Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches

doi:10.3389/fnmol.2017.00034

PMC full text:

Front Mol Neurosci. 2017; 10: 34.

Published online 2017 Feb 21. doi: 10.3389/fnmol.2017.00034

Table 1

Studies showing linkage between ASD and mitochondrial dysfunction in ASD patients (only those reporting more than 25 subjects are included in this table).

References	Cases	Evidence of mitochondrial dysfunction
GENETIC LINKAGE BETWEEN MITOCHONDRIA-RELATED GENES AND AUTISM
Celestino-Soper et al., 2012	909 or 130	Deficiency of the gene TMLHE (trimethyl-lysine hydroxylase epsilon), which encodes the first enzyme in carnitine biosynthesis, was more frequent in probands from male-male multiplex ASD families.
Glessner et al., 2009	859	Copy number variations in genes involved in the ubiquitin degradation were implicated in susceptibility for ASD.
Kent et al., 2006	129	The 3243A>G mitochondrial DNA mutation was concluded to be a rare cause of isolated Asperger syndrome.
Silverman et al., 2008; Kim et al., 2011	Multiple families	Polymorphism in SLC25A12 gene, which encodes a mitochondrial aspartate/glutamate carrier, was found to be associated with restricted repetitive behaviors in autism.
Maestrini et al., 2010	127	A gene encoding an inner mitochondrial membrane protease-like protein (IMMP2L) was implicated in susceptibility for ASD.
Nava et al., 2012	501	Mutations in TMLHE were identified in patients with ASD and led to an increase in trimethyl-lysine, the precursor of carnitine biosynthesis, in the plasma.
Ramoz et al., 2004; Segurado et al., 2005; Turunen et al., 2008	Multiple families	Polymorphism in SLC25A12 gene was found to be associated with autism.
INDICATIONS OF IMPAIRED MITOCHONDRIAL FUNCTION IN THE BRAIN
Goh et al., 2014	75	Lactate doublets detected by brain magnetic resonance spectroscopic imaging were present at a higher rate in autistic patients.
Palmieri et al., 2010	Six or multiple families	Transport rates of mitochondrial aspartate/glutamate carrier (AGC) were higher in temporo-cortical gray matter. In addition, expression of AGC1, cytochrome c oxidase activity, and oxidized mitochondrial proteins were increased. However, variants of the AGC1-encoding SLC25A12 gene were not correlated with AGC activation or autism phenotype.
Tang et al., 2013	45	Mitochondrial function and intracellular redox status were compromised in the pyramidal neurons of the temporal cortex.
ABNORMAL LEVELS OF MITOCHONDRIA-RELATED METABOLITES IN BLOOD SAMPLES
Al-Mosalem et al., 2009	30	Increased plasma lactate levels and activity of creatine kinase.
Cohen et al., 1976	25	Increased serum creatine phosphokinase levels.
Correia et al., 2006	241	Increased plasma lactate levels and lactate/pyruvate ratio, but not associated with the variation at the SLC25A12 gene.
Filipek et al., 2004	100	Reduced levels of carnitine and pyruvate, but increased levels of alanine and ammonia in serum.
Frye et al., 2013	213	Abnormal acyl-carnitine panels and glutathione metabolism in blood samples.
Kuwabara et al., 2013	25	Higher plasma levels of arginine and taurine, and lower levels of 5-oxoproline and lactic acid.
László et al., 1994	30	Increased serum lactate and pyruvate levels.
Moreno et al., 1992	60	Increased lactate and pyruvate levels.
Oliveira et al., 2005	69	20% of ASD patients showed significantly increased lactic acidemia, while 7% were classified with a definite mitochondrial respiratory chain disorder.
Poling et al., 2006	159	Increased blood aspartate aminotransferase and creatine kinase levels.
ABNORMAL MITOCHONDRIAL FUNCTION AND DNA STRUCTURE IN PERIPHERAL CELLS OR CELL LINES
Boccuto et al., 2013	87	Decreased tryptophan metabolism in lymphoblastoid cell lines.
Chen et al., 2015	78	Mitochondrial DNA copy number in peripheral blood cells was elevated in children with ASD.
Rose et al., 2012	43	Primary immune cells in the blood had a more oxidized intracellular and extracellular microenvironment and a deficit in glutathione-mediated redox/antioxidant capacity.
Rose et al., 2014	25	Mitochondrial dysfunction observed in a subset of autism lymphoblastoid cell lines.
Wong et al., 2016	66	Mitochondrial DNA deletions and higher p53 gene copy ratios in peripheral blood monocytic cells were more common in children with autism and their fathers.