Background
Glutathione redox and autism spectrum disorders
Methods
Selection of studies for review
Information retrieval
Data extraction and methodological quality assessment
1. Selection | ||
---|---|---|
Case definition | Yes, with independent validation | 2 |
Yes, record linkage/self report | 1 | |
No description | 0 | |
Representativeness | Consecutive cases | 1 |
Potential for selection bias/not stated | 0 | |
Selection of controls | Community | 2 |
Hospital/clinic/school | 1 | |
Potential for selection bias/not stated | 0 | |
Definition of controls | No family history of autism spectrum disorder | 2 |
Healthy/other psych/developmental/genetic | 1 | |
disorder | ||
Poorly defined/not stated | 0 | |
2. Comparability of cases and controls on the basis of the design
| ||
Study controls for age | 1 | |
Study controls for gender | 1 | |
3. Exposure
| ||
Ascertainment of exposure | ||
Laboratory blinded to case/control status | 1 | |
Laboratory unblinded/not stated | 0 | |
Method of ascertainment same for cases and controls | ||
Yes | 1 | |
No | 2 | |
4. Additional criteria for genetic studies
| ||
a. Consideration of Hardy Weinberg Equilibrium | ||
Yes | 1 | |
No | 0 | |
b. Power calculations | ||
Yes | 1 | |
No | 0 | |
c. Correction for multiple comparisons | ||
Yes | 1 | |
No | 0 | |
d. Adjustment for population stratification | ||
Yes | 1 | |
No | 0 |
Level of evidence | Description |
---|---|
I
| Evidence obtained from a systematic review of all relevant randomised controlled trials. |
II
| Evidence obtained from at least one properly designed randomised controlled trial. |
III - 1
| Evidence obtained from well designed pseudo-randomised controlled trials (alternate allocation or some other method). |
III - 2
| Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case control studies or interrupted time series with control group. |
III - 3
| Evidence obtained from comparative studies with historical control, two or more single arm studies, or interrupted time series without a parallel control group. |
IV
| Evidence obtained from a case series, either post-test or pre-test and post-test. |
Statistical analyses
Results
Authors (country) | Study size | Participant characteristics1 | Ascertainment | Case definition | Outcome measures of interest | Quality Score | |
---|---|---|---|---|---|---|---|
Cases
|
Controls
| ||||||
Level II (Double blinded randomised controlled trial)
| |||||||
Bertoglio et al. 2010 [64] (USA) | 30 cases | Cases 3-8 y, 93%M | Clinical referrals and internal database. | Cross-over study design. | DSM-IV-TR and ADOS plus non-verbal IQ ≥ 49 measured by Wechsler Preschool and Primary Scale of Intelligence, Mullen Scales of Early Learning or Wechsler Intelligence Scale for Children. | Plasma GSH and GSH: GSSG linked to Global Clinical Impressions Score and other objective behavioural measures. | I5 |
Adams et al (USA) | Baseline 77 cases RCT 41 cases (26 intervention, 15 placebo) | Baseline Cases 6.3 (3-8)y, 89.6% M (95% autistic disorder, 3% PDD- NOS, 3% Asperger's Syndrome. RCT Intervention 6.7 y, 92.3%M (96% autistic disorder, 4% Asperger's) Placebo 6.5 y, 93.3%M (100% autistic disorder) | Arizona residents. | Immunosciences reference range for adults. | Previous diagnosis of ASD. No standardised definition. | Erythrocyte glutathione. Behavioural measures. | 3* I5 |
Open-labelled non-randomised control trial
| |||||||
Rossignol et al. 2007 [49] (USA) | 18 cases | Cases 3-16 y, 78%M No seizures. Many supplemented with folinic acid and/or methyl-cobalamin. | Not stated. | Glutathione values from controls in James et al. 2006 | DSM-IV for autistic disorder, CARS | Plasma GSH measured before and after 40 treatments with hyperbaric oxygen. Behavioural measures. | 2* I5 |
Level III-2 (Casecontrol)
| |||||||
Golse et al. 1978 [63] (France) | 36 cases, 21 controls | Cases 4-19 y, 58%M Controls 5-18 y, 43%M | Referred from 4 clinics in France & 1 from Belgium. | Not stated. | Social isolation, no language, stereotypical behaviour. | Erythrocyte and platelet GPx activity. | 2 |
