Table 1.

Association of SAM (metabolism) and transmethylation pathway with several neuropsychiatric diseases in early life stages

Disease	Condition	Target	Methylation effect	Read-out	Cell/tissue	Reference
NTDs	Excessive methionine (≥ 5 mM)	Genomic DNA	↓	SAM/SAH↓; cranial mesenchyme density↓	Mouse embryos	[84]
	Periconceptional maternal folic acid	IGF2	↑	A significant correlation between the maternal SAMe concentration and IGF-2 methylation of the child	Venous blood	[88]
	Folic acid deficiency methionine deficiency	H3K4	↓		Human K562 cells	[162]
	MTX Betaine addition	Global DNA Siah1b Prkx	↓ ↓ ↓	5-MeTHF, 5-FoTHF, SAMe↓ Hcy, SAH↑ Hcy↓, methionine↑, SAMe↑	NTD mice model Venous blood	[86, 87]
Rett’s syndrome	Folate-betaine addition Folinic acid addition Folinic acid addition			Mutant MeCP2; binding affinities for methylated DNA↓ Dimethylglycine↑, betaine↑, Hcy↓ Objective signs of clinical improvement (N) CSF 5-MTHF↑ Objective signs of clinical improvement (N) CSF 5-MTHF↑, SAMe-, SAH-, SAM/SAH- plasma SAMe↑, SAH↑, SAM/SAH-	Venous blood Venous blood CSF CSF Venous blood	[92, 93, 95, 96]
DS	CBS overexpression Children with DS Methionine addition folinic acid addition Children with DS	ASPA ITGA2B lymphocyte DNA mtDNA	↓ ↓ ↑ ↓	Plasma SAH↑, Aβ↑, SAM/SAH↓ Plasma Hcy↓, SAMe↓, SAH↓ Cystathionine↑, cysteine↑ SAM↑, SAH↑, adenosine↑ tHcy↑, methionine↑, SAM↑, SAH↑ cystathionine↑, cysteine↑, betaine↑, choline↑, SAH↑, SAM↑, SAM/SAH↓ Mitochondrial SAMe↓; SAMC↑; GSH↓ total glutathione↓	Venous blood Venous blood Lymphoblastoid cells Venous blood Lymphoblastoid cells	[98–100, 103]
	Vitamin B12 deficiency Hyperhomocysteinema	Overall DNA	↑ ↓	Vitamin B12↓; Hcy↑; FA ,vitamin B12 ↓with increasing age	Venous blood	[102]

SAH = S-adenosylhomocysteine; NTD = neural tube defect; SAMe = S-adenosyl-L-methionine; IGF-2 = insulin-like growth factor 2; MTX = methotrexate; 5-MeTHF = 5-methyltetrahydrofolate; 5-FoTHF = 5-formyltetrahydrofolate; Hcy = homocysteine; MeCP2 protein 2; CSF = cerebrospinal fluid; 5-MTHF = 5-methyltetrahydrafolate; DS = Down’s cystathionine β-synthase; Aβ = amyloid-β; tHcy = total homocysteine; GSH = Glutathione; FA = folic acid