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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