MTHFD1 deficiency is an autosomal recessive inborn error of folate-mediated one-carbon metabolism caused by biallelic loss-of-function variants in MTHFD1, which encodes the cytoplasmic trifunctional C1-tetrahydrofolate synthase. The single polypeptide carries three activities - 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, and 10-formyltetrahydrofolate synthetase - and is the principal entry point for one-carbon units into the cytosolic folate pool. The clinical core is megaloblastic anemia with a combined immunodeficiency severe enough to have been described as SCID, frequently with hyperhomocysteinemia and, in several patients, atypical hemolytic uremic syndrome. The "with or without hyperhomocysteinemia" in the MONDO label is real: one reported patient developed megaloblastic anemia, infection and autoimmune disease without ever becoming hyperhomocysteinemic, so the biochemical marker is not obligate and its absence does not exclude the diagnosis. What makes this entry worth reading rather than filing as one more folate disorder is that the causal pathway was actually discriminated rather than assumed. Two mechanisms were available a priori: impaired purine synthesis, the classical route to severe combined immunodeficiency, and impaired de novo thymidylate synthesis, the classical route to megaloblastic anemia. Flux measurements in patient fibroblasts settled it - formate incorporation into methionine fell by 90% and into dTMP by 50%, while flux through de novo purine biosynthesis was unaffected. So a single lesion in nuclear de novo thymidylate biosynthesis, acting through uracil misincorporation and DNA double-strand breaks, accounts for both the anemia and the immunodeficiency. The purine route is not merely unproven here; it was looked for and was not there. The disorder is folate-responsive, which is unusual and clinically decisive. Folinic acid supplementation reversed the immune phenotype in one family to the point that all prophylactic therapy was discontinued, and the treatment target is the metabolic block rather than its downstream consequences.
Ask a research question about MTHFD1 Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: MTHFD1 Deficiency
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
- CIMAH
- methylenetetrahydrofolate dehydrogenase 1 deficiency
- MTHFD1 deficiency
- C1-THF synthase deficiency
description: >-
MTHFD1 deficiency is an autosomal recessive inborn error of folate-mediated one-carbon
metabolism caused by biallelic loss-of-function variants in MTHFD1, which encodes the
cytoplasmic trifunctional C1-tetrahydrofolate synthase. The single polypeptide carries
three activities - 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate
cyclohydrolase, and 10-formyltetrahydrofolate synthetase - and is the principal entry point
for one-carbon units into the cytosolic folate pool.
The clinical core is megaloblastic anemia with a combined immunodeficiency severe enough to
have been described as SCID, frequently with hyperhomocysteinemia and, in several patients,
atypical hemolytic uremic syndrome. The "with or without hyperhomocysteinemia" in the MONDO
label is real: one reported patient developed megaloblastic anemia, infection and autoimmune
disease without ever becoming hyperhomocysteinemic, so the biochemical marker is not obligate
and its absence does not exclude the diagnosis.
What makes this entry worth reading rather than filing as one more folate disorder is that the
causal pathway was actually discriminated rather than assumed. Two mechanisms were available a
priori: impaired purine synthesis, the classical route to severe combined immunodeficiency, and
impaired de novo thymidylate synthesis, the classical route to megaloblastic anemia. Flux
measurements in patient fibroblasts settled it - formate incorporation into methionine fell by
90% and into dTMP by 50%, while flux through de novo purine biosynthesis was unaffected. So a
single lesion in nuclear de novo thymidylate biosynthesis, acting through uracil misincorporation
and DNA double-strand breaks, accounts for both the anemia and the immunodeficiency. The purine
route is not merely unproven here; it was looked for and was not there.
The disorder is folate-responsive, which is unusual and clinically decisive. Folinic acid
supplementation reversed the immune phenotype in one family to the point that all prophylactic
therapy was discontinued, and the treatment target is the metabolic block rather than its
downstream consequences.
disease_term:
preferred_term: combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
term:
id: MONDO:0060611
label: combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
parents:
- Inborn Disorder of Folate Metabolism
- Combined Immunodeficiency
references:
- reference: PMID:21813566
title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
- reference: PMID:25633902
title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
- reference: PMID:25548164
title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
- reference: PMID:27707659
title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
inheritance:
- name: Autosomal recessive
description: >-
Biallelic MTHFD1 variants, compound heterozygous in every family reported to date rather
than homozygous. Reported allele pairs include a splice-site plus a missense variant, a
missense plus a nonsense variant, and - in a family where standard exome analysis found only
one heterozygous change - a maternal missense variant paired with a paternally inherited
exon 13 deletion that was recovered only by manually inspecting exome coverage depth.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both parents carry a single mutation and an unaffected sibling carries neither mutation."
explanation: Segregation in the founding pedigree establishes biallelic recessive inheritance.
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A deletion involving exon 13 that was shared with their father was identified."
explanation: >-
The second, paternally inherited allele in this family is a structural deletion invisible
to standard variant calling, which is why the case initially appeared monoallelic.
pathophysiology:
- name: MTHFD1 Trifunctional Enzyme Loss of Function
description: >-
Biallelic MTHFD1 variants disable the cytoplasmic trifunctional C1-tetrahydrofolate
synthase. Reported alleles hit the enzyme in several ways: c.517C>T (p.Arg173Cys) alters a
critical arginine in the NADP-binding site, c.727+1G>A and c.1674G>A disrupt splicing, an
exon 13 deletion removes coding sequence outright, and c.673G>T (p.Glu225*) truncates the
protein. The shared consequence is loss of the enzyme that condenses formate with
tetrahydrofolate.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: MTHFD1
term:
id: hgnc:7432
label: MTHFD1
notes: >-
No mouse model of this disease exists, and the reason is worth recording so nobody adds the
wrong one. Homozygous Mthfd1 disruption in mouse is early embryonic lethal, so there is no
viable null. The available Mthfd1S(+/-) mouse models the common R653Q synthetase
polymorphism, which is a distinct entity from this Mendelian disorder - a low-penetrance
susceptibility allele studied for neural tube and congenital heart defect risk, not a model
of biallelic MTHFD1 deficiency. Human patient fibroblasts are therefore the only system in
which this disease's mechanism has been measured.
molecular_functions:
- preferred_term: 5,10-methylenetetrahydrofolate dehydrogenase activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0004488
label: methylenetetrahydrofolate dehydrogenase (NADP+) activity
- preferred_term: 10-formyltetrahydrofolate synthetase activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0004329
label: formate-tetrahydrofolate ligase activity
- preferred_term: 5,10-methenyltetrahydrofolate cyclohydrolase activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0004477
label: methenyltetrahydrofolate cyclohydrolase activity
downstream:
- target: Depletion of the Cytosolic One-Carbon-Loaded Folate Pool
causal_link_type: DIRECT
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein. Mutations affecting this arginine have previously been shown to affect enzyme activity."
explanation: >-
Identifies the founding missense allele and the structural basis for its effect on
catalytic activity.
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel."
explanation: >-
Establishes allelic heterogeneity across missense, splice and nonsense classes in two
independent families.
- reference: PMID:32414565
reference_title: "Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "There was no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts from any of the four patients."
explanation: >-
The first direct measurement of MTHFD1 enzyme function in patients, and the strongest
evidence that the disease alleles abolish catalytic activity rather than merely reducing it.
- reference: PMID:32414565
reference_title: "Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "MTHFD1 protein expression determined by Western blotting in fibroblast extracts from three of the patients was markedly decreased compared to expression in wild type cells (between 4.8 and 14.3% of mean control values)."
explanation: >-
Quantifies residual protein. Note the dissociation: a fourth patient retained ~44% of
control protein yet still had no detectable dehydrogenase activity, so protein level and
catalytic function are not interchangeable readouts in this disease.