Rolf et al. 1993 [68] (Germany) | 18 cases, 14 controls | Cases 9.9 ± 2.8 y (5-14 y) 89%M, medication free. Controls 11.5 ± 2.0 y (8-14 y) 57%M. | Not stated. | Not stated. | DSM-III for autistic disorder. | Platelet glutamic acid. | 4 |
Visconti et al. 1994 [69] (Italy) | 37 cases (18 with EEG abnormalities), 19 controls | Cases 7 y (3-12 y), 89%M Controls 7 y (3-13 y), 68%M 1 case and 1 control on thioridazine. Fasted. | Patients attending the Department of Child Neurology and Psychiatry, University of Bologna, Italy. | Not stated. | DSM-III-R for autistic disorder. | Serum serine, glutamic acid, glycine and cysteine. | 4 |
D'Eufemia et al. 1995 [70] (Italy) | 40 cases, 46 controls | Cases 12 y 4 mo (7-17 y), 68%M, 32 F Controls 11 y, 2 mo (5-15 y). Medication free for previous month. Fasted. | Referred by the Italian Association of Parents of Autistic Children. | Not stated. | DSM-III-R for autistic disorder. | Serum glutamic acid, glycine and cystine. | 5 |
Yorbik et al. 2002 [71] (Turkey) | 45 cases, 41 controls | Cases 6.4 ± 2.2 y (4-12 y) 87%M Controls 6.7 ± 2.5 y (4-12 y) 85%M Medication free for previous month and fasted. | Child and adolescent departments of 3 educational hospitals in Ankara. | Children attending the Department of Pediatrics at Gulhane Military Medical School for routine vaccinat- ions. | DSM-IV for autistic disorder. | Plasma and erythrocyte GPx activity. | 4 |
Söğüt et al. 2003 [72] (Turkey) | 27 cases, 30 controls | Cases 4.7 ± 2.7 y (2-12 y), 59%M Controls 5.1 ± 2.9 y (2-13 y) 53%M Medication free and fasted. | Patients of the Child & Adolescent Psychiatry Dept at Gaziantep University Medical School. | Students at a Gaziantep kindergarten & primary school. | DSM-IV for autistic disorder and CARS > 30. | Plasma GPx activity | 5 |
James et al. 2004 [46] (USA) | 20 cases (19 regressive autism), 33 controls for the cross sectional study then 8 cases for the intervention. | Cases 6.4 ± 1.5 y, 70%M, 16 supplemented with 400 μg folic acid and 3 μg vitamin B12. Controls 7.4 ± 1.3 y, gender not stated. Supplemented with over the counter multivitamins. Both groups medication free and fasted. | Participants referred to the Arkansas Children's Hospital Research Institute and Dept Pediatrics, University of Arkansas. | Siblings of children with Down syndrome. | DSM-IV for autistic disorder plus diagnostic interview. | Plasma homocysteine, cystathionine, cysteine, tGSH & GSSG measured in all participants. The same parameters were measured before and after 3 mo. folinic acid (800 μg) & betaine (1000 mg) and additional month on same regimen plus vitamin B12 (75 μg\kg) for the intervention study. | 3 I4 |
Adams et al. 2004 [73] (USA) | 24 cases, 11 controls | Cases 4.9 ± 1.4 y, 92%M Controls 6-9 y | Mail out to Greater Phoenix Chapter of the Autism Society of America and the Southwest Autism Research Centre. | Not stated. Appears to be from the same mail out. | Diagnosis of an autism spectrum disorder by a psychiatrist or developmental paediatrician. | Plasma vitamin B6. | 4 |
James et al. 2006 [47] (USA) | 80 cases 73 controls | Cases 7.3 ± 3.2 y (3-14 y), 89% M Controls 10.8 ± 4.1 y, gender not stated. Medication and supplement free. Fasted. | Participants referred from autism clinics of participating physicians in New York and Florida. | Participants of studies of children with Down syndrome or cystic fibrosis. These studies had 53 controls combined including 35 siblings of children with Down's syndrome. | DSM-IV, ADOS or CARS for autistic disorder. | Plasma homocysteine, cystathionine, cysteine, cysteinylglycine, tGSH, fGSH, GSSG. | 2 |
Rose et al. 2008 [50] (USA) | 242 cases, 75 controls | Cases aged 6.9 ± 2.9 y (3-14 y) Controls aged 10.8 ± 4.1. Gender not stated. Fasted. | Participants referred by the Dennis Develop- mental Center at the University of Arkansas for Medical Sciences and from clinics of participating physicians in New York and Florida. | As for James 2006. | DSM-IV and ADOS or CARS. | tGSH, fGSH, GSSG. Cases stratified by ALAD polymorphism. | 2 |
Pasca et al. 2006 [74] (Romania) | 12 cases, 9 controls | Cases 8.3 ± 2.8 y, 75% M Controls aged 8.3 ± 1.8 y 66% M Medication and supplement free. | Not stated. | Not stated. | DSM-IV for autistic disorder. | Plasma homocysteine and GPx activity. | 3 |
