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Table 9 In vivo studies examining an association between metabolites of the γ-glutamyl cycle or trans-sulfation pathway and autism spectrum disorders

From: The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis

   Study Cases1 Controls1 P values Overall
finding 		Comments
Total glutathione (μmol/L)      
Plasma AD Rose et al. 2008 [50] 5.69 ± 1.37
5.08 ± 1.38 		7.53 ± 1.7 < 0.001 lower ALAD CG + CC significantly lower than GG p = 0.007.
   Pastural et al. 2009 [82] Not provided Not provided < 0.05 lower  
Erythrocyte ASD Adams et al. 2009 [65, 67] 501 ± 246 427-714   same Paediatric values are lower than the reference range for adults provided by the laboratory.
Whole AD Pasca et al. 20094 [60] 161.16 ± 41.36 242.67 ± 118.77 0.02 lower SEM converted to SD. Not treated to prevent oxidation
Blood PDD-NOS Pasca et al. 20094 [60] 209.96 ± 94.63 213.32 ± 98.55 ns same As above.
  AS Pasca et al. 20094 [60] 147.31 ± 74.26 171.29 ± 92.69 ns same As above.
Free glutathione (μmol/L)      
Plasma AD James et al. 20063,4 [47] 1.4 ± 0.5 2.2 ± 0.9 < 0.0001 lower  
   Rose et al. 2008 [50] 1.60 ± 0.57 2.2 ± 0.9 < 0.001 lower ALAD CG + CC significantly lower than GG P = 0.02
    1.4 ± 0.48     Same controls as James et al. 2006.
   James et al. 20093,4 [48] 1.5 ± 0.4 2.8 ± 0.8 0.008 lower Cases with abnormal methylation or tGSH:GSSG only.
Reduced glutathione (μmol/L)      
Plasma ASD Geier & Geier 2006 [66] 64% lower   < 0.01 lower Sample preparation not provided.
   Geier & Geier 2009 [90] 3.1 ± 0.53 4.2 ± 0.72 < 0.0001 lower  
  ASD Geier & Geier 2009 [91] 3.14 ± 0.56 4.2 ± 0.72 < 0.0001 lower  
   Adams et al. 2011 [87] 3.23 ± 0.48 4.09 ± 0.79 < 0.0001 lower  
Oxidised glutathione (μmol/L)      
Plasma AD Rose et al. 2008 [50] 0.32 ± 0.127
0.32 ± 0.128 		0.24 ± 0.1 < 0.001 higher No significant difference between ALAD CG + CC and GG.
Total glutathione: oxidised glutathione      
Plasma AD James et al. 20043 [46] 8.6 ± 3.5 25.5 ± 8.9 < 0.001 lower  
   James et al. 20063,4 [47] 14.7 ± 6.2 28.2 ± 7.0 < 0.001 lower  
   Rossignol et al. 20075 [49] 28.47 ± 4.599 28.2 ± 7.0    Cases more likely to be severe as requested
    44.68 ± 14.1910     HBOT. Controls from James et al. 2006.
   Rose et al. 2008 [50] 20.45 ± 8.77 28.2 ± 7.0 < 0.001 lower ALAD CG + CC significantly lower than GG
    17.4 ± 5.78     P = 0.03. Controls from James et al. 2006.
   James et al. 20093,4 [48] 21 ± 6 47 ± 18 < 0.005 lower Cases abnormal methylation or tGSH:GSSG only.
Free: oxidised glutathione      
Plasma AD James et al. 20063,4 [47] 4.9 ± 2.2 7.9 ± 3.5 < 0.0001 lower  
   Rose et al. 2008 [50] 5.64 ± 2.67
4.81 ± 1.88 		7.9 ± 3.5 < 0.001 lower ALAD CG + CC significantly lower than GG P = 0.05
Reduced: oxidised glutathione      
Plasma ASD Adams et al. 2011 [87] 8.0 ± 3.2 10.1 ± 4.5 0.01 lower  
   Al-Yafee et al. 2011 [85] 8.03 ± 2.46 26.07 ± 5.03 0.001 lower  
Homocysteine (μmol/L)      
Plasma AD Moretti et al. 2005 [54] 6 4-14   ns Case study compared with reference values
   Pastural et al. 2009 [82] Not provided Not provided ns ns Result control normalised graph.