- name: Depletion of the Cytosolic One-Carbon-Loaded Folate Pool
description: >-
MTHFD1 is the primary entry point for single carbons into cytosolic folate metabolism,
condensing formate with tetrahydrofolate to generate 10-formyl- and
5,10-methylenetetrahydrofolate. Losing it starves the downstream folate-dependent pathways
of activated one-carbon units. The starvation is not uniform: patient fibroblast flux
measurements show it falls hardest on methionine synthesis, next on thymidylate synthesis,
and not at all on purine synthesis.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: tetrahydrofolate metabolic process
modifier: DECREASED
term:
id: GO:0046653
label: tetrahydrofolate metabolic process
- preferred_term: one-carbon metabolic process
modifier: DECREASED
term:
id: GO:0006730
label: one-carbon metabolic process
downstream:
- target: Impaired Nuclear de novo Thymidylate Biosynthesis
causal_link_type: DIRECT
- target: Impaired Homocysteine Remethylation to Methionine
causal_link_type: DIRECT
- target: Failure to thrive
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Global developmental delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "MTHFD1 functions to condense formate with tetrahydrofolate and serves as the primary entry point of single carbons into folate-dependent one-carbon metabolism in the cytosol."
explanation: States the enzyme's position as the entry point whose loss depletes the pool.
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected."
explanation: >-
Quantifies the differential depletion across the three downstream pathways in patient
fibroblasts, and is the measurement that discriminates the causal route.
- name: Impaired Nuclear de novo Thymidylate Biosynthesis
description: >-
Nuclear conversion of dUMP to dTMP by thymidylate synthase requires
5,10-methylenetetrahydrofolate, for which MTHFD1 is the main source. Patient fibroblasts
show lower de novo dTMP synthesis with a compensatory rise in salvage-pathway dTMP, and
MTHFD1 protein becomes enriched in the nucleus at the expense of the cytosol - the cell
prioritising thymidylate synthesis over homocysteine remethylation when the enzyme is
limiting. That prioritisation is why the methionine deficit is the larger of the two.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: de novo thymidylate (dTMP) biosynthesis
modifier: DECREASED
term:
id: GO:0006231
label: dTMP biosynthetic process
downstream:
- target: Uracil Misincorporation into Nuclear DNA
causal_link_type: DIRECT
evidence:
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts."
explanation: >-
Directly measures the reduced de novo dTMP synthesis and the salvage-pathway compensation
in cells from the affected proband.
- name: Uracil Misincorporation into Nuclear DNA
description: >-
When dTMP runs short the dUTP/dTTP ratio rises and DNA polymerase incorporates uracil in
place of thymine. Uracil in DNA is elevated in patient fibroblasts. Base-excision repair
then excises the misincorporated uracil, and when opposing lesions are excised close
together the transient abasic sites and nicks are converted into strand breaks.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: base-excision repair of misincorporated uracil
modifier: INCREASED
term:
id: GO:0006284
label: base-excision repair
downstream:
- target: Genome Instability with DNA Double-Strand Breaks
causal_link_type: DIRECT
evidence:
- reference: PMID:26853819
reference_title: "MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Impairments in de novo thymidylate synthesis result in uracil misincorporation into DNA, which leads to single- and double-strand breaks during base-excision DNA repair."
explanation: >-
States the mechanism converting a nucleotide-pool imbalance into physical DNA damage, which
is the step linking the metabolic lesion to the cellular phenotype.
- name: Genome Instability with DNA Double-Strand Breaks
description: >-
Patient fibroblasts carry more double-stranded DNA breaks than controls. Because the damage
is generated during DNA replication, it falls hardest on the two most rapidly proliferating
compartments in the body - erythroid precursors and developing lymphocytes - which is what
gives this metabolic disorder its haematological and immunological presentation rather than
a diffuse one.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: double-strand break repair burden
modifier: INCREASED
term:
id: GO:0006302
label: double-strand break repair
downstream:
- target: Megaloblastic Erythropoiesis
causal_link_type: DIRECT
- target: Lymphocyte Developmental and Proliferative Failure
causal_link_type: DIRECT
evidence:
- reference: PMID:26853819
reference_title: "MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Patient fibroblasts exhibited increased DNA damage (double-stranded DNA breaks) compare to control fibroblasts."
explanation: >-
Measures the double-strand break burden in patient cells. Quoted verbatim including the
source's grammatical slip.
- reference: PMID:26853819
reference_title: "MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These results provide strong evidence for the role of MTHFD1 in nuclear de novo dTMP biosynthesis, and connect impaired MTHFD1 specific activity to both megaloblastic anemia and SCID."
explanation: >-
The authors' own statement that this single pathway accounts for both arms of the clinical
phenotype, which is the claim the downstream edges encode.
- name: Megaloblastic Erythropoiesis
description: >-
Replication-associated DNA damage and nucleotide-pool imbalance in erythroid precursors
produce nuclear-cytoplasmic asynchrony: cytoplasmic maturation proceeds while nuclear
division stalls, giving the enlarged precursors of megaloblastic marrow and an ineffective,
macrocytic anemia.
biological_scale: TISSUE
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: erythroid precursor
term:
id: CL:0000547
label: proerythroblast
downstream:
- target: Megaloblastic anemia
causal_link_type: DIRECT
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid."
explanation: >-
Documents megaloblastic anemia as a presenting feature, and in a patient without
hyperhomocysteinemia, which separates this arm of the mechanism from the methionine arm.
- name: Lymphocyte Developmental and Proliferative Failure
description: >-
Developing lymphocytes are among the most rapidly dividing cells in the body and depend on
de novo thymidylate for clonal expansion, so the same replication-linked DNA damage produces
lymphopenia across all subsets and poor proliferative responses. The immune defect is
quantitative and metabolic rather than a fixed developmental block: in one family in vitro
dendritic cell and lymphocyte function was comparable to healthy volunteers despite
lymphopenia and poor vaccine responses, and the whole phenotype reversed on folinic acid.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
downstream:
- target: Combined immunodeficiency
causal_link_type: DIRECT
- target: Autoimmunity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Lymphopenia
causal_link_type: DIRECT
- target: Recurrent infections
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Routine laboratory data showed lymphopenia involving all subsets and poor response to vaccines."
explanation: >-
Establishes the pan-subset lymphopenia and functional antibody failure that define the
combined immunodeficiency.
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In vitro analysis of dendritic cell and lymphocyte function was comparable to that in healthy volunteers."
explanation: >-
Cells that are present function normally in vitro, supporting a defect of lymphocyte
production and expansion rather than of intrinsic effector capacity.
- reference: PMID:23296427
reference_title: "Severe combined immunodeficiency resulting from mutations in MTHFD1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution."
explanation: >-
An independent patient meeting SCID criteria. Note the reconstitution here was *partial*,
where another family achieved full enough recovery to stop prophylaxis, so the degree of
immune rescue is not uniform across patients.
- name: Impaired Homocysteine Remethylation to Methionine
description: >-
Remethylation of homocysteine to methionine by methionine synthase requires
5-methyltetrahydrofolate derived from the MTHFD1-generated pool. This is the arm the cell
sacrifices when MTHFD1 is limiting, and correspondingly it is the arm with the largest flux
deficit - a 90% fall in formate incorporation into methionine. Patient fibroblasts show
severely reduced methionine formation that does not respond to cobalamin supplementation but
does respond to folic and folinic acid, locating the block on the folate side rather than
the cobalamin side.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: L-methionine biosynthesis by homocysteine remethylation
modifier: DECREASED
term:
id: GO:0071265
label: L-methionine biosynthetic process
downstream:
- target: Systemic Homocysteine Accumulation
causal_link_type: DIRECT
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid"
explanation: >-
The clause describes patient-fibroblast methionine formation from labelled formate, and
localises the block to folate rather than cobalamin availability, which is what makes
folate the rational therapy. Quoted from the clause after the isotope label because the
validator strips bracketed spans from the query side.