Shinohe et al. 2006 [75] (Japan) | 18 cases, 19 controls | Cases 21.2 ± 2.1 y, (18-26 y) 100% M Controls 22.2 ± 2.2 y, (18-26 y) 100%M Medication free. | Advocacy groups in Nagoya and Hamamatsu cities | Recruited through advertisements in Hamamatsu city. | DSM-IV, ADI-R for autistic disorder. | Serum glutamate, glycine and serine. Objective behavioural scores. | 9 |
Adams et al. 2006 [76] (USA) | 11 cases, 11 controls | Cases 7.2 ± 1.4 y, 73%M Controls 7.8 ± 1.2 y, 91%M Both groups were not supplemented with vitamin B6 for the last two months. | Arizona residents | Arizona residents. | Diagnosis of an autism spectrum disorder by a psychiatrist or developmental paediatrician. | Plasma vitamin B6. | 3 |
Adams et al. 2007 [59] (Australia) | 17 cases, 16 controls | Cases 2-16 years. Controls age not stated | Not stated. | Not stated. | DSM-IV for autistic disorder. | Plasma homocysteine. | 4 |
Suh et al. 2008 [77] (USA) | 31 cases, 11 controls | Cases 4.17 ± 1.3 y, 84%M Controls 6.9 ± 1.6 y, 82%M Medication and supplementation free. Not stated whether fasting. | Pfeiffer Clinic | Pfeiffer Clinic. | DSM-IV, ADI-R for autism spectrum disorders. | Plasma homocysteine, cystathione, cysteine, tGSH, cysteinyl-glycine. | 5 |
Jory & McGinnis 2008 [78] (Canada) | 20 cases, 15 controls | Cases 3.9 ± 1.7 y, 80% M Controls 3.87 ± 1.1 y 40% M Medication and supplement free. Fasted. | Not stated. Parent assertion, hard copy confirmation not sought. | Not stated. | DSM-IV for autistic disorder. | Erythrocyte selenium levels. | 2 |
Vojdani et al. 2008 [79] (USA) | 1027 cases, 113 controls | Cases 2-15 y, 75%M Controls aged 5-15, gender not stated | Participating clinicians from 10 clinics. | Children without autism attending the laboratory for allergy testing who obtained normal results. | DSM-IV and/or ICD-10 For autistic disorder. | Correlation between glutathione and natural killer cell (NK) activity. NK activity and treatment with glutathione. | 3 |
James et al. 2009 [80] (USA) | 10 case lymphoblastoid cell lines 10 control lymphoblastoid cell lines | Cases 7.8 ± 3.1 y 100%M Controls 27.7 ± 9.1 y 100%M. | AGRE | Coriell Cell Repository. No documented behavioural or neurological disorders. | DSM-IV for autistic disorder | Intracellular glutathione redox status, effect of thimerosal induced and nitrosative oxidative stress on GSH:GSSG. | 5 |
James et al. 2009 [48] (USA) | 48 cases, 42 controls | Cases 4.8 ± 0.8 y, 82%M Controls 4.5 ± 0.9 y, gender not stated. Supplement free and fasted. | Not stated. | Not stated. No history of developmental delay or neurological symptoms. | DSM-IV for autistic disorder and CARS > 30 | Plasma homocysteine, cysteine, cysteinylglycine, tGSH, fGSH, GSSG before and after 3 mo. intervention with folinic acid (400 μg) and vitamin B12 (75 μg/kg). | 4 I4 |
Al-Gadani et al. 2009 [81] (Saudi Arabia) | 30 cases, 30 controls | Cases 3-15 y, 73%M Controls 3-15 y, 67%M Medication and supplementation free. Fasted. | Not stated. | Not stated. | DSM-IV for autistic disorder. | Plasma GSH and GSH-Px activity. | 4 |
Pasca et al. 2009 [60] (Romania) | 15 cases, 13 controls. | Cases 5.1 ± 0.45 y, 87%M Age and gender matched. Supplement free. Fasted. | Not stated. | Not stated. | DSM-IV-R for autistic disorder, PDD-NOS or Asperger's Syndrome. | Plasma homocysteine, cysteine, cystathionine, serine, glycine. Whole blood tGSH. | 6 |
Pastural et al. 2009 [82] (Canada) | 15 cases, 12 controls | Cases 7.9 y (2-13 y) 100%M Controls 8.7 y (4-17 y) 75%M | Enrolled by Jonty Foundation | 9/12 siblings 3/12 community controls with no family history of autism, age not gender matched. | DSM-IV for autistic disorder. | Plasma homocysteine, cysteine and tGSH. Glutamate toxicity in neuronal, astrocyte and hepatocyte cell cultures. | 2 |
Mostafa et al. 2010 [83] (Egypt) | 44 cases, 44 controls | Cases median 8 y (3.5-12 y), 68%M Controls median 8 y (4-12 y), | Patients attending the Pediatric Neuro-Psychiatric Clinic, Children's Hospital, Ain Shams University | Siblings of children with minor illnesses attending the Out- patients' Clinic, Children's Hospital, Ain Shams University. | DSM-IV for autistic disorder. | Plasma GPx activity | 7 |
