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Oxidative Stress
Control Autistic
Table 1
Children Children
p
n=33 n=20
value
Methionine (µmol/L) 30.6 ± 6.5 19.3 ± 9.7 0.001
SAM (nmol/L) 90.0 ± 16.2 75.8 ± 16.2 0.01
SAH (nmol/L) 20.1 ± 4.3 26.1 ± 5.4 0.001
Homocysteine (µmol/L) 6.3 ± 1.2 5.4 ± 0.9 0.01
Adenosine (µmol/L) 0.28 ± 0.16 0.39 ± 0.19 0.05
Cysteine (µmol/L) 210 ± 18.5 163 ± 14.6 0.001
Total glutathione (µmol/L) 7.9 ± 1.8 4.1 ± 0.5 0.001
Oxidized Glutathione
0.3 ± 0.1 0.55 ± 0.2 0.001
(nmol/L)
GSH/GSSG Ratio 25.5 ± 8.9 8.6 ± 3.5 0.001
Because methionine is the precursor for cysteine, the rate-limiting amino acid for
glutathione synthesis, it is not surprising that low methionine levels are associated with
the low cysteine and glutathione levels in these children. The significant increase in
adenosine is consistent with the increase in SAH since adenosine binds to the active site
of SAH hydrolase and inhibits its activity. The increase in SAH is of concern in autistic
children because of its ability to inhibit SAM-dependent methyltransferase activity and
cellular methylation reactions. The reduction in total glutathione (GSH) and increase in
oxidized glutathione resulted in a 3- fold reduction in the ratio of reduced (active) GSH to
oxidized glutathione (GSSG). This is of major concern because it reflects a significant
decrease in antioxidant capacity associated with an increase in oxidative stress in the
autistic children.
After nutritional intervention for only 3 weeks, a highly significant increase in plasma
methionine, cysteine, and glutathione levels were associated with almost 2- fold increase
in the ratio of reduced to oxidized glutathione (GSH/GSSG). These results would suggest
that supplementation with folinic acid and betaine had a strong positive impact on
antioxidant capacity in the autistic children. Although SAM levels were significantly
increased, the decrease in SAH and adenosine levels did not reach statistical significance
due to high inter- individual variability. Eight of the 20 children continued the
intervention with betaine and folinic acid for an additional 3-4 months. After the
extended intervention period, SAM levels increased to 112 nmol/L, SAH levels
decreased to 17 nmol/L, and adenosine levels decreased to 0.18 µmol/L; all well within
normal ranges.
After p
Table 2 Baseline
Intervention value
Methionine (µmol/L) 19.3 ± 9.7 28.0 ± 7.2 <0.001
75.8 ±
SAM (nmol/L) 81.4 ± 10 <0.03
16.2
SAH (nmol/L) 26.1 ± 5.4 25.1 ± 8.4 NS
Homocysteine (µmol/L) 5.4 ± 0.9 7.0 ± 1.0 <0.002
Adenosine (µmol/L) 0.39 ± 0.2 0.33 ± 0.1 NS
Cysteine (µmol/L) 163 ± 14.6 225 ± 37 <0.002
Total glutathione (µmol/L) 4.1 ± 0.5 5.7 ± 1.0 <0.001
Oxidized Glutathione
0.55 ± 0.2 0.48 ± 0.2 NS
(nmol/L)
GSH/GSSG Ratio 8.6 ± 3.5 13.8 ± 4.8 <0.001
Targeted nutritional intervention with folinic acid and betaine successfully increased both
methylation capacity and glutathione antioxidant capacity in the 20 participating autistic
children, especially after 3-4 months of intervention. A list of supportive nutrients or
synthetic precursors is presented below.
It is well-established that females have lower homocysteine levels than males. After
menopause, however, the difference in homocysteine levels between sexes narrows,
suggesting that estrogen regulates the rate and activity of methionine turnover and
transsulfuration 35 . Consistent with this possibility, females have been shown to have
higher MAT activity than males in humans 36 . Estrogen has been shown to increase
plasma glutathione levels in a dose-dependent manner in experimental animals 37 . By
enhancing the activity of glucose-6 phosphate dehydrogenase, estrogen supports the
regeneration of reduced glutathione from NADPH and increases antioxidant potential 38 .
Mitochondrial glutathione levels and antioxidant capacity have been reported to be higher
in females than in males 39 . Taken together, the evidence suggests that both cellular
methylation capacity and antioxidant activity are higher in females than males. The
increased rate of methionine transsulfuration and glutathione antioxidant activity in
females may have a protective effect against the development of autism.