- name: Systemic Homocysteine Accumulation
description: >-
Homocysteine that cannot be remethylated accumulates in blood. It is a frequent but not
obligate feature - at least one reported patient with the full haematological and
immunological phenotype never became hyperhomocysteinemic, which is the observation the
MONDO label's "with or without" records.
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
downstream:
- target: Hyperhomocysteinemia
causal_link_type: DIRECT
- target: Thrombotic Microangiopathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency, elevated blood levels of homocysteine and methylmalonic acid, and a selective decreased synthesis of methylcobalamin in cultured fibroblasts."
explanation: Documents elevated blood homocysteine in the founding case alongside aHUS.
- name: Thrombotic Microangiopathy
description: >-
Several patients have developed atypical hemolytic uremic syndrome with microangiopathy,
the recognised vascular complication of severe remethylation defects. The mechanistic route
from hyperhomocysteinemia to endothelial injury is not established in this disorder
specifically, so the edge is recorded as indirect. Notably this arm is also the one that
can leave permanent damage: in the second reported patient every feature resolved on
treatment except the retinopathy.
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
downstream:
- target: Hemolytic-uremic syndrome
causal_link_type: DIRECT
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid."
explanation: >-
Documents microangiopathy and HUS co-occurring with hyperhomocysteinemia, and the
incomplete reversibility of the retinal component.
phenotypes:
- category: Hematologic
name: Megaloblastic anemia
description: >-
Macrocytic anemia with megaloblastic marrow change, present in every reported patient and
usually the presenting problem. It is folate-responsive.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Megaloblastic anemia
term:
id: HP:0001889
label: Megaloblastic anemia
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively."
explanation: >-
Megaloblastic anemia in two further affected siblings, here with a fatal early course.
Quoted verbatim including the source's misspelling of the gene symbol as "MTFHD1".
- category: Immunologic
name: Combined immunodeficiency
description: >-
Impairment of both cellular and humoral immunity, described in the founding case as severe
combined immune deficiency. Unlike most SCID, it is metabolically correctable.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Combined immunodeficiency
term:
id: HP:0005387
label: Combined immunodeficiency
evidence:
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exome sequencing demonstrated MTHFD1 deficiency as a novel cause of a combined immunodeficiency."
explanation: Establishes combined immunodeficiency as the immunological diagnosis.
- category: Immunologic
name: Lymphopenia
description: Reduced lymphocyte counts across all subsets, with poor vaccine responses.
phenotype_term:
preferred_term: Lymphopenia involving all subsets
term:
id: HP:0001888
label: Decreased total lymphocyte count
evidence:
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Routine laboratory data showed lymphopenia involving all subsets and poor response to vaccines."
explanation: Reports the pan-subset lymphopenia directly.
- category: Metabolic
name: Hyperhomocysteinemia
description: >-
Elevated blood homocysteine from the remethylation block. Frequent but explicitly not
obligate; its absence does not exclude the diagnosis.
frequency: FREQUENT
phenotype_term:
preferred_term: Hyperhomocysteinemia
term:
id: HP:0002160
label: Hyperhomocystinemia
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "elevated blood levels of homocysteine and methylmalonic acid"
explanation: Records elevated blood homocysteine in the founding proband.
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia"
explanation: >-
Refutes hyperhomocysteinemia as an obligate feature: a patient with the full
haematological and immunological phenotype who never became hyperhomocysteinemic.
- category: Renal
name: Hemolytic-uremic syndrome
description: >-
Atypical hemolytic uremic syndrome with microangiopathy, reported in the founding case and
in a second family, and reversible on metabolic treatment.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Atypical hemolytic uremic syndrome
term:
id: HP:0005575
label: Hemolytic-uremic syndrome
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency"
explanation: aHUS as a presenting feature of the founding case.
- category: Infectious
name: Recurrent infections
description: >-
Infection is a common presenting event and contributed to the fatal course in the two
siblings who died at nine weeks of age.
frequency: FREQUENT
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis"
explanation: Infection as a contributor to early death in two affected siblings.
- category: Immunologic
name: Autoimmunity
description: >-
Autoimmune disease occurs alongside the immunodeficiency. It is reported in at least two
named patients and enumerated at cohort level in the biochemical review, so it is a
recurring feature rather than an isolated observation.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:42301236
reference_title: "MTHFD1 Deficiency in Two Unrelated Children: Highlights on Phenotypic Spectrum and Response to Folic Acid Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The first patient, a 10-year-old girl, was diagnosed with combined immunodeficiency and autoimmune thyroiditis."
explanation: A named autoimmune diagnosis co-occurring with the combined immunodeficiency.
- reference: PMID:32414565
reference_title: "Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "variable phenotypes, including megaloblastic anemia, atypical hemolytic uremic syndrome, hyperhomocysteinemia, microangiopathy, infections and autoimmune diseases"
explanation: >-
Cohort-level enumeration listing autoimmune disease among the recurring features across
the reported patients.
- category: Ophthalmologic
name: Retinopathy
description: >-
Reported in the patient who presented with microangiopathy and HUS. It is the entry's only
irreversible finding: every other feature in that patient resolved on treatment and the
retinopathy did not.
frequency: VERY_RARE
phenotype_term:
preferred_term: Retinopathy
term:
id: HP:0000488
label: Retinopathy
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid"
explanation: >-
Records both the retinopathy and, by exception, that it alone failed to reverse on
metabolic treatment.
- category: Hepatic
name: Hepatic fibrosis
description: Moderate liver fibrosis, reported in a single patient.
frequency: VERY_RARE
phenotype_term:
preferred_term: Moderate liver fibrosis
term:
id: HP:0001395
label: Hepatic fibrosis
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia"
explanation: >-
Single-patient observation of liver fibrosis, in the same patient who establishes that
hyperhomocysteinemia is not obligate.
- category: Metabolic
name: Metabolic acidosis
description: >-
Severe acidosis contributed to the fatal neonatal course in the two siblings who died at
nine weeks of age.
frequency: VERY_RARE
phenotype_term:
preferred_term: Severe metabolic acidosis
term:
id: HP:0001942
label: Metabolic acidosis
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis"
explanation: >-
Severe acidosis as part of the fatal presentation in two siblings. Bound to HP:0001942
Metabolic acidosis; the deep-research report suggested HP:0002153 for this, which is
Hyperkalemia and would have been wrong.
- category: Growth
name: Failure to thrive
description: >-
Poor growth, reported alongside recurrent infection and megaloblastic anemia as part of the
presenting picture in childhood.
frequency: FREQUENT
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:42301236
reference_title: "MTHFD1 Deficiency in Two Unrelated Children: Highlights on Phenotypic Spectrum and Response to Folic Acid Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both cases presented with unexplained megaloblastic anemia, recurrent sinopulmonary infections, failure to thrive, and developmental delay."
explanation: Failure to thrive in both children of an independent two-patient report.
- category: Neurologic
name: Global developmental delay
description: >-
Developmental delay is part of the phenotype, and neurologic abnormalities were present in
the founding case and in an independent SCID report.
frequency: FREQUENT
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:42301236
reference_title: "MTHFD1 Deficiency in Two Unrelated Children: Highlights on Phenotypic Spectrum and Response to Folic Acid Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both cases presented with unexplained megaloblastic anemia, recurrent sinopulmonary infections, failure to thrive, and developmental delay."
explanation: Developmental delay in both children of an independent two-patient report.
- reference: PMID:23296427
reference_title: "Severe combined immunodeficiency resulting from mutations in MTHFD1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities"
explanation: Neurologic abnormalities as part of the presenting syndrome in a separate patient.
genetic:
- name: MTHFD1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
variants:
- name: c.517C>T (p.Arg173Cys)
description: >-
Missense change to a critical arginine in the NADP-binding site. Recurrent: it is one of
the two alleles in the founding proband and is homozygous in two unrelated Kuwaiti
children, so it spans compound-heterozygous and homozygous genotypes.
functional_effects:
- function: MTHFD1 trifunctional C1-tetrahydrofolate synthase activity
description: >-
Abolishes or severely reduces MTHFD1 function. Enzymology in patient fibroblasts found
no detectable methylenetetrahydrofolate dehydrogenase specific activity in any of four
patients tested.
type: loss-of-function
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein."
explanation: Identifies the allele and the structural basis for its effect.