Vergani et al. 2011 [84] (Italy) | 28 cases, 32 controls | Cases 2-6 y, 75%M Controls 62.5%M | Not stated. | Not stated. | DSM-IV for autistic disorder. | Erythrocyte GPx activity. | 3 |
Al-Yafee et al. 2011 [85] (Saudi Arabia) | 20 cases 20 controls | Cases (3-16 y), 100%M, 100% IQ < 80. Controls 3-16 y, 100% M. | Autism Research and Treatment Centre clinic. | Well Baby Clinic, King Khaled University Hospital. | ADI-R and ADOS and Developmental, dimensional diagnostic interview. | Total glutathione, oxidised glutathione, tGSH:GSSG, glutathione reductase and gluthathione-s-transferase activity. | 5 |
Tirouvanziam et al. 2011 [86] (USA) | 27 cases 20 controls | Cases 7.0 ± 2.3 y, 77.8%M Controls 7.3 ± 2.5 y, 45%M | Community referrals. | Community advertisements. | ADI-R and ADOS for autistic disorder. ADI-R score 7-10 plus ADOS criteria for autism for PDD-NOS. | Platelet poor plasma glutamine, serine and glycine. | 5 |
Adams et al. 2011 [87] (USA) | 55 cases 44 controls | Cases 10.0 ± 3.1 y, 89%M Controls 11.0 ± 3.1 y, 89%M | Autism Society of Greater Phoenix and Arizona Division of Developmental Disorders. | Autism Society of Greater Phoenix and Arizona Division of Developmental Disorders. | Prior diagnosis by a child psychiatrist or developmental paediatrician. | Plasma glutamate, serine, GSH and GSSG. Selenium (whole blood and erythrocyte). | 6 |
Case Control Level III-3
| |||||||
Aldred et al. 2003 [88] (UK) | 23 cases (12 autistic disorder, 11 Asperger's syndrome), 32 parents, 23 siblings. | Cases Autism 16.4 ± 9.04 y, 92%M Aspergers 15.7 ± 8.63 y, 91%M Parents 44.1 ± 6.9 y, 44%M Siblings 16.5 ± 6.4 y, 39%M | Child psychiatric out-patient clinics in Dublin and Tipperary. | Children admitted to Birmingham Children's Hospital for trauma or minor elective surgery. | DSM-IV for autistic disorder or Asperger's Syndrome. | Plasma serine and glycine. | 5 |
Arnold et al. 2003 [89] | 36 cases (mixed autistic disorder and PDD-NOS) (10 gluten/casein free diet). 24 controls. | Cases Aged < 5 years, gender unknown. Controls Age and gender matched with cases on a regular diet. | Retrospective medical records from Kirsch Developmental Services Center or the Genetic Consultation Clinic at the University of Rochester School of Medicine & Dentistry 1996-1998. | Children with developmental delay not autism. Source not stated. | DSM-IV supported by CARS or the pervasive Developmental Disorders Screening Test. | Plasma glutamine. | 5 |
Geier & Geier 2009 [90] (USA) | 28 cases (20 autistic disorder, 8 other ASD) 64 controls for cysteine and 120 controls for glutathione measurements. | Cases 5.8 ± 2.7 y, 82% M 50% mild, 50% severe autism. Controls 2-16 y. Gender unknown. | Dallas/Fort Worth, Texas area. | Prospective samples from non- autistic children aged 2-16 y collected by the participating laboratory. | CARS > 30. Mild autism CARS 30-38.5 Severe autism CARS > 38.5 | Cysteine, reduced and oxidised glutathione. | 3 |
Geier & Geier 2009 [91] (USA) | 38 cases (28 10 other ASD) Controls as above. | Cases 6.0 ± 2.6 y, 89.5% M Controls as above. | As above. | As above | CARS > 30 | As above. | 3 |
Sankar 1979 [92] (USA) | 19 cases | Age within the range 5-16 y, 100%M Medication and supplement free for 3 weeks prior to fasted blood draw. | Children admitted to Creedmoor State Hospital | Used reference ranges from literature. | Onset from infancy with severe emotion-al isolation; failure to relate to objects & persons; failure to develop speech & communication. If speech present, it is a non-communicative type. Stereotypy of motor behaviour. | Serum vitamin B6. | 4 |
Khaludeenin & Philpott 1980 [93] (USA) | 9 cases | Cases mean 9 y, 78%M | Consecutive cases at Philpott clinic | Used reference range from literature. | Not provided | Plasma cystine, cystathione, glutamic acid and vitamin B6. | |
Level IV (Case series)
| |||||||
Geier & Geier 2006 [66] (USA) | 16 cases | Cases 5.9 ± 2.1 y | Consecutive pre-pubertal age children (≤ 11 y) with a previous diagnosis of regressive autism or PDD-NOS presenting as an outpatient at the Genetic Centres of America between Nov. 2004 and Nov. 2005. | Reference range provided by participating laboratories. | Not provided, relied on previous diagnosis. | Plasma cysteine and reduced glutathione, serum cystathionine and cysteine. | |
