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. | Â |
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. | Â |
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 |