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Autism Studies Rev7 Jan 2009[1] Autism Studies & Related Medical Conditions January 2009 Table of Contents 1 - Autism and Mitochondrial Dysfunction (19 citations) Page 2 2 - Autism and Gastrointestinal Inflammation (101 citations) Page 11 3 - Autism and Neuroinflammation (42 Citations) Page 41 4 - Autism and Treatment of Inflammation (29 citations) Page 59 5 - Autism and Oxidative Stress (70 citations) Page 69 6 - Autism and oxidative stress treatments (5 citations) Page 103 7 - Autism and Infections (22 citations) Page 106 8 - Aluminum Toxicity (19 citations) Page 125 9 - Dietary Intervention Studies (102 citations) Page 140 10 - Correcting Nutritional Deficiencies (81 citations) Page 179 11 - Immune Dysregulation in Autism (71 citations) Page 229 12 - Enviornmental Toxicities (4 citations) Page 271 13 - Thimerosal and Toxicity (132 citations) Page 273 14 - Binstock Citations – Misc. Papers & Articles (incl. Vaccines ref.) Page 304 15 - Which Vaccines Contain Thimerosal & Aluminum as of March 2008 Page 365 16 - How much money is spent on vaccine promotion & safety studies Page 372 17 - Studies Against Vaccines & Autism Relationship with rebuttals Page 375 18 - Difference between Number of Vaccines Given in 1983 vs. 2008 Page 383 Citation Notes Page 384 Contributions to this document Autism Studies & Related Medical Conditions – TACA © Page 1 1- Autism and Mitochondrial Dysfunction (19 citations): Blasi, F., E. Bacchelli, et al. (2006). "SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample." Eur J Hum Genet 14(1): 123-6. Autism is a severe neurodevelopmental disorder with a complex genetic predisposition. Linkage findings from several genome scans suggest the presence of an autism susceptibility locus on chromosome 2q24-q33, making this region the focus of candidate gene and association studies. Recently, significant association with autism has been reported for single-nucleotide polymorphisms (SNPs) in the SLC25A12 and CMYA3 genes on chromosome 2q. We attempted to replicate these findings in the collection of families from the International Molecular Genetic Study of Autism Consortium (IMGSAC), using the transmission disequilibrium test and case-control comparison. Our study failed to reveal any significant association for the SNPs tested at either locus, suggesting that these variants are unlikely to play a major role in genetic susceptibility to autism in our sample. Clark-Taylor, T. and B. E. Clark-Taylor (2004). "Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl- CoA dehydrogenase." Med Hypotheses 62(6): 970-5. Long chain acyl-CoA dehydrogenase (LCAD) has recently been shown to be the mitochondrial enzyme responsible for the beta-oxidation of branched chain and unsaturated fatty acids [Biochim. Biophys. Acta 1393 (1998) 35; Biochim. Biophys. Acta 1485 (2000) 121]. Whilst disorders of short, medium and very long chain acyl dehydrogenases are known, there is no known disorder of LCAD deficiency in humans. Experimental LCAD deficiency in mice shows an acyl- carnitine profile with prominent elevations of unsaturated fatty acid metabolites C14:1 and C14:2 [Hum. Mol. Genet. 10 (2001) 2069]. A child with autism whose acyl-carnitine profile also shows these abnormalities is presented, and it is hypothesized that the child may have LCAD deficiency. Additional metabolic abnormalities seen in this patient include alterations of TCA energy production, ammonia detoxification, reduced synthesis of omega-3 DHA, and abnormal cholesterol metabolism. These metabolic changes are also seen as secondary abnormalities in dysfunction of fatty acid beta-oxidation, and have also been reported in autism. It is hypothesized that LCAD deficiency may be a cause of autism. Similarities between metabolic disturbances in autism, and those of disorders of fatty acid beta-oxidation are discussed. Filipek, P. A., J. Juranek, et al. (2004). "Relative carnitine deficiency in autism." J Autism Dev Disord 34(6): 615-23. A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Autism Studies & Related Medical Conditions – TACA © Page 2 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. Filipek, P. A., J. Juranek, et al. (2003). "Mitochondrial dysfunction in autistic patients with 15q inverted duplication." Ann Neurol 53(6): 801-4. Two autistic children with a chromosome 15q11-q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function. Fillano, J. J., M. J. Goldenthal, et al. (2002). "Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome." J Child Neurol 17(6): 435-9. A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded. Gargus, J. J. and F. Imtiaz (2008). "Mitochondrial energy-deficient endophenotype in autism." American Journal of Biochemistry and Biotechnology 4(2): 198-207. While evidence points to a multigenic etiology of most autism, the pathophysiology of the disorder has yet to be defined and the underlying genes Autism Studies & Related Medical Conditions – TACA © Page 3 and biochemical pathways they subserve remain unknown. Autism is considered to be influenced by a combination of various genetic, environmental and immunological factors; more recently, evidence has suggested that increased vulnerability to oxidative stress may be involved in the etiology of this multifactorial disorder. Furthermore, recent studies have pointed to a subset of autism associated with the biochemical endophenotype of mitochondrial energy deficiency, identified as a subtle impairment in fat and carbohydrate oxidation. This phenotype is similar, but more subtle than those seen in classic mitochondrial defects. In some cases the beginnings of the genetic underpinnings of these mitochondrial defects are emerging, such as mild mitochondrial dysfunction and secondary carnitine deficiency observed in the subset of autistic patients with an inverted duplication of chromosome 15q11- q13. In addition, rare cases of familial autism associated with sudden infant death syndrome (SIDS) or associated with abnormalities in cellular calcium homeostasis, such as malignant hyperthermia or cardiac arrhythmia, are beginning to emerge. Such special cases suggest that the pathophysiology of autism may comprise pathways that are directly or indirectly involved in mitochondrial energy production and to further probe this connection three new avenues seem worthy of exploration: 1) metabolomic clinical studies provoking controlled aerobic exercise stress to expand the biochemical phenotype, 2) high- throughput expression arrays to directly survey activity of the genes underlying these biochemical pathways and 3) model systems, either based upon neuronal stem cells or model genetic organisms, to discover novel genetic and environmental inputs into these pathways. Graf, W. D., J. Marin-Garcia, et al. (2000). "Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation." J Child Neurol 15(6): 357-61. We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA)Lys mutation. The phenotype of one child in the family was consistent
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