Level IV (Case report)
| |||||||
Moretti et al. 2005 [54] (USA) | 1 case | Case aged 6 y, F | Not stated. | n/a | ADOS, ADI-R for autistic disorder. | Cerebral spinal fluid homocysteine. | |
Genetic studies
| |||||||
Bowers et al. 2011 [94] (USA) | 318 families (1,149 individuals including 457 children) plus 3,327 participants from independent AGRE families for replication. | Cases 77.6% M, 321 sibships, Caucasian 91.68%, American black 0.22%, unknown 8.1%. | Autism Genetic Resource Exchange. | Family members of cases from the Autism Genetic Resource Exchange. | ADI-R and ADOS for autism spectrum disorders. | 308 SNPs of 42 candidate genes related to glutathione. | 4 |
Ming et a l. 2010 [95] (USA) | 103 cases, (101 autistic disorder, 2 PDD-NOS) including 68 case trios. | Cases 86%M | New Jersey Center for Outreach & Services for the Autism Community and Department of Pediatrics UMDNJ. | Not relevant. | ADI-R and ADOS-G for autistic disorder. | GPx-1 polymorphisms. | 3 |
Rose et al. 2008 [50] (USA) | 451 cases, 251 controls | Cases aged 6.9 ± 2.9 y (3-14 y) Controls aged 10.8 ± 4.1. Gender not stated. | Participants referred by the Dennis Developmental Center at the University of Arkansas for Medical Sciences and from clinics of participating physicians in New York and Florida. | Glutathione values from controls in James 2006. | DSM-IV and ADOS or CARS. | tGSH, fGSH, GSSG stratified by ALAD polymorphism. | 4 |
Buyske et al. 2006 [96] USA) | 54 case parent trios 172 controls | 45 cases diagnosed as autistic disorder using both instruments, 9 diagnosed as autistic disorder using one instrument and PDD- NOS using the other. | New Jersey Center for Outreach Services for the Autism Community and the Dept of Pediatrics, UMDNJ -Robert Wood Johnson Medical School. | UMDNJ clinics and individuals married into dominant pedigrees of other disorders. | ADI-R and ADOS-G for autistic disorder. | GST-M1 polymorphisms | 4 |
James et al. 2006 [47] (USA) | 360 cases 205 controls (comprising 73 children and 132 adult females). | Cases 7.3 ± 3.2 y (3-14 y), 89% M Controls 10.8 ± 4.1 y, gender not stated (n = 73) plus adult females of child bearing age (n = 132). | Participants referred from autism clinics of participating physicians in New York and Florida. | Participants of studies of Down syndrome, cystic fibrosis and a congenital heart failure risk study. | DSM-IV, ADOS or CARS for autistic disorder. | GST-M1 and T1 polymorphisms. | 3 |
Serajee et al. 2004 [97] (USA) | 196 case parent trios (581 individuals). | Not stated. | Autism Genetic Resource Exchange. Random selection of one affected sibling from each multiplex family. | Not relevant. | DSM-IV for autism spectrum disorder. | GST-P1 polymorphisms. | 6 |
Golse et al. 1978 | Sankar et al. 1979 | Khaleel uddin & Philpot 1980 | Rolf et al. 1993 | Visconti et al. 1994 | D'Eufe mia et al. 1995 | Yorbik et al. 2002 | Sogut et al. 2003 | Aldred et al. 2003 | James et al. 2004 | Adams et al. 2004 | James et al. 2006 | Pasca et al. 2006 | Shinohe et al. 2006 | Adams et al. 2006 | Adams et al. 2007 | Rossign ol et al. 2007 | Suh et al.2008 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1. Selection | ||||||||||||||||||
Case definition | 0 | 2 | 0 | 1 | 2 | 2 | 1 | 2 | 1 | 1 | 1 | 1 | 1 | 2 | 1 | 2 | 1 | 1 |
Representativeness | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Selection of controls | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 1 |
Definition of controls | 0 | 0 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 2 | 0 | 1 | 0 | 2 |
2. Comparability | ||||||||||||||||||
Control for confounding | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
3. Exposure | ||||||||||||||||||
Ascertainment | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Method same for cases/controls | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
Overall score
|
1
|
4
|
3
|
4
|
4
|
5
|
4
|
5
|
5
|
3
|
4
|
2
|
2
|
9
|
3
|
4
|
2
|
5
|