Serum   Geier & Geier 2006 [66] 62% lower   < 0.01   Does not state whether fasted or not.
CSF AD Moretti et al. 2005 [54] 0.424 0.032-0.114   high Case study compared with reference values
Cysteine (μmol/L)       
Plasma AD Pastural et al. 2009 [82] Not provided Not provided < 0.05 lower Result provided graphically as relative to homocysteine.
  ASD Geier & Geier 2006 [66] 81% lower   < 0.01   
Serum AD Visconti et al. 19946 [69] 40.56 ± 5.6811
41.04 ± 15.5612 		40.26 ± 12.72 ns same  
Cystine (mmol/L)       
Plasma AD Khaleeluddin & Philpott 1980 [93] 5/6 low     Concentrations and reference range not provided.
   D'Eufemia et al. 19953 [70] 78.3 ± 17.5 72.5 ± 19.9 ns ns Units incorrectly labelled mmol/L in Table 1. Correctly labelled μmol/L in Figure 3.
  ASD Adams et al. 2011 [87] 32.2 ± 8.2 34.8 ± 7.4 ns ns Fasted.
Cystathione (μmol/L)       
Plasma AD Khaleeluddin & Philpott 1980 [93] 1/6 high     
Serum ASD Geier & Geier 2006 [66] 68% low   < 0.05   Details of sample preparation not provided.
Cysteinylglycine (μmol/L)      
Plasma AD James et al. 20064,5 [47] 38.9 ± 11 39.4 ± 7.3 0.78 ns  
   James et al. 20094,5 [48] 40 ± 9 45 ± 6 < 0.005 lower Cases abnormal methylation or tGSH:GSSG only.
  ASD Suh et al. 2008 [77] 17.5 ± 6.8 10.5 ± 4.1 0.0008 higher  
Serine (μmol/L)      
Serum AD Visconti et al. 19946 [69] 130.59 ± 24.849 143.79 ± 30.08 ns ns  
    151.45 ± 50.4310 143.79 ± 30.08 ns ns  
   D'Eufemia et al. 19953 [70] 163.5 ± 32.1 169.1 ± 47.3 ns ns Units incorrectly labelled mmol/L in Table 1. Correctly labelled μmol/L in Figure 3.
   Shinohe et al. 20064 [75]    ns ns Results presented graphically
Plasma AD Pasca et al. 20095 [60] 99.46 ± 13.56 125.23 ± 47.31 0.08 trend SEM converted to SD.
  ASD Aldred et al. 2003 [88]    ns ns Results presented graphically.
   Adams et al. 2011 [87] 104 ± 25 94.7 ± 21 0.04 high  
(platelet poor) Tirouvanziam et al. 2011 [86] 85.23 ± 26.5 112.30 ± 27.3 0.0013 low Data obtained from author.
  PDD-NOS Pasca et al. 20095 [60] 113.31 ± 22.84 114.6 ± 38.23 ns ns SEM converted to SD.
  AS Pasca et al. 20095 [60] 96.2 ± 14.3 124.75 ± 49.07 ns ns SEM converted to SD.
Glycine (μmol/L)       
Serum AD Visconti et al. 19946 [69] 225.88 ± 36.238 245.63 ± 60.19 ns ns  
    225.06 ± 24.079   ns ns  
   D'Eufemia et al. 19953 [70] 246.7 ± 52.2 257.7 ± 55.3 ns ns Units incorrectly labelled mmol/L in Table 1. Correctly labelled μmol/L in figures.
   Shinohe et al. 20064 [75]    ns ns Results presented graphically
Plasma AD Pasca et al. 2009 [60] 184.20 ± 46.67 217.23 ± 52.46 0.09 ns SEM converted to SD
  ASD Aldred et al. 2003 [88]    ns ns Results presented graphically.