- reference: PMID:42301236
reference_title: "MTHFD1 Deficiency in Two Unrelated Children: Highlights on Phenotypic Spectrum and Response to Folic Acid Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe 2 unrelated Kuwaiti children with MTHFD1 deficiency caused by a homozygous pathogenic variant [c.517C>T (Arg173Cys)]."
explanation: The same allele in the homozygous state in two unrelated children.
- name: c.727+1G>A
description: Splice donor variant of intron 8, the second allele in the founding proband.
functional_effects:
- function: MTHFD1 trifunctional C1-tetrahydrofolate synthase activity
description: >-
Abolishes or severely reduces MTHFD1 function. Enzymology in patient fibroblasts found
no detectable methylenetetrahydrofolate dehydrogenase specific activity in any of four
patients tested.
type: loss-of-function
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "One mutation (c.727+1G>A) affects the splice acceptor site of intron 8."
explanation: >-
The founding proband's splice allele. Quoted verbatim: the source says "splice acceptor"
for a +1 donor-site position.
- name: c.806C>T (p.Thr296Ile) and c.1674G>A
description: >-
The compound-heterozygous pair in the patient who presented with hyperhomocysteinemia,
HUS, microangiopathy and retinopathy. The second causes exon skipping.
functional_effects:
- function: MTHFD1 trifunctional C1-tetrahydrofolate synthase activity
description: >-
Abolishes or severely reduces MTHFD1 function. Enzymology in patient fibroblasts found
no detectable methylenetetrahydrofolate dehydrogenase specific activity in any of four
patients tested.
type: loss-of-function
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient"
explanation: Names both alleles and the splicing consequence of the second.
- name: c.146C>T (p.Ser49Phe) and c.673G>T (p.Glu225*)
description: >-
The missense plus nonsense pair carried by three affected siblings, two of whom died at
nine weeks of age.
functional_effects:
- function: MTHFD1 trifunctional C1-tetrahydrofolate synthase activity
description: >-
Abolishes or severely reduces MTHFD1 function. Enzymology in patient fibroblasts found
no detectable methylenetetrahydrofolate dehydrogenase specific activity in any of four
patients tested.
type: loss-of-function
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel"
explanation: The allele pair shared across three affected siblings in one family.
- name: Exon 13 deletion
description: >-
A structural deletion invisible to standard exome variant calling, recovered only by
manual inspection of per-exon coverage depth. It is the reason this family initially
appeared to carry a single heterozygous change.
functional_effects:
- function: MTHFD1 trifunctional C1-tetrahydrofolate synthase activity
description: >-
Abolishes or severely reduces MTHFD1 function. Enzymology in patient fibroblasts found
no detectable methylenetetrahydrofolate dehydrogenase specific activity in any of four
patients tested.
type: loss-of-function
evidence:
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A deletion involving exon 13 that was shared with their father was identified."
explanation: The paternally inherited structural allele completing the biallelic genotype.
notes: >-
MTHFD1 encodes the cytoplasmic trifunctional C1-tetrahydrofolate synthase. Disease alleles
are biallelic and span missense variants in the NADP-binding site, splice-site variants
causing exon skipping, nonsense variants, and at least one multi-exon deletion.
gene_term:
preferred_term: MTHFD1
term:
id: hgnc:7432
label: MTHFD1
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two mutations were identified in the MTHFD1 gene, which encodes a protein that catalyses three reactions involved in cellular folate metabolism."
explanation: Establishes MTHFD1 as the disease gene and its trifunctional product.
prevalence:
- population: Worldwide, reported cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Ultra-rare. One patient was on record when the second series was published, which added four
more from two families, and a further family was reported separately. No population rate has
been estimated and none is asserted here.
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified"
explanation: >-
Establishes that a single patient was known before this series, which is the basis for the
cases-in-literature reading.
- reference: PMID:32414565
reference_title: "Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Since the first reported case of severe combined immunodeficiency resulting from MTHFD1 mutations, seven additional patients ascertained through molecular analysis have been reported with variable phenotypes, including megaloblastic anemia, atypical hemolytic uremic syndrome, hyperhomocysteinemia, microangiopathy, infections and autoimmune diseases."
explanation: >-
Updates the reported cohort to eight and enumerates the phenotypic range across it, which
is the basis for the frequencies recorded in this entry.
biochemical:
- name: Absent MTHFD1 Dehydrogenase Activity
presence: PRESENT
notes: >-
Measured in cultured patient fibroblasts. Note the dissociation from protein level: three
patients retained 4.8-14.3% of control MTHFD1 protein and a fourth about 44%, yet none had
detectable dehydrogenase specific activity. Protein abundance is therefore not a
substitute readout for enzyme function in this disease.
evidence:
- reference: PMID:32414565
reference_title: "Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "There was no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts from any of the four patients."
explanation: The direct enzymatic measurement, and the first reported in patients.
- name: Elevated Blood Homocysteine
presence: PRESENT
notes: >-
Frequent but explicitly not obligate: one patient with the full haematological and
immunological phenotype never became hyperhomocysteinemic.
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "elevated blood levels of homocysteine and methylmalonic acid"
explanation: Raised homocysteine in the founding proband.
- name: Elevated Methylmalonic Acid
presence: PRESENT
notes: >-
Raised methylmalonic acid in the founding case is the finding that makes this disorder look
like a cobalamin defect on presentation. It is diagnostically load-bearing in the wrong
direction, which is why the fibroblast cobalamin-versus-folate discrimination matters.
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "elevated blood levels of homocysteine and methylmalonic acid"
explanation: Raised methylmalonic acid alongside homocysteine in the founding proband.
- name: Elevated Uracil in Nuclear DNA
presence: PRESENT
notes: >-
The direct molecular readout of the thymidylate lesion, measured in patient fibroblasts
alongside reduced de novo dTMP synthesis and increased salvage-pathway compensation.
evidence:
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts."
explanation: Measures uracil misincorporation together with the pathway changes that produce it.
experimental_models:
- name: MTHFD1-deficient patient fibroblasts
experimental_model_type: PRIMARY_CELL_CULTURE
publication: PMID:25548164
description: >-
Cultured skin fibroblasts from affected patients. Because homozygous Mthfd1 disruption is
early embryonic lethal in mouse and the only available mouse line models the common R653Q
polymorphism rather than this disease, patient fibroblasts are the sole system in which the
mechanism of MTHFD1 deficiency has been measured. Every mechanistic claim in this entry
that is not a clinical observation comes from them.
modeled_mechanisms:
- target: Impaired Nuclear de novo Thymidylate Biosynthesis
relationship: MEASURES
fidelity: HIGH
model_scale: MOLECULAR
description: >-
Patient-derived and human, carrying the disease genotype, so the thymidylate lesion is
measured rather than inferred from a surrogate.
limitations: >-
Fibroblasts are not an affected tissue. The disease manifests in erythroid precursors and
developing lymphocytes, and the argument that those compartments are hit hardest because
they proliferate fastest is an inference from fibroblast measurements, not something
shown in the affected cells.
readouts:
- name: Formate flux into dTMP
target: Impaired Nuclear de novo Thymidylate Biosynthesis
direction: DECREASED
interpretation: Direct flux measure of the node, reduced by 50%.
evidence:
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected."
explanation: >-
The measurement that both quantifies this node and, by the purine result, excludes the
competing mechanism.
evidence:
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we examined the impact of MTHFD1 loss of function on folate-dependent purine, dTMP, and methionine biosynthesis in fibroblasts from the proband with MTHFD1 deficiency"
explanation: Establishes the model system and what was measured in it.
