MTHFR – homocystinuria due to methylene tetrahydrofolate reductase deficiency

MTHFR encodes the 5,10-methylenetetrahydrofolate reductase enzyme critical for remethylation of homocysteine to methionine. Homozygous or compound heterozygous loss-of-function variants cause autosomal recessive homocystinuria characterized by hyperhomocysteinemia, hypomethioninemia, and a spectrum of neurologic and vascular manifestations.

Genetic evidence supports a definitive association between MTHFR and homocystinuria due to methylene tetrahydrofolate reductase deficiency. Since initial case reports in 1994, more than 200 affected individuals have been described with biallelic MTHFR variants (PMID:8892013; PMID:24323041). A landmark series of four siblings harboring homozygous c.1069C>T (p.Arg357Cys) demonstrated segregation in three additional relatives (PMID:10767000).

The variant spectrum includes missense mutations (e.g., c.1069C>T (p.Arg357Cys)), loss-of-function alleles (nonsense, frameshift, splice-site), and the common thermolabile variant c.665C>T (p.Ala222Val). Recurrent alleles such as c.665C>T confer partial activity and mild hyperhomocysteinemia, whereas rare coding and regulatory mutations ablate enzyme function.

Functional studies corroborate pathogenicity. Homozygous Mthfr knockout mice recapitulate hyperhomocysteinemia, global DNA hypomethylation, cerebellar pathology, and aortic lipid deposition, establishing a mechanism of metabolic toxicity (PMID:11181567). Yeast complementation of human MTHFR mutants (e.g., p.Arg377Cys) confirms loss of enzymatic activity and increased thermolability (PMID:10551815). The p.Leu439Pro variant induces proteasomal degradation, highlighting defective protein stability (PMID:33290257).

Although the common c.665C>T (p.Ala222Val) allele has been variably associated with neural tube defects, case–control studies have not confirmed a significant risk in some populations (PMID:9341863).

Integration of comprehensive genetic and functional data establishes MTHFR deficiency as a definitive autosomal recessive cause of homocystinuria, for which early molecular diagnosis enables timely interventions such as betaine supplementation and folate repletion.

Key Take-home: MTHFR deficiency is a definitive AR homocystinuria with neurologic and vascular phenotypes wherein molecular testing guides early treatment.

References

• Journal of inherited metabolic disease • 1996 • Molecular genetics of methylenetetrahydrofolate reductase deficiency. PMID:8892013
• JAMA neurology • 2014 • Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. PMID:24323041
• American journal of medical genetics • 2000 • Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical, biochemical, and molecular study of the family. PMID:10767000
• Human molecular genetics • 2001 • Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. PMID:11181567
• The Journal of biological chemistry • 1999 • Functional characterization of human methylenetetrahydrofolate reductase in Saccharomyces cerevisiae. PMID:10551815
• Aging • 2020 • The 1316T>C missenses mutation in MTHFR contributes to MTHFR deficiency by targeting MTHFR to proteasome degradation. PMID:33290257
• Human genetics • 1997 • Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects. PMID:9341863

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