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.

Vitamin B6 and Its Role in Cell Metabolism and Physiology

“…The biosynthesis of epinephrine, serotonin, and dopamine is independently influenced by a universal methyl donor, S-adenosylmethionine (SAM), a critical intermediate in the methionine-cycle [ 140 , 155 , 156 , 157 , 158 , 159 , 160 ] ( Figure 5 ). Consequently, several studies have shown that a deficiency in vitB 6 correlates with a deficiency in folate and cobalamin [ 138 , 140 , 153 , 154 ].…”

Role of Key Micronutrients from Nutrigenetic and Nutrigenomic Perspectives in Cancer Prevention

“…A significant polymorphism at the level of the MTHFR gene is C677T, which induces increased homocysteine concentrations and DNA hypomethylation. Furthermore, it has been shown to be associated with neural tube defects, white matter integrity in Alzheimer patients, venous thrombosis, colorectal cancer survival, breast cancer and leukemia [143,144,145,146,147,148,149]. Continuing on, the links between MTHFR polymorphisms and lung cancer have also been extensively studied.…”

Pharmacodynamic Gene Testing in Prader-Willi Syndrome

“…This epigenetic process of DNA methylation is the one-carbon metabolic pathway essential for DNA and neurotransmitter synthesis. When MTHFR function is impaired, abnormalities of the methylation cycle lead to oxidative stress (Fryar-Williams, 2016). As a result, serum folate may decrease, and serum homocysteine may increase.…”

“…The data from the NIH PWS Registry indicates that over the past 10 years, there has been a downward trend in the age that children with PWS first receive treatment with selective serotonin reuptake inhibitors (SSRIs). Nearly 50% of children age 5-12 year were receiving SSRIs, and this increased to 70% in the 12-21 years age group, often together with an atypical antipsychotic medication (Forster, 2019). Polypharmacy leads to drug-drug interactions, a significant problem contributing to medical and psychiatric co-morbidity (Olashore and Rukewe, 2017).…”