Mitochondrial disease in ASD

The most interesting thing about mitochondrial disease is that symptoms that appear can be very similar to ASD.  As a result of this the worry must be that many cases of ASD are in fact thought to be of unknown cause but if we looked hard enough for it we would find mitochondrial disease.  Claims of 7% of ASD patients may actually be like this and the worry has been simply that we don’t know how to do all the searching. 

 

Background.  Mitochondria are the energy creating organelles of each individual cell of the body in that they can make more energy from the glucose that arrives.  What happens is that normal cells can make lactate (and release energy) from glucose but gut little further.  It is only with good activity of mitochondria to we see full breakdown of this and release full energy as useful ATP.   Mitochondria are also thought to have been derived from bacteria in the distant past and carry their own DNA and RNA, which are affected by antibiotics.

 

Mitochondrial disease:

 

 

 

The mitochondrion, which is around 100th of the length of a cell.

(taken from www.kathleensworld.com/mitochon.html)

 

 

Hypothesis

This came by suggesting that the symptoms of ASD were very similar to those in the cases of mitochondrial disease that Lombard had seen.  The reasons why it is considered to be particularly important is because so many of the ASD population appear to carry the condition, and that many have hyperlactate, and are easily and quickly tired (as would be expected in mitochondrial disease).

Autism: a mitochondrial disorder?  Lombard J.  Med Hypotheses. 1998 Jun;50(6):497-500.  His idea was aimed at the biochemistry of the body that was known at the time. A likely etiological possibility may involve mitochondrial dysfunction with concomitant defects in neuronal oxidative phosphorylation within the central nervous system. This hypothesis is supported by a frequent association of lactic acidosis and carnitine deficiency in autistic patients. Mitochondria are vulnerable to a wide array of endogenous and exogenous factors which appear to be linked by excessive nitric oxide production.

(it should be noticed that Lazlo also was working on the same subject but his work is in Hugarian: Specific enzyme diagnosis in mitochondrial myopathies and encephalomyopathies] László A, Sümegi B, Alkonyi I, Horváth E, Sztriha L, Várkonyi A, Zombori J. Orv Hetil. 1994 Apr 3;135(14):747-50.)

Autism, epilepsy and mitochondrial disease: points of contact] García-Peńas JJ. Rev Neurol. 2008;46 Suppl 1:S79-85. Review.

Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl-CoA dehydrogenase.Clark-Taylor T, Clark-Taylor BE. Med Hypotheses. 2004;62(6):970-5

 

Biochemistry

This tries to show that autistic patients tend to have specific biochemical changes not readily found in others.  The problem with this is simply that we find a wide variation in the ASD population and so to get statistics showing their findings to be valid are difficult.

Autism and lactic acidosis. Coleman M, Blass JP. J Autism Dev Disord. 1985 Mar;15(1):1-8.  Four patients are described who have two coexistent syndromes: the behavioral syndrome of autism and the biochemical syndrome of lactic acidosis. One of the four patients also had hyperuricemia and hyperuricosuria.  Coleman went on in other papers to suggest that there were simply different biochemical types of autism.

Serum serotonin, lactate and pyruvate levels in infantile autistic children. László A, Horváth E, Eck E, Fekete M. Clin Chim Acta. 1994 Sep;229(1-2):205-7.

Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O, Gaylor DW. FASEB J. 2009 Aug;23(8):2374-83.The idea being that mitochondrial enzymes action may tip the oxidative process the wrong way such that there is an excess of oxidative materials forms (see oxidative stress)

Oxidative stress in autism. Chauhan A, Chauhan V. Pathophysiology. 2006 Aug;13(3):171-81. Additionally, altered glutathione levels and homocysteine/methionine metabolism, increased inflammation, excitotoxicity, as well as mitochondrial and immune dysfunction have been suggested in autism. A review in which they try to go through all the potential reasons for autism.

Relative carnitine deficiency in autism. Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ. J Autism Dev Disord. 2004 Dec;34(6):615-23. 100 patients.  Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p < 0.001), and pyruvate (p = 0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children.

Novel plasma phospholipid biomarkers of autism: Mitochondrial dysfunction as a putative causative mechanism.Pastural E, Ritchie S, Lu Y, Jin W, Kavianpour A, Khine Su-Myat K, Heath D, Wood PL, Fisk M, Goodenowe DB. Prostaglandins Leukot Essent Fatty Acids. 2009 Jul 14 Biomarkers of fatty acid elongation and desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were statistically elevated in all autistic subjects.

 

Neurological presentation of mitochondrial disease

Multiple presentation of mitochondrial disorders. Nissenkorn A, Zeharia A, Lev D, Fatal-Valevski A, Barash V, Gutman A, Harel S, Lerman-Sagie T. Arch Dis Child. 1999 Sep;81(3):209-14.

Neurologic presentations of mitochondrial disorders. Nissenkorn A, Zeharia A, Lev D, Watemberg N, Fattal-Valevski A, Barash V, Gutman A, Harel S, Lerman-Sagie T. J Child Neurol. 2000 Jan;15(1):44-8.

