S-adenosylmethionine (SAM) is an over-the-counter supplement marketed at improving mood and overall mental health. Although well known for decades to be an antidepressant, very little data exists with respect to the impact of oral SAM administration on whole brain concentrations of specific neurotransmitters. Male Sprague-Dawley rats were fed a AIN93 diet and provided a daily oral supplement of SAM (10 mg/ kg bwt), a level that is comparable to the recommended dosage for humans. After 20 d of treatment, rats were killed and whole brain samples were analyzed for the concentration of dopamine, norepinephrine, and serotonin, as well as their respective transporters. Oral SAM supplementation increased the intracellular concentration of SAM in the liver and brain approximately 2- and 4-fold respectively. S-adenosylhomocysteine (SAH) concentrations were significantly elevated by oral SAM treatment in the brain, but were not affected in liver tissue. For whole brain tissue, SAM also markedly increased the concentration of dopamine and norepinephrine 15-fold and 50%, respectively, whereas it did not have a statistically significant impact on serotonin concentrations. Moreover, SAM administration was without effect on the concentrations of the transporters for dopamine, norepinephrine, or serotonin. Therefore, oral daily provision of SAM to rats at a dosage recommended for humans dramatically increased the intracellular concentrations of specific neurotransmitters, dopamine in particular. The significant increase in brain SAH concentrations may result in the allosteric inhibition of a number of SAM-dependent methyltransferases that function to metabolize dopamine and norepinephrine, thereby elevating their tissue concentrations.

Results: Eighteen subjects ranged from 21 months to 8.5 years at the time of AGIL-AADC administration. At baseline no child had developed full head control, sitting unassisted or standing capability, consistent with the published, natural history cohort of 82 severe AADC patients who never achieve these motor milestones over their lifetime. Of the 18 subjects given AGIL-AADC, 15 are now two-years, and 7 five-years post-gene therapy. Subjects had evidence of sustained de novo dopamine production by F-DOPA PET imaging. Compared to the natural history cohort, after AGIL-AADC administration 5/15 gain full head control (p<0.0001); 4/15 gain sitting unassisted (p=0.0004) and one subject standing with support at 2 years. After five years 4/7 gain full head control and sit unassisted (p<0.0001) and 2/7 stand with support (p=0.0054). Adverse events, in general, were associated with overall disease state.

Conclusions: Gene therapy with AGIL-AADC is a potential therapeutic for patients with AADC deficiency to achieve and maintain motor milestones inconsistent with the natural disease course


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Figure 6: Effects of SAM supplementation on DNA methylation. (A) Total methylation level of liver DNA was decreased

What is AADC Deficiency?

Aromatic Amino Acid Decaboxylase (AADC) deficiency is a neurotransmitter metabolism disorder inherited in an autosomal recessive fashion.

The enzyme of AADC is responsible for making dopamine and serotonin by decarboxylation of L-DOPA and 5-HTP (precursors of dopamine and serotonin for those who don't know)>

This deficiency leads to a lack of serotonin and dopamine and all their resulting metabolites. 

The diagnosis can be confirmed through genetic testing.

AADC is rare. The most common symptoms are developmental delay, oculogyric crises and dystonia.

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