   Adams et al. 2011 [87] 267 ± 81 273 ± 101 ns ns  
(platelet poor) Tirouvanziam et al. 2011 [86] 192.8 ± 46.8 190.3 ± 49.5 ns ns Data obtained from author.
  PDD-NOS Pasca et al. 20095 [60] 207.94 ± 10.31 209.73 ± 42.31 ns ns SEM converted to SD.
  AS Pasca et al. 20095 [60] 188.6 ± 30.39 224.0 ± 49.81 ns ns SEM converted to SD.
Glutamate (μmol/L)       
Serum AD Visconti et al. 19946 [69] 61.89 ± 22.698 77.16 ± 50.01 ns ns  
    72.28 ± 44.429 77.16 ± 50.01 ns ns  
   D'Eufemia et al. 19953 [70] 77.3 ± 24.5 72.4 ± 21.2 ns ns Units incorrectly labelled mmol/L in Table 1. Correctly labelled μmol/L in figures.
   Shinohe et al. 20064 [75] 89.2 ± 21.5 61.1 ± 16.5 < 0.001 higher High correlation with ADI-R social scores (r = 0.523, P = 0.026)
  ASD Adams et al. 2011 [87] 65 ± 15 55 ± 13 0.001 higher  
Plasma   Arnold et al. 2003 [89] 51 ± 3213 48 ± 15   ns  
    42 ± 2314 48 ± 15   ns  
Plasma (platelet poor)   Tirouvanziam et al. 2011 [86] 104.06 ± 33.85 82.71 ± 34.20 0.039 higher Data obtained from authors.
Glutamate (nmol/10 8 )       
Platelets AD Rolf et al. 19934 [68] 4.8 ± 1.2 6.0 ± 1.2 < 0.02 lower Findings presented graphically.
Vitamin B6 (nmol/L)       
Plasma AD Sankar 19797 [92] 753.6 ± 31.7 Reference Not higher  
     Range (147.8-254.2) provided   
   Khaleeluddin & Philpott 4/9 high   Not higher  
   1980 [93]    provided higher  
  ASD Adams et al. 2004 [73] 224.55 ± 30.35 129.47 < 0.001 higher  
   Adams et al. 2006 [76] 226.58 ± 84.97 145.66 ± 35.60 0.001 higher  
Vitamin B6 as pyridoxyl-5-phosphate (nmol/L)      
Erythrocyte ASD Adams et al. 2011 [87] 72.44 ± 64.75 61.51 ± 21.45 ns ns  
Selenium (μmol/L)       
Erythocytes AD Jory and McGinnis 20074,5 [78] 3.12 ± 0.54 3.67 ± 0.38 0.0006 lower  
Whole blood ASD Adams et al. 2011 [87] 2.63 ± 0.36 2.67 ± 0.25 ns ns  
Selenium (μg/g)       
Erythrocytes ASD Adams et al. 2011 [87] 0.24 ± 0.04 0.23 ± 0.03 ns ns  
  1. 1Mean ± standard deviation 2 Cases relative to controls 3 Free from relevant medications 4 Free from supplementation5 Most on folinic acid or methyl-cobalamin 6One case, one control on thioridazine 7 ALAD GG polymorphism 8 ALAD CG + CC polymorphism 9Prior to 40 sessions HBOT at 1.3 atm 10Prior to 40 sessions HBOT at 1.5 atm 11 Normal EEG 12Abnormal EEG13 Normal diet 14Gluten/caseine free diet ns not significant AD Autistic disorder
  2. ASD Autism spectrum disorder PDD-NOS Pervasive developmental disorder- not otherwise specified. GSH Reduced glutathione GSSG Oxidised glutathione tGSH Total glutathione ALAD Delta aminolevulinic acid dehydratase HBOT Hyperbaric oxygen therapy SEM Standard error of the mean SD standard deviation
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