Autistic spectrum disorders and mitochondrial encephalopathies. Holtzman D. Acta Paediatr. 2008 Jul;97(7):859-60.

Association between autistic spectrum and mitochondrial pathology] Castro-Gago M, Blanco-Barca O, Gómez-Lado C, Pintos-Martínez E, Campos-González Y, Eirís-Puńal J.  Rev Neurol. 2008 Jul 1-15;47(1):52-3.  (in Spanish)

Developmental regression and mitochondrial dysfunction in a child with autism. Poling JS, Frye RE, Shoffner J, Zimmerman AW. J Child Neurol. 2006 Feb;21(2):170-2

Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome. Fillano JJ, Goldenthal MJ, Rhodes CH, Marín-García J. J Child Neurol. 2002 Jun;17(6):435-9

 

Proportions of ASD patients with mitochondrial disease of any kinds

It has been claimed that 7% of patients with diagnosed ASD do in fact have mitochondrial disease.  In a normal population the conditions are found in one in 5-10,000 children.

Autistic disorder in 2 children with mitochondrial disorders. Tsao CY, Mendell JR.  J Child Neurol. 2007 Sep;22(9):1121-3.

Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, Mitchell RL, Kern RL, Natowicz MR. PLoS One. 2008;3(11):e3815.  What they were actually trying to find out with this study was whether ASD (but also known to have mitochondrial disease) patients did in fact have symptoms and signs of mitochondrial disease and then, to follow up what kind of disease it was.  They took muscular biopsies of the 25 patients, and did DNA analysis of the mitochondria.  Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.

Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Oliveira G, Diogo L, Grazina M, Garcia P, Ataíde A, Marques C, Miguel T, Borges L, Vicente AM, Oliveira CR. Dev Med Child Neurol. 2005 Mar;47(3):185-9.  they investigated 120 patients with ASD. Epilepsy was present in 19 patients. Plasma lactate levels were measured in 69 patients, and in 14 we found hyperlactacidemia. Five of 11 patients studied were classified with definite mitochondrial respiratory chain disorder, suggesting that this might be one of the most common disorders associated with autism (5 of 69; 7.2%)

 

 

Genetic alterations of mitochondria in ASD

It is interesting that the mitochondria multiply (increase in number) separately from the multiplications of the cell they are in.  They are passed down from the mother to the child while the egg is formed in utero and as such it is significant that some aspects of a boy with autism are also held by its mother.  (also see Weissman’s article above)

Nuclear and mitochondrial genome defects in autisms. Smith M, Spence MA, Flodman P. Ann N Y Acad Sci. 2009 Jan;1151:102-32. A review of review information on alterations of structure of mitochondrial DNA and abnormal mitochondrial function in autism and indications that interactions of the nuclear and mitochondrial genomes may play a role in autism pathogenesis

Mitochondrial aspartate/glutamate carrier SLC25A12 gene is associated with autism. Turunen JA, Rehnström K, Kilpinen H, Kuokkanen M, Kempas E, Ylisaukko-Oja T.  Autism Res. 2008 Jun;1(3):189-92. See genetics for further information about this gene.

Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, Hager J, Rousseau F, Curatolo P, Manzi B, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Lenti C, Saccani M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM. Mol Psychiatry. 2008.  They go through the genetic mechanism by which the AGC1 change and the effect on mitochondrial action may be involved with autism.

An investigation of mitochondrial haplogroups in autism. Kent L, Gallagher L, Elliott HR, Mowbray C, Chinnery PF. Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):987-9.  The mothers of boys with autism share autistic traits, raising the possibility of a maternally inherited factor. Mitochondrial DNA (mtDNA) is almost exclusively inherited down the maternal line. We therefore explored the possibility that a particular mtDNA lineage contributes to the risk of developing autism. The mtDNA haplogroup was determined in 162 autism probands, and compared to two sets of population controls. Results show no compelling evidence of an association of any mitochondrial haplogroup in autism.

Mitochondrial dysfunction in autistic patients with 15q inverted duplication. Filipek PA, Juranek J, Smith M, Mays LZ, Ramos ER, Bocian M, Masser-Frye D, Laulhere TM, Modahl C, Spence MA, Gargus JJ. Ann Neurol. 2003 Jun;53(6):801-4.

Mitochondrial DNA abnormalities and autistic spectrum disorders. Pons R, Andreu AL, Checcarelli N, Vilŕ MR, Engelstad K, Sue CM, Shungu D, Haggerty R, de Vivo DC, DiMauro S. J Pediatr. 2004 Jan;144(1):81-5.  they looked at 5 patients with ASD.  Autistic spectrum disorders with or without additional neurologic features can be early presentations of the A3243G mtDNA mutation and can be a prominent clinical manifestation of mtDNA depletion. Mitochondrial dysfunction should be considered in patients who have autistic features

Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA, Courchesne E, Haas RH. J Child Neurol. 2000 Jun;15(6):357-61

 

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