Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency

Abstract

Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

“…For MTHFR deficiency (OMIM 6070993) the majority of mutations are private and neither type nor location of mutation correlates with clinical phenotype (Froese et al 2016). Genetic testing for MTFHR deficiency should be interpreted with caution since there are numerous polymorphisms in this gene, which have been related to various common disorders and conditions.…”

Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: Data from the E‐HOD registry

“…Remethylation of Hcy to Met is performed by the enzymes methionine synthase (MS, defective in cblG disease) and methionine synthase reductase (MSR, defective in cblE disease). Deficiency of the enzyme 5,10‐methylenetetrahydrofolate reductase (MTHFR) leads to impaired provision of 5‐methylenetetrahydrofolate, resulting in decreased MS capacity . Remethylation also depends on the cofactor methylcobalamin, which requires a unique set of intracellular cobalamin (Cbl) transport and processing mechanisms.…”

Isolated and Combined Remethylation Disorders

“…Over 126 disease-causing mutations have been reported to date. 16 In addition to the severe deficiency, a number of functional polymorphisms have been described, which increase the risk of developing cardiovascular disease, Alzheimer disease, diabetes mellitus, neural tube defects, and some forms of cancer. Two of these functional polymorphisms, c.677C>T and c.1298A>C, are associated with reduced MTHFR activity.…”