- target: Impaired Homocysteine Remethylation to Methionine
relationship: MEASURES
fidelity: HIGH
model_scale: MOLECULAR
description: >-
The same system localises the block to folate rather than cobalamin, which is the result
that makes folate the rational therapy.
limitations: >-
A cell-autonomous readout: it says nothing about tissue-level homocysteine handling or
about why some patients never become hyperhomocysteinemic.
readouts:
- name: Methionine formation from labelled formate
target: Impaired Homocysteine Remethylation to Methionine
direction: DECREASED
interpretation: Reduced by 90%, the larger of the two flux deficits.
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid"
explanation: >-
The cobalamin-versus-folate discrimination, measured in the same fibroblast system.
diagnosis:
- name: Exome sequencing with explicit structural-variant review
description: >-
The diagnosis is molecular. Two features of these cases are worth carrying forward. First,
the biochemical picture is misleading: the founding patient had a selective decrease in
methylcobalamin synthesis in fibroblasts and raised methylmalonic acid, which points toward
a cobalamin disorder rather than a folate one, and the fibroblast studies that resolved it
showed the methionine defect was unresponsive to cobalamin but responsive to folate.
Second, standard exome variant calling can find only one allele: in one family the paternal
allele was an exon 13 deletion, recovered only by manually inspecting per-exon coverage
depth after the phenotype made a second hit likely.
evidence:
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In view of highly suggestive phenotype, we extended our bioinformatics interrogation for structural variants in the MTHFD1 gene by manual evaluation of the exome data for sequence depth coverage of all the exons."
explanation: >-
Documents that the second allele was found only by deliberate structural-variant review,
which is the practical diagnostic lesson from this family.
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid"
explanation: >-
The fibroblast discrimination that separates this disorder from the cobalamin disorders its
biochemistry can mimic.
classifications:
harrisons_chapter:
- classification_value: ENDOCRINOLOGY_METABOLISM
evidence:
- reference: PMID:21813566
reference_title: "Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein."
explanation: Places the disorder among the inherited metabolic diseases.
- classification_value: IMMUNE_RHEUMATOLOGIC
evidence:
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exome sequencing demonstrated MTHFD1 deficiency as a novel cause of a combined immunodeficiency."
explanation: >-
Also classifiable as a primary immunodeficiency, which is how these patients usually
reach specialist care.
treatments:
- name: Folinic Acid
description: >-
Reduced folate that bypasses the MTHFD1 block by supplying a one-carbon-loaded folate
directly. It is disease-modifying rather than supportive: in one family folinic acid
produced immune reconstitution sufficient to discontinue all prophylactic therapy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: folinic acid
term:
id: CHEBI:15640
label: 5-formyltetrahydrofolic acid
target_mechanisms:
- target: Depletion of the Cytosolic One-Carbon-Loaded Folate Pool
description: >-
Supplies reduced folate downstream of the missing enzyme activity, restoring the
one-carbon-loaded pool the mutant enzyme cannot generate.
evidence:
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Treatment with folinic acid led to immune reconstitution, enabling discontinuation of all prophylactic therapies."
explanation: >-
Reports reversal of the immunological phenotype on folinic acid, establishing it as
targeted rather than supportive therapy.
- reference: PMID:27707659
reference_title: "Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Folinic acid was established as precision therapy to reverse the clinical and laboratory phenotype of this primary immunodeficiency."
explanation: The authors' explicit designation of folinic acid as precision therapy.
- reference: PMID:42301236
reference_title: "MTHFD1 Deficiency in Two Unrelated Children: Highlights on Phenotypic Spectrum and Response to Folic Acid Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Precision therapy with prompt folate or folinic acid supplementation can significantly improve outcomes, as evidenced by the survival of one patient with minimal intervention."
explanation: >-
Reinforces folate as precision therapy, and the qualifier "prompt" is load-bearing: in the
same report the second child died on day 18 of intensive care despite antibiotics,
antifungals, IVIG and dexamethasone. The determinant of outcome is reaching the molecular
diagnosis in time, not the intensity of supportive treatment.
- name: Folic Acid
description: >-
In at least one patient the regimen was successfully reduced to folic acid alone for
long-term maintenance, so the fully reduced form is not always required.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: folic acid
term:
id: CHEBI:27470
label: folic acid
target_mechanisms:
- target: Depletion of the Cytosolic One-Carbon-Loaded Folate Pool
description: Raises folate availability to drive the residual pathway flux.
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "was successfully treated with a regime that included and was eventually reduced to folic acid"
explanation: Documents long-term maintenance on folic acid alone in one patient.
- name: Hydroxocobalamin
description: >-
Given as part of the combination regimen in the patient with hyperhomocysteinemia and
microangiopathy, and with folate in an independent SCID patient. Its role here is empiric
and adjunctive rather than mechanistically targeted: the fibroblast studies this entry
already cites show methionine formation in patient cells did not increase on cobalamin
supplementation but did respond to folate, which places the block on the folate side. It is
plausibly given before that localisation is known, since the presenting biochemistry - raised
methylmalonic acid and reduced methylcobalamin synthesis - points at a cobalamin disorder.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: hydroxocobalamin
term:
id: CHEBI:27786
label: hydroxocobalamin
target_mechanisms:
- target: Impaired Homocysteine Remethylation to Methionine
description: >-
Given to support cobalamin-dependent methionine synthase. The patient-fibroblast evidence
indicates this is not the limiting step in this disease, so the link is recorded as
adjunctive rather than corrective.
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid"
explanation: Hydroxocobalamin as a component of the regimen that resolved the microangiopathic features.
- reference: PMID:23296427
reference_title: "Severe combined immunodeficiency resulting from mutations in MTHFD1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hydroxocobalamin and folate therapy provided partial immune reconstitution"
explanation: >-
Independent use of hydroxocobalamin with folate. The reconstitution was partial, and the
entry does not attribute the benefit to the cobalamin component specifically.
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: REFUTE
evidence_source: IN_VITRO
snippet: "which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid"
explanation: >-
Refutes a cobalamin-corrigible block: patient-fibroblast methionine formation was
unresponsive to cobalamin, which is why this treatment is recorded as adjunctive.
- name: Betaine
description: >-
Provides an alternative, folate-independent route for remethylating homocysteine to
methionine via betaine-homocysteine methyltransferase, used as part of the combination
regimen in the patient with hyperhomocysteinemia and microangiopathy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: betaine
term:
id: CHEBI:17750
label: glycine betaine
target_mechanisms:
- target: Impaired Homocysteine Remethylation to Methionine
description: >-
Bypasses the folate-dependent remethylation step, lowering homocysteine independently of
the MTHFD1 block.
evidence:
- reference: PMID:25633902
reference_title: "Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid"
explanation: >-
Betaine as a component of the combination regimen that resolved the microangiopathic and
haematological features.
discussions:
- discussion_id: purine_versus_thymidylate_route_to_scid
kind: INTERPRETATION
prompt: >-
Does the combined immunodeficiency in MTHFD1 deficiency arise from impaired purine
synthesis, as in the classical purine-pathway SCIDs, or from impaired de novo thymidylate
synthesis?
rationale: >-
Both routes were plausible before the flux experiment. Severe combined immunodeficiency is
classically associated with impaired purine nucleotide metabolism (ADA and PNP deficiency),
while megaloblastic anemia is classically associated with impaired de novo thymidylate
biosynthesis - and this disorder has both phenotypes, so a two-lesion explanation was
available. Labelled flux measurement in patient fibroblasts discriminated between them:
purine biosynthesis was unaffected, so one lesion in thymidylate synthesis accounts for both
arms. This is recorded because the resolved answer is easy to lose - the entry's causal
chain now runs only through thymidylate, and a reader should know that the purine route was
tested rather than overlooked.
attaches_to:
- pathophysiology#Lymphocyte Developmental and Proliferative Failure
- pathophysiology#Impaired Nuclear de novo Thymidylate Biosynthesis
evidence:
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SCID has been associated with impaired purine nucleotide metabolism, whereas megaloblastic anemia has been associated with impaired de novo thymidylate (dTMP) biosynthesis."
explanation: States the two competing prior expectations that the experiment was designed to separate.
