Fundamental Role of Methylenetetrahydrofolate Reductase 677 C → T Genotype and Flavin Compounds in Biochemical Phenotypes for Schizophrenia and Schizoaffective Psychosis

Abstract

The Mental Health Biomarker Project (2010-2016) explored variables for psychosis in schizophrenia and schizoaffective disorder. Blood samples from 67, highly characterized symptomatic cases and 67 gender and age matched control participants were analyzed for methyl tetrahydrofolate reductase (MTHFR) 677C → T gene variants and for vitamin B6, B12 and D, folate, unbound copper, zinc cofactors for enzymes in the methylation cycle, and related catecholamine pathways. Urine samples were analyzed for indole-catecholamines, their metabolites, and oxidative-stress marker, hydroxylpyrolline-2-one (HPL). Rating scales were Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale, Global Assessment of Function scale, Clinical Global Impression (CGI) score, and Social and Occupational Functioning Assessment Scale (SOFAS). Analysis used Spearman's correlates, receiver operating characteristics and structural equation modeling (SEM). The correlative pattern of variables in the overall participant sample strongly implicated monoamine oxidase (MAO) enzyme inactivity so the significant role of MAO's cofactor flavin adenine nucleotide and its precursor flavin adenine mononucleotide (FMN) within the biochemical pathways was investigated and confirmed as 71% on SEM of the total sample. Splitting the data sets for MTHFR 677C → T polymorphism variants coding for the MTHFR enzyme, discovered that biochemistry variables relating to the wild-type enzyme differed markedly in pattern from those coded by the homozygous variant and that the hereozygous-variant pattern resembled the wild-type-coded pattern. The MTHFR 677C → T-wild and -heterozygous gene variants have a pattern of depleted vitamin cofactors characteristic of flavin insufficiency with under-methylation and severe oxidative stress. The second homozygous MTHFR 677TT pattern related to elevated copper:zinc ratio and a vitamin pattern related to flavin sufficiency and risk of over-methylation. The two gene variants and their different biochemical phenotypes govern findings in relationship to case-identification, illness severity, duration of illness, and functional disability in schizophrenia and schizoaffective psychosis, and establish a basis for trials of gene-guided precision treatment for the management of psychosis.

Keywords: MTHFR 677C → T polymorphisms; copper; psychosis; riboflavin; schizophrenia.

Figure 1

A diagrammatic outline of the biochemical territory covered in the MHBP and presented in this manuscript. Enzymes: BHMT, betaine homocysteine methyltrasferase; COMT, catechol-o-methyl-transferase; CBS, cystathione beta synthase, MAT, methionine adenosyltransferase, MTHFR, methylenetetrahydrofolate reductase, SAMe, S-denosylmethionine, MT, methyltransferase, SAHH, S-adenosylhomocysteine-hydrolase, MSR, methionine sulfoxide reductase, MS, methionine synthase. Vitamin cofactors: vitamin B6 (pyridoxine), vitamin B12 (cobalamin), vitamin C, folic acid, 5 methyl tetrahydrofolate. Mineral enzyme cofactors: free (unbound) copper (Cu), zinc. Intermediate substrates: BH4, tetrahydrobiopterin BH2 – dihydrobiopterin; DMG, Dimethylglycine; DOPAL, dihydroxyphenylacetaldehyde; DOPAC, dihydroxyphenylacetic acid; DOPEGAL, dihydroxyphenylglycolaldehyde; DOMA, dihydroxymandelic acid; DHPG, dihydroxyphenylglycal; DOPA, dihydroxyphenylalanine; FAD, flavin adenine dinucleotide, 5HIAA, 5-hydroxyindolacetic acid, HVA, homovanillic acid, MAO, monoamine oxidase; MHMA, 3-methoxy-4-hydroxymandelic acid; MHPG, 4-hydroxy-3-methoxyphenylglycol; SAH, S-adenosylhomocysteine; TMG, trimethylglycine, VMA, vanillylmandelic acid. HPL, urinary hydroxyhemopyrroline-2-one.

Figure 2

Variables examined by SEM analysis in the context of their relationship within the biochemical pathways of interest.

Figure 3

Summary outcome when there is no MTHFR Polymorphism governing activity of the MTHFR enzyme, and where folate, vitamins, and flavins are low. Where correlation significance index [SI] = [(1 – P-value) × 1000], caseness for schizophrenia or schizoaffective disorder relates to NA [SI = 100] and HPL/Creatinine [SI = 93], in a setting where catecholamines held significant correlates with the wild-type enzyme and where NA relates to SIR [SI = 100], GSI [SI = 100], DOI [SI = 100], and NA relates to NA/MHMA [SI = 100]. With respect to vitamin levels, Low Vitamin B6 relates to SOFAS [SI = 94], CGI [SI = 93], and DOI [SI = 86]. Low vitamin D relates to SIR [SI = 79], CGI [SI = 59], SOFAS [SI = 45], and low folate levels relate to Psychosis Caseness [SI = 49]. All catecholamines formed highly significant positive correlates with HPL. All catecholamines held significant inverse correlates with folate, vitamin B6 and vitamin D. Free copper to zinc ratio formed no correlates of significance within this data-set. Within the data set, homocysteine held significant inverse correlates with folate and vitamin B6. UNDER-METHYLATION DIMENSION CHARACTERISTICS. HIGH oxidative stress levels. HIGH catecholamine levels, where elevated DA and NA predominate. LOW vitamin B6, D and folate levels. LOW unbound Cu levels with tendency to high DA. Tendency to higher histamine and higher 5 HIAA excretion.

Figure 4

Summary outcome when there is a homozygous 677TT polymorphism governing low activity of the MTHFR enzyme, but where folate and flavin availability in the presence of normal hormonal conditions and sufficient sources of flavins and folate from dietary and gastrointestinal sources. Where significance index [SI] = [(1 − P-value) × 1000], caseness for psychosis is only marginally related to HPL/Creatinine [SI = 33]. Caseness was also marginally related to Free Cu/Zn ratio [SI = 33], where Free Cu/Zn also relates to GAF [SI = 43] and CGI [SI = 30]. Catecholamine held no significant correlates within this data set. Levels of folate are low in relationship to high homocysteine [SI = 84], and B12 [SI = 45] and high homocysteine levels correlate with low B6 levels [SI = 14]. There is no inference in the correlates to suggest that vitamin D levels are low. Flavin sufficiency is implied. Less severe oxidative stress severity and disability compared to the wild-type enzyme. High Cu levels promote DA metabolism to NA, with tendency to lower DA than NA levels. Vitamin levels are normal or increased. Tendency to lower histamine and no 5HIAA excretion. RISK OF OVER-METHYLATION EXISTS.