Jory & McGinnis 2008 | Rose et al. 2008 | Vojdani et al. 2008 | James et al. 2009 | James et al. 2009 (in vitro) | Al-Gadani et al. 2009 | Pasca et al. 2009 | Pastural et al. 2009 | Geier & Geier 2009 | Adams et al. 2009 | Mostafa et al. 2010 | Vergani et al. 2011 | Al-Yafee et al. 2011 | Adams et al. 2011 | Tirouvanzium et al. 2011 | Max score | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 Selection | ||||||||||||||||
Case definition | 1 | 1 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 2 | 1 | 2 | 1 | 1 |
2
|
Representativeness | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
1
|
Selection of controls | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
2
|
Definition of controls | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 2 | 1 |
2
|
2 Comparability | ||||||||||||||||
Control for confounding | 0 | 0 | 0 | 1 | 1 | 1 | 2 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 2 |
2
|
3 Exposure | ||||||||||||||||
Ascertainment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
1
|
Method same for cases/controls | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
1
|
Overall score |
2
|
2
|
3
|
4
|
5
|
4
|
6
|
2
|
3
|
3
|
7
|
3
|
5
|
5
|
5
|
9
|
Bowers et al. 2011 | Ming et al. 2010 | Buyske et al. 2006 | James et al. 2006 | Rose et al. 2006 | Serajee 2004 | Max Score | |
---|---|---|---|---|---|---|---|
1 Selection | |||||||
Case definition | 2 | 2 | 1 | 1 | 1 | 2 |
2
|
Representativeness | 0 | 0 | 0 | 0 | 0 | 0 |
1
|
Selection of controls | trios | trios | trios | 0 | 0 | trios |
2
|
Definition of controls | n/a | n/a | n/a | 0 | 0 | n/a |
2
|
2 Comparability | |||||||
Control for confounding | n/a | n/a | n/a | 0 | 0 | n/a |
n/a
|
3 Exposure | |||||||
Ascertainment | 0 | 0 | 0 | 0 | 0 | 0 |
1
|
Method same cases/controls | 1 | 1 | 1 | 1 | 1 | 1 |
1
|
4 Genetics | |||||||
HW equilibrium | 1 | 0 | 1 | 1 | 1 | 1 |
1
|
Power calculations | n/a | 0 | 1 | 0 | 0 | 1 |
1
|
Control multiple comparisons | 0 | 0 | 0 | 0 | 1 | 1 |
1
|
Population stratification | n/a | n/a | 0 | 0 | 0 | n/a |
1
|
Overall score
|
4
|
3
|
4
|
3
|
4
|
6
|
13
|
Risk of bias | Bertoglio et al. 2011 | James et al. 2009 | Adams et al. 2009 | Rossignol et al. 2007 | James et al. 2004 |
---|---|---|---|---|---|
Randomisation | Uncertain | Open label | Uncertain | Open label | Open label |
Concealment of allocation | Low risk | Open label | Low risk | Open label | Open label |
Blinding | Low risk | Open label | Low risk | Open label | Open label |
Incomplete outcome data | High risk | Low risk | High risk | Low risk | Low risk |
Selective reporting | High risk | Low risk | High risk | Low risk | Low risk |
Overall score
| 5 | 4 | 5 | 4 | 4 |
In vitro studies of the γ-glutamyl cycle
Model | Metabolite | Study | Cases1 | Controls1 | P values | Overall finding2 | Comments |
---|---|---|---|---|---|---|---|
Lymphoblastoid cell lines | Free glutathione | James et al. 2009 [80] | 21.72 ± 4.3 | 26.48 ± 3.5 | 0.021 | lower | Whole cell etract - intracellular glutathione |
1.75 ± 0.3 | 2.64 ± 0.7 | 0.001 | lower | Mitochondria - intracellular glutathione | |||
19.8 ± 4.1 | 23.5 ± 4.5 | < 0.04 | lower | Whole cell extract - without nitrosative stress | |||
17.4 ± 3.9 | 18.3 ± 4.1 | Whole cell extract - with nitrosative stress | |||||
Oxidised glutathione | James et al. 2009 [80] | 0.36 ± 0.06 | 0.29 ± 0.07 | < 0.001 | higher | Whole cell extract - intracellular glutathione | |
0.37 ± 0.11 | 0.26 ± 0.12 | 0.059 | higher | Mitochondria - intracellular glutathione | |||
0.26 ± 0.08 | 0.19 ± 0.04 | < 0.04 | higher | Whole cell extract - without nitrosative stress | |||
0.51 ± 0.35 | 0.48 ± 0.30 | Whole cell extract - with nitrosative stress | |||||
Free: oxidised glutathione | James et al. 2009 [80] | 61.81 ± 10.6 | 99.14 ± 33.5 | < 0.001 | lower | Whole cell extract - intracellular glutathione | |
5.06 ± 1.3 | 11.63 ± 3.9 | < 0.001 | lower | Mitochondria - intracellular glutathione | |||
19.8 ± 4.1 | 23.5 ± 4.5 | < 0.04 | lower | Whole cell extract - without nitrosative stress | |||
17.4 ± 3.9 | 18.3 ± 4.1 | Whole cell extract - with nitrosative stress |
Metabolites and cofactors of the γ-glutamyl cycle and trans-sulphuration pathway