- reference: PMID:25548164
reference_title: "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These results provide evidence that impaired nuclear de novo dTMP biosynthesis can lead to both megaloblastic anemia and SCID in MTHFD1 deficiency."
explanation: The authors' conclusion that a single thymidylate lesion explains both phenotypes.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Review round 1 on PR #10990: autoimmunity phenotype, hydroxocobalamin, structured variants · 2026-09-04T18:37:14Z · View source
Applied all three blocking findings from the automated review of PR #10990, plus the two suggestions, in a single push (main has dismiss_stale_reviews, so each round costs a full re-review cycle). Blocking 1 - missing autoimmunity phenotype. Added Autoimmunity (HP:0002960, OCCASIONAL) with evidence from PMID:42301236 and PMID:32414565, and wired it into the pathograph as an INDIRECT_UNKNOWN_INTERMEDIATES downstream target of Lymphocyte Developmental and Proliferative Failure rather than leaving it as an unconnected clinical observation. While in the phenotype section, also added Retinopathy (HP:0000488), Hepatic fibrosis (HP:0001395) and Metabolic acidosis (HP:0001942). Term trap worth recording: the deep-research report suggested HP:0002153 for "severe metabolic acidosis". HP:0002153 is Hyperkalemia. The correct term is HP:0001942. The report's CURIE was checked against the ontology rather than taken on trust, per the dismech-terms rule that a report CURIE is a lead. This is noted in the evidence explanation on that phenotype so a later curator does not re-import the wrong code. Blocking 2 - hydroxocobalamin treatment. Added as pharmacotherapy with CHEBI:27786, carrying three evidence items including a REFUTE on cobalamin-responsiveness. The treatment is recorded as adjunctive and empiric, not mechanistically targeted: MTHFD1 sits upstream of the cobalamin-dependent step, so B12 repletion does not correct the enzyme defect, and the cited series does not report a response attributable to it. Blocking 3 - structured genetics. Added relationship_type CAUSATIVE, variant_origin GERMLINE, and five structured variants covering all seven reported alleles (c.517C>T p.Arg173Cys; c.727+1G>A; c.806C>T p.Thr296Ile with c.1674G>A; c.146C>T p.Ser49Phe with c.673G>T p.Glu225*; exon 13 deletion). functional_effects is a list of FunctionalEffect objects (function/description/type), not a bare enum - two earlier shapes failed schema validation before this was established. Suggestions taken: added a biochemical section (four markers) and an experimental_models section (patient fibroblasts with modeled_mechanisms, readouts and limitations). Open question answered for the reviewer: there is no GeneReviews chapter for MTHFD1 deficiency. This was checked against PubMed directly; the reviewer flagged it as unverified because their runner has no network egress. A note was added on the molecular node recording why no mouse model is cited: homozygous Mthfd1 disruption is early embryonic lethal so there is no viable null, and the available Mthfd1S(+/-) mouse models the common R653Q synthetase polymorphism, which is a distinct entity from this Mendelian disorder. Validation after the round: 64/64 snippets verified against cached references; schema, terms, entity refs, causal targets, duplicate keys and qualifier terms all clean.
Create: MTHFD1 Deficiency (MONDO:0060611, CIMAH) · 2026-09-04T18:16:55Z · View source
De-novo curation of MTHFD1 deficiency (MONDO:0060611). Deep research: openscientist, 2663s. The recipe exited 3 because term validation hit a 5s OLS read timeout (dismech#10396); reference validation was retro-fitted successfully (16/16 resolved, 0 confabulations, 13/16 assessed on topic, 0 off topic) but term validation could NOT be recovered - two further attempts failed, once on HP:0004430 and once on MedGen:1615364, so this report carries no Term Validation section. That is safe here because no ontology CURIE in this entry came from the report: every term was selected and validated independently, and just validate-terms passes. The report was checked for Named Entity Confusion: just preflight-dr PASSES, and although the report cites neural-tube-defect polymorphism literature, it does so under an explicit 'Common susceptibility (distinct entity)' heading contrasting the common R653Q variant against this Mendelian disorder, which is the correct distinction. The report contributed four references the initial curation had missed, three of which were used: PMID:32414565 (the first direct measurement of MTHFD1 enzyme function in patients - no detectable dehydrogenase activity in any of four, with protein at 4.8-14.3% of control in three and ~44% in a fourth, so protein level and catalytic function dissociate), PMID:23296427 (an independent SCID patient in whom immune reconstitution was only partial), and PMID:42301236 (two Kuwaiti children homozygous for c.517C>T p.Arg173Cys, adding failure to thrive, developmental delay and autoimmune thyroiditis, and a stark outcome contrast where one improved on folic acid and the other died on day 18 of intensive care). The fourth, PMID:26408344, was deliberately NOT used as an animal model: it is the Mthfd1S(+/-) mouse modelling the common R653Q polymorphism, a distinct entity, and adding it would have imported exactly the confusion the report avoided. A note on the molecular node records why no mouse model of this disease exists (homozygous Mthfd1 disruption is early embryonic lethal). The causal chain is built around the discriminating flux experiment: formate incorporation into methionine fell 90% and into dTMP 50% while purine biosynthesis was unaffected, so a single lesion in nuclear de novo thymidylate biosynthesis accounts for both the megaloblastic anemia and the immunodeficiency; that resolved question is recorded as an INTERPRETATION discussion. Validation: just validate passes with 43/43 snippets verified; check-entity-refs, check-causal-targets, check-duplicate-keys and check-qualifier-terms all pass.
Disease: MTHFD1 Deficiency (Methylenetetrahydrofolate Dehydrogenase 1 Deficiency) Category: Mendelian (autosomal recessive inborn error of folate metabolism / inborn error of immunity) Report type: Literature-based knowledge synthesis (no primary patient data provided) Date: 2026-09-04
Evidence-source note: Because this is an ultra-rare disorder (<20 molecularly confirmed patients worldwide as of the primary literature reviewed), most clinical statements derive from individual case reports and small case series (human clinical evidence). Mechanistic statements draw on patient-fibroblast studies (in vitro) and mouse models (model organism). Where a claim is inferred rather than demonstrated, this is stated explicitly.
Overview. MTHFD1 deficiency is a rare autosomal recessive inborn error of the cytoplasmic (and nuclear) folate cycle caused by biallelic loss-of-function variants in MTHFD1. The gene encodes a trifunctional enzyme carrying three catalytic activities: 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, and 10-formyltetrahydrofolate synthetase. Loss of function disrupts the supply of one-carbon folate coenzymes required for de novo purine synthesis, de novo thymidylate (dTMP) synthesis, and remethylation of homocysteine to methionine. Clinically it manifests as a multisystem, folate-responsive disorder combining megaloblastic anemia, combined/severe combined immunodeficiency, atypical hemolytic-uremic syndrome (aHUS), hyperhomocysteinemia, and neurologic abnormalities (PMID: 21813566; 25548164; 32414565).
It was first described in 2011 by Watkins et al., who identified it via exome sequencing in a single infant — "the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein" (PMID: 21813566).
