BH4 can be depleted by ammonia which could be a by-product of upregulation of the trans-sulfuration pathway. If the BHMT pathway is down-regulated and / or the cystathione beta synthase gene is defective (up-regulated) then too much of homocysteine may be directed to make ammonia and alpha keto-glutarate which leads to glutamate often. On the other hand heavily driving the methylation cycle may still result in increased trans-sulfuration activity (depends on other factors I wager) on its own. Also people with COMT -/- may often have less catecholamines due to more effective cleanup, which is almost guaranteed if SAMe is present which is one of inherent goals of methylation support. I am MTHFR A1298c +/- but also COMT +/- and VDR -/- so methyl cleanup is a problem for me. Lastly if I may ask what sort of neurological defects? The reason I ask is many people associate neurological symptoms with dopamine and serotonin (both of which are affected by BH4 of course). But only some symptoms fit into that category. If anything far more neurological symptoms (including pain, seizures, insomnia, over-stimulation of nerves, etc.) are due to glutamate-GABA imbalances and over-activation of NMDA receptors. I know this one all too well since my auto-immune disease is Stiff Person Syndrome which means my body seeks to destroy glutamic acid decarboxylase enzymes in my CNS (and pancreas) hence my high levels of corticosteroids. Ironically high methylation support can stimulate glutamate imbalances by virtue of the efficient conversion histidine into glutamate using THF as a cofactor for the last step in the process. This leads to low histamine but higher glutamate.