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IEMbase 0072: MTHFR-related 5,10-methylenetetrahydrofolate reductase deficiency

Scope

Field Value
IEMbase ID 72
Nosology 21.8.03.01
Gene MTHFR
External IDs OMIM:236250
Generated mapping UNMAPPED
Candidate DisMech targets Inborn_Disorder_of_Methionine_Cycle_and_Sulfur_Amino_Acid_Metabolism.yaml#MTHFR deficiency; also covered in Homocystinuria.yaml
Review date 2026-07-07

IEMbase phenotype signal

IEMbase represents this as autosomal recessive MTHFR-related 5,10-methylenetetrahydrofolate reductase deficiency, with alternate labels homocystinuria due to deficiency of MTHFR activity and MTHFR. Treatability is marked yes.

The characteristic biochemical signal includes abnormal plasma homocysteine and abnormal CSF 5-methyltetrahydrofolic acid. Additional rows include plasma methionine and CSF biogenic amine metabolites such as 5-HIAA and HVA.

Characteristic clinical rows include developmental regression and intellectual disability. Additional rows include apnea, ataxia, psychotic behavior, behavioral disorder, depression, feeding difficulty, gait disturbance, hydrocephalus, infantile spasms, microcephaly, muscle weakness, peripheral neuropathy, ovarian insufficiency, psychiatric disturbance, myoclonic and tonic-clonic seizures, thromboembolic episodes, and selected endocrine rows.

Treatment rows include betaine, carnitine, folate, and methionine.

DisMech phenotype coverage

The generated mapping is a false negative rather than a true absence. DisMech contains local MTHFR coverage in two places:

  • Inborn_Disorder_of_Methionine_Cycle_and_Sulfur_Amino_Acid_Metabolism.yaml has a MTHFR deficiency subtype and a MTHFR Remethylation Deficiency pathophysiology node.
  • Homocystinuria.yaml contains an explicit MTHFR remethylation pathway deficiency branch and an MTHFR genetic block.

Together these cover biallelic MTHFR variants, reduced methylenetetrahydrofolate reductase activity, abnormal folate-dependent remethylation, elevated homocysteine, low or low-normal methionine, nonclassical homocystinuria, autosomal recessive inheritance, and genetic counseling. The methionine-cycle entry also covers pathway-level diagnosis and betaine-based remethylation support.

Concordance and completeness

Judgement: false negative; local subtype/branch coverage exists.

The best canonical mapping depends on desired mapping granularity. If IEMbase records can map to pathway-group subtypes, use Inborn_Disorder_of_Methionine_Cycle_and_Sulfur_Amino_Acid_Metabolism.yaml#MTHFR deficiency. If disease-level clinical coverage is preferred, Homocystinuria.yaml is the most detailed local target for MTHFR-deficiency homocystinuria.

IEMbase adds granular neurologic and psychiatric rows, CSF 5-MTHF, CSF biogenic amine metabolites, carnitine and methionine treatment rows, and endocrine features that are not central in the local entries. DisMech is stronger for the remethylation mechanism and shared homocystinuria context.

Curation actions

  • Treat the generated UNMAPPED status as a false negative.
  • Prefer a subtype-level mapping to Inborn_Disorder_of_Methionine_Cycle_and_Sulfur_Amino_Acid_Metabolism.yaml#MTHFR deficiency, with Homocystinuria.yaml as a detailed secondary local target.
  • Consider IEMbase's neurologic, psychiatric, CSF 5-MTHF, and treatment detail as future enrichment for the MTHFR branch.