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Table 3 Overview of studies included in the systematic review

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

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 2009 [65, 67] (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
  1. 1Unless otherwise stated, children with epilepsy, genetic, mental health or metabolic conditions were excluded.
  2. DSM Diagnostic and Statistical Manual of Mental Disorders CARS Childhood Autism Rating Scale
  3. ADI-R Autism Diagnostic Interview (Revised) ADOS Autism Diagnostic Observation Schedule
  4. ASD Autism Spectrum Disorder PDD-NOS Pervasive developmental disorder -not otherwise specified
  5. AGRE Autism Genetic Resource Exchange UMDNJ University of Medicine and Dentistry of New Jersey
  6. ALAD delta-amino levulinic acid dehydratase GPx-1 Glutathione peroxidase
  7. SHMT1 Serine hydroxyl methyl transferase GST-P1 Glutathione-s-transferase Pi 1
  8. tGSH Total glutathione GSSG Oxidised glutathione
  9. GST Glutathione-S-transferase HBOT Hyperbaric oxygen therapy
  10. * Based on baseline data for cases and controls