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 | 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 |
Study | NK Activity (LU) | GSH (ng/3 × 106PBMCs) | Significance | Finding |
---|---|---|---|---|
Vojdani et al. 2008 | 0-10 | 610 ± 286 | ANOVA F = 3.99, P < 0.05 | Direct correlation between cellular levels of reduced glutathione and NK lytic activity. |
[79] | 11-20 | 947 ± 458 | ||
21-50 | 1760 ± 895 | |||
51-100 | 2280 ± 1341 |
Intervention studies
Study | Intervention | Dose & duration | Study size | Findings | Comments |
---|---|---|---|---|---|
Interventions involving folate cycle metabolites
| |||||
Bertoglio et al. 2010 [64] | Methyl-cobalamin | 64.5 μg/kg methyl-cobalamin or placebo injected every third day 6 wks washout period). | 32+ cases started the trial of which 30 finished. | Overall, no significant difference in GSH, GSH: GSSG or behaviouraloutcomes. ↑ GSH, ↑GSH:GSSG and improved behavioural outcomes in 9/30 children. | Primary outcome behavioural response. Findings for GSH and tGSH:GSSG presented as bar charts for responder group only. Dispersion and units not provided. |
James et al. 2009 [48] | Folinic acid + methyl-cobalamin | 400 μg folinic acid bd + 75 μg/kg methyl-cobalamin injected every third day 3 mo. | 48 cases selected for low SAM:SAH or GSH: GSSG. | ↑ homocysteine, ↑ cystathione ↑ cysteine, ↑ tGSH & ↑tGSH: GSSG. | Excluded 26% of cases because normal SAM: SAH and/or tGSH: GSSG. Following the intervention, tGSH:GSSG was still significantly lower in cases than controls. There was no change in SAM or SAH levels. |
James et al. 2004 [46] | Folinic acid + betaine | 800 μg folinic acid + 1,000 μg betaine bd 3 mo. | 8 cases | ↑ homocysteine, ↑ cystathione ↑ cysteine, ↑ tGSH, ↑tGSH: GSSG, ↓SAH & ↓adenosine | Improved but did not normalise tGSH and GSSH. |
Folinic acid + betaine + | As above + 75 μg/kg methyl- | 8 cases | ↑ homocysteine, | Normalised tGSH & tGSH: | |
methyl-cobalamin | cobalamin injected twice weekly 1 mo. | ↑cystathionine, ↑cysteine, ↑ tGSH, ↑tGSH: GSSG, ↓GSSG | GSSG. Improved but did not normalise GSSG. | ||
Moretti et al. 2005 [54] | Folinic acid | 0.5 mg/kg/d folinic acid for 2 wk, 1.0 mg/kg/d thereafter 3 mo. | 1 case | Normalised (↓) cerebral spinal fluid homocysteine. | |
Other interventions
| |||||
Chelation therapy | Glutathione (180 mg) or placebo cream daily for 7 days followed by 10 mg/kg DMSA in 3 doses/day for 3 days to screen for high urinary | 64 cases | Significantly ↓ variance in erythrocyte glutathione levels 1-2 months after one round of DMSA treatment. | Topical glutathione had no effect on erythrocyte glutathione. Behavioural instruments not validated | |
excretion of metal ions. 'High | 26 DMSA | No data provided for | for measurement of autism | ||
excreters' from the topical | 15 placebo | post intervention gluta- | severity. ADOS(diagnostic | ||
glutathione arm given a further | thione. | test) administered pre and | |||
6 rounds of DMSA and those | post second intervention, | ||||
from the topical placebo arm | but not at baseline. | ||||
given 6 rounds of a placebo. | |||||
Rossignol et al. 2007 [49] | Hyperbaric oxygen therapy (HBOT) | 1.3 atm (n = 12) or 1.5 atm (n = 6) for 45 mins × 40 sessions (ie 4.6 times/wk × 9 wk) | 18 cases | No significant difference in plasma tGSH:GSSG before or after either intervention. |
Genetic studies of the γ-glutamyl cycle and trans-sulphuration pathway
Study | Study Size | Population | Gene | Polymorphism | P value | Finding |
---|---|---|---|---|---|---|
Glutathione-s- transferases
| ||||||
GST-M1
| ||||||
Buyske et al. 2006 [96] | 172 controls (54 case parent trios) | U.S. (non-Hispanic Caucasians) | GST-M1 | GST-M1*0 | 0.028 (Pearson's) 0.046(Likelihood ratio) | Homozygotes with deletion at increased risk. |
James et al. 2006 [47] | 360 cases 205 controls | U.S. (97% Caucasian) | GST-M1 | GST-M1*0 | 0.0671,2 | Suggestive increase of null genotypes in cases. |
Bowers et al. 2011 [94] | 318 families (1,149 individuals) | U.S. | GST-M1 | tag SNPs | ns | No association. |
James et al. 2006 [47] | As above | As above | GST-M1 + | GST-M1*0: RFC | 0.000141,2 | This combination more frequent |
RFC | 80A > G interaction | in cases. OR 3.78(95%CI 1.80, 7.95). | ||||
