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

Main, Penelope AE; Angley, Manya T; O'Doherty, Catherine E; Thomas, Philip; Fenech, Michael

doi:10.1186/1743-7075-9-35

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. 2006^3,4 [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. 2009^3,4 [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. 2006^3,4 [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. 2009^3,4 [48]	21 ± 6	47 ± 18	< 0.005	lower	Cases abnormal methylation or tGSH:GSSG only.
*Free: oxidised glutathione*
Plasma	AD	James et al. 2006^3,4 [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. 2006^4,5 [47]	38.9 ± 11	39.4 ± 7.3	0.78	ns
		James et al. 2009^4,5 [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 2007^4,5 [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

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
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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