterogeneity of the autistic syndrome: a study of 60 families]. Invest Clin 33: 13–31
Arnold GL, Hyman SL, Mooney RA, Kirby RS 2003 Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord 33: 449–454
Chugani DC, Sundram BS, Behen M, Lee ML, Moore GJ 1999 Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry 23: 635–641
Boddaert N, Zilbovicius M, Philipe A, Robel L, Bourgeois M, Barthélemy C, Seidenwurm D, Meresse I, Laurier L, Desguerre I, Bahi-Buisson N, Brunelle F, Munnich A, Samson Y, Mouren MC, Chabane N 2009 MRI findings in 77 children with non-syndromic autistic disorder. PLoS ONE 4: e4415
Pancrudo J, Shanske S, Coku J, Lu J, Mardach R, Akman O, Krishna S, Bonilla E, DiMauro S 2007 Mitochondrial myopathy associated with a novel mutation in mtDNA. Neuromuscul Disord 17: 651–654
Fillano JJ, Goldenthal MJ, Rhodes CH, Marin-Garcia J 2002 Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome. J Child Neurol 17: 435–439
Shoffner J, Hyams L, Langley GN, Cossette S, Mylacraine L, Dale J, Ollis L, Kuoch S, Bennett K, Aliberti A, Hyland K 2010 Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol 25: 429–434
Pons R, Andreu AL, Checcarelli N, Vila MR, Engelstad K, Sue CM, Shungu D, Haggerty R, de Vivo DC, DiMauro S 2004 Mitochondrial DNA abnormalities and autistic spectrum disorders. J Pediatr 144: 81–85
Gargus JJ, Imtiaz F 2008 Mitochondrial energy-deficient endophenotype in autism. Am J Biochem Biotechnol 4: 198–207
Chauhan A, Chauhan V, Brown WT 2010 Autism: Oxidative Stress, Inflammation, and Immune Abnormalities . CRC Press, Boca Raton
Filipek PA, Juranek J, Smith M, Mays LZ, Ramos ER, Bocian M, Masser-Frye D, Laulhere TM, Modahl C, Spence MA, Gargus JJ 2003 Mitochondrial dysfunction in autistic patients with 15q inverted duplication. Ann Neurol 53: 801–804
Benvenuto A, Moavero R, Alessandrelli R, Manzi B, Curatolo P 2009 Syndromic autism: causes and pathogenetic pathways. World J Pediatr 5: 169–176
Manzi B, Loizzo AL, Giana G, Curatolo P 2008 Autism and metabolic diseases. J Child Neurol 23: 307–314
Zecavati N, Spence SJ 2009 Neurometabolic disorders and dysfunction in autism spectrum disorders. Curr Neurol Neurosci Rep 9: 129–136
Frye RE 2010 Autism. Carney PR, Geyer JD Pediatric Practice: Neurology. McGraw-Hill, New York, NY 348–361
Malik M, Sheikh AM, Wen G, Spivack W, Brown WT, Li X 2011 Expression of inflammatory cytokines, Bcl2 and cathepsin D are altered in lymphoblasts of autistic subjects. Immunobiology 216: 80–85
Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M 2007 Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 36: 361–365
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M 2009 Elevated immune response in the brain of autistic patients. J Neuroimmunol 207: 111–116
Samavati L, Lee I, Mathes I, Lottspeich F, Huttemann M 2008 Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem 283: 21134–21144
Vempati UD, Diaz F, Barrientos A, Narisawa S, Mian AM, Millan JL, Boise LH, Moraes CT 2007 Role of cytochrome C in apoptosis: increased sensitivity to tumor necrosis factor alpha is associated with respiratory defects but not with lack of cytochrome C release. Mol Cell Biol 27: 1771–1783
Kurup RK, Kurup PA 2003 A hypothalamic digoxin-mediated model for autism. Int J Neurosci 113: 1537–1559
Clark-Taylor T, Clark-Taylor BE 2004 Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl-CoA dehydrogenase. Med Hypotheses 62: 970–975
Poling JS, Frye RE, Shoffner J, Zimmerman AW 2006 Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol 21: 170–172
Fernández-Checa JC, Garcia-Ruiz C, Colell A, Morales A, Mari M, Miranda M, Ardite E 1998 Oxidative stress: role of mitochondria and protection by glutathione. Biofactors 8: 7–11
James SJ, Melnyk S, Fuchs G, Reid T, Jernigan S, Pavliv O, Hubanks A, Gaylor DW 2009 Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr 89: 425–430
James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, Cutler P, Bock K, Boris M, Bradstreet JJ, Baker SM, Gaylor DW 2006 Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet 141B: 947–956
James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O, Gaylor DW 2009 Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB J 23: 2374–2383
Vali S, Mythri RB, Jagatha B, Padiadpu J, Ramanujan KS, Andersen JK, Gorin F, Bharath MM 2007 Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson's disease: a dynamic model. Neuroscience 149: 917–930
Fernández-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A, Miranda M, Mari M, Ardite E, Morales A 1997 GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Physiol 273: G7–G17
Wallace DC 1999 Mitochondrial diseases in man and mouse. Science 283: 1482–1488
Rubenstein JL, Merzenich MM 2003 Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2: 255–267
Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT 2004 Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119: 19–31
Krey JF, Dolmetsch RE 2007 Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol 17: 112–119
Demaurex N, Poburko D, Frieden M 2009 Regulation of plasma membrane calcium fluxes by mitochondria. Biochim Biophys Acta 1787: 1383–1394
Kriaucionis S, Paterson A, Curtis J, Guy J, Macleod N, Bird A 2006 Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol 26: 5033–5042
MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, Boon F, Taylor AR, Kavaliers M, Ossenkopp KP 2007 Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 176: 149–169
MacFabe DF, RodrÃguez-Capote K, Hoffman JE, Franklin AE, Mohammad-Asef Y, Taylor AR, Boon F, Cain DP, Kavaliers M, Possmayer F, Ossenkopp K-P 2008 A novel rodent model of autism: intraventricular infusions of propionic acid increase locomotor activity and induce neuroinflammation and oxidative stress in discrete regions of adult rat brain. Am J Biochem Biotechnol 4: 146–166
Shultz SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R, Cain DP 2008 Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology 54: 901–911
Thomas RH, Foley KA, Mepham JR, Tichenoff LJ, Possmayer F, MacFabe DF 2010 Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further development of a potential model of autism spectrum disorders. J Neurochem 113: 515–529
Oliveira G, Ataide A, Marques C, Miguel TS, Coutinho AM, Mota-Vieira L, Goncalves E, Lopes NM, Rodrigues V, Carmona da Mota H, Vicente AM 2007 Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical characterization, and medical conditions. Dev Med Child Neurol 49: 726–733
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Supported, in part, by the National Institute of Neurological Disorders and Stroke (NINDS), Grant K23NS046565, and the Jane Botsford Johnson Foundation.
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Frye, R., Rossignol, D. Mitochondrial Dysfunction Can Connect the Diverse Medical Symptoms Associated With Autism Spectrum Disorders. Pediatr Res 69, 41–47 (2011). https://doi.org/10.1203/PDR.0b013e318212f16b
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DOI: https://doi.org/10.1203/PDR.0b013e318212f16b
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