GST-P1
| ||||||
Serajee et al. 2004 [97] | 196 case parent trios | U.S. | GST-P1 | rs947894 | ns | |
Bowers et al. 2011 [94] | As above | GST-P1 | tag SNPs | ns | ||
GST-T1
| ||||||
James et al. 2006 [47] | As above | As above | GST-T1 | GST-T1*0 | ns2 | |
Glutathione peroxidase
| ||||||
Ming et al. 2010 [95] | 101 cases (results | U.S | GPx-1 | GCG repeat | ||
based on 68 trios | ALA5 | ns | ||||
and 3 duos) | ALA6 | 0.017 | Under-transmitted | |||
ALA7 | ns | |||||
Bowers et al. 2011 [94] | As above | As above | GPx-1 | tag SNPs | ns | |
ALAD
|
Single SNP analysis
| |||||
Rose et al. 2008 [50] | 451 cases | U.S. | ALAD | rs1800435 | 0.023 | GC OR 1.65 (1.05-2.63) |
251 controls | 0.6 | CC OR 1.82 (0.14-95.73) | ||||
Interaction analysis
| ||||||
ALAD rs1800435*GC | ALAD/RFC GG/AA reference | |||||
RFC 80A > G combined | 0.162 | ALAD/RFC GC/AA OR 2.25 (0.72-7.06) | ||||
genotype associated with | 0.001 | ALAD/RFC GCAG OR 3.98 (1.70-9.32) | ||||
increased risk of autism. | 0.237 | ALAD/RFC GC/GG OR 1.79 (0.68-4.73) | ||||
Study
|
Study Size
|
Population
|
Gene
|
Polymorphism
|
P value
|
Finding
|
Other relevant genes
|
Single SNP analysis
| |||||
Bowers et al. 2011 [94] | As above | CTH | rs12737233 | 0.002 (0.30)3 | CT OR 0.91 (0.65-1.28) | |
(Validation study in 3327 individuals from independent
| TT OR 4.83 (1.85-12.59) | |||||
AGRE families)
| GCLC | rs761141 | 0.02 (0.10)3 | CT OR 2.10 (1.20-3.69) TT OR 1.67 (0.91-3.09) | ||
rs524553 | 0.003 (0.08)3 | CT OR 2.70 (1.47-4.98) | ||||
TT OR 2.23 (1.16-4.28) | ||||||
DPP-1 | tag SNPs | ns | ||||
DPP-2 | tag SNPs | ns | ||||
DPP-3 | tag SNPs | ns | ||||
GGT-7 | tag SNPs | ns | ||||
GGT-5 | tag SNPs | ns | ||||
GGT-LA4 | tag SNPs | ns | ||||
GPx-2 | tag SNPs | ns | ||||
GPx-4 | tag SNPs | ns | ||||
GPx-7 | tag SNPs | ns | ||||
GST-A2 | tag SNPs | ns | ||||
GST-A3 | tag SNPs | ns | ||||
GST-A4 | tag SNPs | ns | ||||
GST-K1 | tag SNPs | ns | ||||
GST-M2 | tag SNPs | ns | ||||
GST-M3 | tag SNPs | ns | ||||
GST-M4 | tag SNPs | ns | ||||
GST-M5 | tag SNPs | ns | ||||
GST-O1 | tag SNPs | ns | ||||
GST-T2 | tag SNPs | ns | ||||
GST-Z1 | tag SNPs | ns | ||||
GST-CD | tag SNPs | ns | ||||
Interaction analysis
| ||||||
CTH rs12737233*C | OR 3.78 (95%CI 2.36-6.04) | |||||
GLRX3 rs370834*A | ||||||
GLRX rs17216887*G | ||||||
allele combination associated | ||||||
with increased risk of autism. |
Studies of glutathione related enzyme activity
Source | Study | Study size (Male:Female) | Cases1 | Controls1 | P values | Overall finding | Units of measure |
---|---|---|---|---|---|---|---|
Glutathione peroxidase
| |||||||
Plasma | Yorbik et a l. 2002 [71] | 45 cases, (39 M, 6 F) 41 controls, (35 M, 6 F) | 270 ± 40 | 390 ± 80 | < 0.05 | low | U/L |
Söğüt et al. 2003 [72] | 27 cases, (16 M, 11 F) 30 controls, (16 M, 14 F) | 40.9 ± 11.3 | 24.2 ± 6.3 | < 0.0001 | high | U/L | |
Al-Gadani et al. 2009 [81] | 30 cases, (22 M, 8 F) 30 controls, (20 M, 10 F) | 2468.8 ± 999.3 | 1438.5 ± 611.2 | < 0.05 | high | U/L | |
Mostafa et al. 2010 [83] | 44 cases, (30 M,14 F) 44 controls, (30 M, 14 F) | 441.5 (100)2 | 589 (176)2 | < 0.001 | low | U/L | |
Erythrocytes | Golse et al. 1978 [63] | 24 cases, (17 M, 7 F) 6 controls, (2 M, 4 F) | 4.7 ± 0.29 | 8.45 ± 0.95 | < 0.0001 | low | U/g haemoglobin |
Yorbik et al. 2002 [71] | 45 cases, (39 M, 6 F) 41 controls, (35 M, 6 F) | 28.72 ± 2.64 | 38.01 ± 5.03 | < 0.05 | low | U/g haemoglobin | |
Pasca et al. 2006 [74] | 12 cases, (9 M, 3 F) 9 controls, (6 M, 3 F) | 7.75 ± 0.93 | 7.45 ± 0.65 | ns | ns | U/g haemoglobin | |
Vergani et al. 2011 [84] | 28 cases (21 M, 7 F) 32 controls (20 M, 12 F) | ns | ns | nmols NADPH/min/mg haemoglobin | |||
Platelets | Golse et al. 1978 [63] | 36 cases, (15 M, 21 F) 21 controls, (9 M, 12 F) | 51.53 ± 1.61 | 46.56 ± 2.69 | ns | ns | U/g platelet protein |
Glutathione reductase
| |||||||
Plasma | Al-Yafee et al. 2011 [85] | 20 cases (20 M, 0 F) 20 controls (20 M, 0 F) | 70.25 ± 16.35 | 60.19 ± 15.42 | 0.052 | trend high | U/L |
Glutathione-s-transferase
| |||||||
Plasma | Al-Yafee et al. 2011 [85] | 20 cases (20 M, 0 F) 20 controls (20 M, 0 F) | 0.42 ± 0.18 | 0.73 ± 0.37 | 0.002 | low | μmol/min/ml |