Key identifiers. - Mondo: MONDO:0060611 — "combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia" (acronym CIMAH) (verified via EBI OLS4/MONDO) - OMIM (phenotype): #617780 — same name - OMIM (gene): MTHFD1 172460 - Orphanet: ORPHA:658813 - UMLS: C4540434 · GARD: 0026001 · MedGen: 1615364 - HGNC: 7432 · NCBI Gene: 4522 · Ensembl: ENSG00000100714 · UniProt: P11586 · cytoband: 14q23.3 (verified via MyGene.info) - ICD-11: 4A00.xx (combined immunodeficiencies) / 5C50.x (metabolic disorders) — no dedicated code; ICD-10: D81.x (combined immunodeficiencies) / E53.8 as closest approximations - MeSH: no dedicated descriptor; indexed under "Immunologic Deficiency Syndromes," "Anemia, Megaloblastic," and "Folic Acid" metabolism terms
Synonyms / alternative names. MTHFD1 deficiency; Methylenetetrahydrofolate dehydrogenase 1 deficiency; CIMAH (Combined ImmunodeficiencY and Megaloblastic Anemia with or without Hyperhomocysteinemia); MTHFD1-related folate metabolism disorder. Gene aliases: MTHFC, MTHFD.
Data source type. Aggregated disease-level knowledge derived from published individual patient reports and biochemical/model studies — not EHR-derived population data.
Primary cause (genetic). Biallelic (homozygous or compound heterozygous) pathogenic variants in MTHFD1 (14q23.3). Reported causal variants include missense, nonsense, and splice-site changes distributed across the dehydrogenase/cyclohydrolase and synthetase domains (see §4). The defect causes markedly reduced MTHFD1 protein and absent methylenetetrahydrofolate dehydrogenase activity in patient cells (PMID: 32414565).
Genetic risk factors. - Causal: rare biallelic loss-of-function MTHFD1 variants (the disease itself). - Common susceptibility (distinct entity): MTHFD1 R653Q (c.1958G>A, rs2236225) in the synthetase domain — a low-penetrance hypomorphic variant, homozygous in ~20% of individuals of European ancestry, associated with neural tube defects (NTDs), congenital heart defects (CHDs), and adverse pregnancy outcomes (PMID: 23704330; 26408344). It acts predominantly as a maternal risk factor: maternal QQ homozygosity is associated with NTD-affected pregnancy at OR ~1.5 (original Irish cohort OR 1.52, 95% CI 1.16–1.99, P=0.003, PMID 12384833; independent replication OR 1.49, 95% CI 1.07–2.09, P=0.019, PMID 16552426; meta-analysis of 9 studies / 4,302 cases / 4,238 controls confirming a maternal-allele excess, PMID 24977710). A promoter SNP (rs1076991) further modifies risk in combination with R653Q (PMID 19130090). This is a modifier/susceptibility allele, not the Mendelian disease. - Consanguinity: homozygous cases have been reported in consanguineous/founder settings (e.g., Kuwaiti children homozygous for c.517C>T p.Arg173Cys; PMID: 42301236), consistent with AR disease.
Environmental risk factors. Maternal/dietary folate deficiency can exacerbate one-carbon metabolic insufficiency; in mouse models maternal folate-deficient diet interacts with synthetase deficiency (PMID: 26408344). Arsenic (arsenic trioxide) directly targets MTHFD1/SUMO-dependent nuclear dTMP biosynthesis, a teratogenic mechanism converging on the same pathway (PMID: 28265077).
Protective factors. Folate/folinic acid supplementation is the principal disease-modifying (protective) factor — it partially restores one-carbon flux and improves hematologic and immune outcomes (PMID: 23296427; 42301236). Adequate maternal folate status is protective against the R653Q-associated developmental risks (inferred from GxE data, PMID: 26408344).
Gene–environment interaction. Folate availability modulates the phenotype at every level: for the R653Q hypomorph, folate deficiency increases risk of developmental defects; for the Mendelian disease, exogenous reduced folate (folinic acid) partially bypasses the block. Arsenic × folate is a documented toxicant–pathway interaction (PMID: 28265077).
Onset is typically neonatal to infantile; severity and progression are variable (from lethal early infancy to milder, treatment-responsive disease). HPO term suggestions and approximate frequencies (from the small published cohort) below.
| Phenotype | Type | Onset / course | Approx. frequency | HPO suggestion |
|---|---|---|---|---|
| Megaloblastic anemia | Lab / hematologic | Infantile; responsive to therapy | Near-universal (hallmark) | HP:0001889 |
| Combined / severe combined immunodeficiency | Clinical / immune | Infantile; progressive if untreated | Very common | HP:0005387 / HP:0004430 |
| Recurrent infections (bacterial, sinopulmonary; opportunistic incl. Pneumocystis) | Clinical sign | Infantile | Common | HP:0002719 |
| Lymphopenia (all subsets), poor vaccine response | Lab | Infantile | Common | HP:0001888 |
| Atypical hemolytic-uremic syndrome / thrombotic microangiopathy | Clinical / lab | Infancy–childhood, episodic | Subset (several patients) | HP:0005575 / HP:0001937 |
| Hyperhomocysteinemia | Lab | Congenital-biochemical | Frequent (not universal) | HP:0002160 |
| Hypomethioninemia | Lab | Biochemical | Reported | HP:0500152 (low methionine) |
| Neurologic abnormalities (seizures, developmental delay) | Clinical | Infantile | Subset | HP:0001250 / HP:0001263 |
| Failure to thrive | Clinical | Infantile | Common | HP:0001508 |
| Autoimmune disease (e.g., autoimmune thyroiditis) | Clinical | Childhood | Subset | HP:0002960 |
| Retinopathy | Clinical | Variable | Rare (1 patient) | HP:0000488 |
| Liver fibrosis | Clinical / path | Childhood | Rare | HP:0001395 |
| Severe metabolic acidosis | Lab | Neonatal (severe cases) | Rare (lethal cases) | HP:0002153 |
Evidence: PMID 21813566; 23296427; 25633902; 32414565; 42301236.
Quality-of-life impact. Untreated disease is life-threatening (recurrent/opportunistic infection, bone-marrow failure, TMA/renal injury, neurodevelopmental impairment). With early folate/folinic acid therapy, hematologic and immune function can substantially normalize, allowing discontinuation of anti-infective prophylaxis (PMID: 27707659). No formal EQ-5D/SF-36 data exist for this ultra-rare disease.
Causal gene. MTHFD1 (HGNC:7432; OMIM 172460; NCBI Gene 4522; Ensembl ENSG00000100714), chromosome 14q23.3, encoding the ~101 kDa trifunctional protein C1-THF synthase (UniProt P11586). N-terminal domain: dehydrogenase + cyclohydrolase (NADP-binding); C-terminal domain: 10-formyltetrahydrofolate synthetase.
Reported pathogenic variants (germline, biallelic). - c.517C>T, p.Arg173Cys (homozygous; Kuwaiti patients) — PMID: 42301236 - c.517C>T, p.Arg173Cys vicinity / p.R173C critical NADP-binding arginine + c.727+1G>A splice (first proband) — PMID: 21813566 - c.806C>T, p.Thr296Ile + c.1674G>A splice (exon skipping) — PMID: 25633902 - c.146C>T, p.Ser49Phe + c.673G>T, p.Glu225* (nonsense) — PMID: 25633902 - Compound heterozygous missense + exon-13 deletion (structural) — PMID: 27707659 - Additional deleterious compound-heterozygous variants — PMID: 32414565
Variant classes: missense, nonsense, canonical splice-site, and exonic deletions — all consistent with loss of function (no dominant-negative/gain-of-function reported). ACMG classification: reported variants are pathogenic/likely pathogenic based on segregation, functional enzymology, and predicted deleteriousness.
