I'm pretty new to this as I've just discovered I am homozygous for mthfr 1298. The heavy fatigue started about 3 -4 years ago. Was able to find a decent doc last year who found that my thyroid levels were borderline low and put me on 60mg Armour thyroid. This helped decrease my fatigue slightly. Just the past two months I've had more testing done during which I discovered the mthfr 1298 polymorphism. So I'm sure this has been a huge part of why I've struggled with low energy levels and ongoing low level depression. Testing also revealed the following: Low vitamin D (I'm now taking 5,000 a day) Very High c reactive protein levels (inflammation?) Ferritin on the low side (30 out of a 15-150 range) B12 very high (1500 level where as the max range was 900) B6 in normal range. Estrogen/testosterone and progesterone all within normal range (I'm female) Two months ago I started on the methyfolate supplements as soon as I found out about the 1298 polymorphism. The supplements are 800mcg methylfolate and 800mcg methylb12. After a month I didn't notice a difference so I asked my doc for a rx for Deplin 15mg. Have been taking that for almost a month and still don't feel any better. (Fortunately I haven't felt any worse either so I am able to tolerate high levels of methylfolate). At this point I'm unsure of what to do next. Do I need more testing? Different supplements? I've read the those with the 1298 polymorphism have low levels of bh4 and glutathione. Do I need to try supplementing with those? Any advice is greatly appreciated!!