ClinVar landscape (reference transcript NM_005956.4; queried Iteration 4). 64 Pathogenic and 30 Likely pathogenic records (vs 629 VUS and 590 Benign among 681 total gene entries). The disease-associated P/LP spectrum is overwhelmingly loss-of-function/null: among 64 P/LP records — SNVs 39 (predominantly canonical splice ±1/±2, e.g., c.377+1G>C, c.616-2A>C, c.2280-1G>T, c.1264+1G>A; plus nonsense c.316G>T p.Glu106Ter, c.886G>T p.Glu296Ter), frameshift deletions 10 (e.g., c.2375del p.Gly792fs, c.1755_1756del p.Arg585fs, c.153_154del p.Ile53fs), duplications 2 (c.731dup p.Asp244fs; c.253dup p.Ile85fs), insertion 1 (c.2479_2480insTTGCACA p.Arg827fs), and 12 large copy-number gains/losses (chromosomal, largely incidental). Many P/LP entries are explicitly annotated to the trait "Combined immunodeficiency and megaloblastic anemia." The large VUS pool reflects the gene's tolerance of common missense variation (e.g., R653Q) and complicates novel-missense classification. (Source: NCBI ClinVar via E-utilities.)
Functional consequence. Loss of function: MTHFD1 protein reduced to 4.8–14.3% of control (one patient ~44%) with no detectable dehydrogenase activity in fibroblasts (PMID: 32414565).
Allele frequency. Rare disease alleles are absent/ultra-rare in gnomAD. In contrast, the common non-disease modifier R653Q (rs2236225; GRCh38 14-64442127-G-A) is very common — gnomAD v4 global genome AF 0.386, with ancestry-specific AF: Non-Finnish European 0.453 (≈20.5% QQ homozygotes under Hardy-Weinberg), Admixed American 0.519, South Asian 0.505, Finnish 0.446, Ashkenazi Jewish 0.436, Middle Eastern 0.432, East Asian 0.221, African/African-American 0.212 (verified via gnomAD v4 API; consistent with the "~20% of Caucasians homozygous" statement in PMID 23704330).
Somatic vs germline. Disease variants are germline. (Somatic relevance: MTHFD1 is exploited in cancer one-carbon metabolism and is targeted by arsenic trioxide — PMID: 28265077 — but this is not the inherited disease.)
Modifier genes / epigenetics / chromosomal abnormalities. No formally established modifier genes beyond folate-pathway context. Downstream DNA hypomethylation is expected from reduced methionine/SAM (mechanistically inferred; not systematically profiled in patients). No recurrent chromosomal abnormalities; one causal exon-13 deletion is a small intragenic structural variant (PMID: 27707659).
Cell types (CL suggestions): erythroid progenitor (CL:0000038), T cell (CL:0000084), B cell (CL:0000236), hematopoietic stem/progenitor cell (CL:0000037), vascular endothelial cell (CL:0000115).
Laboratory / biochemical. - CBC + blood smear: macrocytic megaloblastic anemia (± pancytopenia), hypersegmented neutrophils (LOINC macrocyte/MCV panels). - Plasma total homocysteine: elevated (hyperhomocysteinemia) in many patients; methionine low/normal. - Methylmalonic acid: elevated in the index case; methylcobalamin synthesis decreased in cultured fibroblasts (PMID: 21813566). - Immunology: lymphopenia across T/B/NK subsets, hypogammaglobulinemia/poor vaccine responses (PMID: 27707659). - Renal / hemolysis markers during aHUS/TMA (schistocytes, ↑LDH, ↑creatinine, thrombocytopenia). - Cellular biomarkers (research): absent MTHFD1 dehydrogenase activity and reduced protein by Western blot in fibroblasts; elevated uracil in DNA; abnormal formate-incorporation flux assays (PMID: 32414565; 25548164).
Genetic testing (definitive). Diagnosis is confirmed by identifying biallelic MTHFD1 variants. Recommended approach: whole-exome sequencing (WES) or a combined immunodeficiency / inborn-errors-of-metabolism gene panel including MTHFD1; WGS or targeted analysis can detect intragenic structural variants (e.g., exon-13 deletion missed by standard SNV calling — requires read-depth/CNV analysis) (PMID: 27707659; 21813566; 23296427). Single-gene sequencing of MTHFD1 is appropriate when phenotype is characteristic. CMA/karyotype/FISH generally not informative (defect is intragenic). Mitochondrial DNA and repeat-expansion testing: not applicable.
Clinical criteria / differential diagnosis. No formal consensus criteria. Consider MTHFD1 deficiency in any infant with megaloblastic anemia + immunodeficiency + hyperhomocysteinemia and/or aHUS. Differentials: other inborn errors of folate/cobalamin metabolism (hereditary folate malabsorption [SLC46A1], cblC/MMACHC and related cobalamin defects, transcobalamin deficiency, DHFR deficiency, MTHFR deficiency), other SCID genotypes, and complement-mediated aHUS. Distinguishing features: MTHFD1 uniquely combines the folate-cycle biochemistry (low methionine, high Hcy, normal purine flux) with combined immunodeficiency (PMID: 32412981).
Screening. Not part of standard newborn screening. Cascade carrier testing of relatives once the familial variants are known; prenatal/preimplantation testing feasible for known biallelic variants.
Core pharmacotherapy (metabolic/precision therapy). - Folinic acid (5-formyltetrahydrofolate / leucovorin) — preferred reduced folate that bypasses the dihydrofolate reductase step; enables immune reconstitution and hematologic correction (PMID: 27707659). NCIT: Leucovorin Calcium (C576) / Folinic acid. - Folic acid — effective in milder/responsive patients; produced significant clinical improvement (PMID: 42301236). NCIT: Folic Acid (C542). - Hydroxocobalamin (vitamin B12) — used to support remethylation; provided partial immune reconstitution with folate in the index case (PMID: 23296427). NCIT: Hydroxocobalamin (C61805). - Betaine — remethylation agent to lower homocysteine (PMID: 25633902). NCIT: Betaine (C61463). - Methionine supplementation — may be considered when hypomethioninemia present (inferred/supportive).
Supportive / adjunctive care. Anti-infective prophylaxis and immunoglobulin (IVIG) while immunodeficient; transfusion support for anemia; management of aHUS/TMA (supportive ± eculizumab per complement-mediated protocols, though MTHFD1-related TMA is metabolic in origin); treatment of autoimmune complications. Discontinuation of prophylaxis becomes possible after immune reconstitution on folinic acid (PMID: 27707659).
Advanced/experimental therapeutics. No approved gene, cell, or RNA therapies. Hematopoietic stem-cell transplantation is generally unnecessary because the immunodeficiency is metabolically correctable — a key contrast with genetic SCIDs (this is an important treatment distinction). No registered disease-specific clinical trials identified.
Pharmacogenomics. Not established; genotype-guided care centers on choosing reduced folate (folinic acid) to bypass downstream steps.
Treatment strategy / algorithm. Suspect → urgent molecular diagnosis → immediate folinic/folic acid ± hydroxocobalamin ± betaine → supportive anti-infective/transfusion care → monitor hematology, homocysteine, and immune reconstitution → taper prophylaxis once reconstituted. Early treatment is the strongest determinant of survival (PMID: 42301236).
Supported: - MTHFD1 deficiency is an AR loss-of-function disorder of the cytoplasmic/nuclear folate cycle (PMID: 21813566; 32414565). - The hematologic + immune phenotype arises chiefly from impaired nuclear de novo dTMP synthesis with uracil misincorporation, with purines relatively spared (PMID: 25548164). - The disorder is folate/folinic-acid responsive, and early treatment improves survival/immune reconstitution (PMID: 27707659; 23296427; 42301236). - The common R653Q synthetase variant is a distinct low-penetrance developmental risk modifier, not the Mendelian disease (PMID: 23704330; 26408344).
Refuted / clarified: - Not primarily a purine-synthesis disorder at the cellular level (purine flux preserved in patient cells) — refutes the intuitive "SCID via purine block" model as the main mechanism (PMID: 25548164). - Not a mitochondrial folate defect — MTHFD1 is cytosolic/nuclear (distinct from MTHFD2/MTHFD1L). - HSCT is generally not required (metabolically correctable), distinguishing it from classical genetic SCID.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 16 |
| Resolved | 16 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 16 |
| On topic | 13 |
| Off topic | 0 |
All extracted references resolved successfully.