Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Summary

Homocystinuria due to methylene tetrahydrofolate reductase deficiency (MONDO:0009353) is a disease caused by MTHFR (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: MTHFR (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 835
• Phenotypes (HPO): 50
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0002011	Morphological central nervous system abnormality	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002156	Homocystinuria	Very frequent (80-99%)
HP:0002160	Hyperhomocystinemia	Very frequent (80-99%)
HP:0002493	Upper motor neuron dysfunction	Very frequent (80-99%)
HP:0003286	Cystathioninemia	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000725	Psychotic episodes	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002518	Abnormal periventricular white matter morphology	Frequent (30-79%)
HP:0003658	Hypomethioninemia	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001345	Psychotic mentation	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001727	Thromboembolic stroke	Occasional (5-29%)
HP:0001977	Abnormal thrombosis	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002625	Deep venous thrombosis	Occasional (5-29%)
HP:0006827	Atrophy of the spinal cord	Occasional (5-29%)
HP:0007359	Focal-onset seizure	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0008935	Generalized neonatal hypotonia	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0000238	Hydrocephalus	Very rare (<1-4%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000478	Abnormality of the eye	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)
HP:0001297	Stroke	Very rare (<1-4%)
HP:0001298	Encephalopathy	Very rare (<1-4%)
HP:0002119	Ventriculomegaly	Very rare (<1-4%)
HP:0002121	Generalized non-motor (absence) seizure	Very rare (<1-4%)
HP:0002123	Generalized myoclonic seizure	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	homocystinuria due to methylene tetrahydrofolate reductase deficiency
Mondo ID	MONDO:0009353
MeSH	C537357
OMIM	236250
Orphanet	395
SNOMED CT	41797007
UMLS	C1856061
MedGen	343470
GARD	0002734
Is cancer (heuristic)	no

Also known as: 5,10 alpha methylenetetrahydro-folate reductase deficiency · 5,10-alpha-methylenetetrahydro-folate reductase deficiency · Homocysteinemia due to methylenetetrahydro-folate reductase deficiency · Homocysteinuria due to methylenetetrahydro-folate reductase deficiency · homocystinuria due to methylene tetrahydrofolate reductase deficiency · homocystinuria due to MTHFR deficiency · methylene tetrahydrofolate reductase deficiency · Methylenetetrahydro-folate reductase deficiency · MTHFR deficiency

Data availability: 835 ClinVar variants · 4 GenCC gene-disease records · 29 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › homocystinuria › homocystinuria due to methylene tetrahydrofolate reductase deficiency

Related subtypes (4): hyperhomocysteinemia, classic homocystinuria, methylmalonic aciduria and homocystinuria, homocystinuria without methylmalonic aciduria

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

335 likely benign, 105 uncertain significance, 58 pathogenic, 29 likely pathogenic, 27 conflicting classifications of pathogenicity, 23 pathogenic/likely pathogenic, 14 benign, 4 benign/likely benign, 3 not provided, 1 pathogenic; risk factor, 1 benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1004148	NM_005957.5(MTHFR):c.1166+5G>C	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1024006	NM_005957.5(MTHFR):c.1228_1242del (p.Ser410_Lys414del)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034230	NM_005957.5(MTHFR):c.552del (p.Ser184fs)	MTHFR	Pathogenic	criteria provided, single submitter
1048667	NM_005957.5(MTHFR):c.584C>T (p.Ala195Val)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066378	NM_005957.5(MTHFR):c.1750A>T (p.Lys584Ter)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066379	NM_005957.5(MTHFR):c.474A>T (p.Gly158=)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068525	NM_005957.5(MTHFR):c.202C>T (p.Arg68Ter)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068573	NM_005957.5(MTHFR):c.1114_1115del (p.Lys372fs)	MTHFR	Pathogenic	criteria provided, single submitter
1070453	NM_005957.5(MTHFR):c.191del (p.Phe64fs)	MTHFR	Pathogenic	criteria provided, single submitter
1072666	NM_005957.5(MTHFR):c.1304_1305del (p.Phe435fs)	MTHFR	Pathogenic	criteria provided, single submitter
1073018	NM_005957.5(MTHFR):c.1063_1075del (p.Pro355fs)	MTHFR	Pathogenic	criteria provided, single submitter
1073673	NM_005957.5(MTHFR):c.1144del (p.Asp382fs)	MTHFR	Pathogenic	criteria provided, single submitter
1363312	NM_005957.5(MTHFR):c.1768del (p.Leu590fs)	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
1370847	NM_005957.5(MTHFR):c.1712del (p.Gln571fs)	MTHFR	Pathogenic	criteria provided, single submitter
1410016	NM_005957.5(MTHFR):c.177G>A (p.Trp59Ter)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445597	NM_005957.5(MTHFR):c.523G>A (p.Ala175Thr)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445648	NM_005957.5(MTHFR):c.860_863del (p.Ile287fs)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451973	NM_005957.5(MTHFR):c.1121dup (p.Tyr374Ter)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452438	NM_005957.5(MTHFR):c.1552del (p.Ser518fs)	MTHFR	Pathogenic	criteria provided, single submitter
1452521	NM_005957.5(MTHFR):c.273dup (p.Asp92fs)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452549	NM_005957.5(MTHFR):c.1069C>T (p.Arg357Cys)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453807	NM_005957.5(MTHFR):c.495G>A (p.Trp165Ter)	MTHFR	Pathogenic	criteria provided, single submitter
1455384	NM_005957.5(MTHFR):c.451A>T (p.Lys151Ter)	MTHFR	Pathogenic	criteria provided, single submitter
1455663	NM_005957.5(MTHFR):c.1852del (p.Leu618fs)	MTHFR	Pathogenic	criteria provided, single submitter
1456126	NC_000001.10:g.(?11850365)(11852446_?)del	MTHFR	Pathogenic	criteria provided, single submitter
1457543	NM_005957.5(MTHFR):c.1262G>A (p.Trp421Ter)	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
1459913	NC_000001.10:g.(?11850365)(11856466_?)del	MTHFR	Pathogenic	criteria provided, single submitter
1460266	NC_000001.10:g.(?11850365)(11851393_?)del	MTHFR	Pathogenic	criteria provided, single submitter
1686637	NM_005957.5(MTHFR):c.1657G>T (p.Glu553Ter)	MTHFR	Pathogenic	criteria provided, single submitter
187868	NM_005957.5(MTHFR):c.176G>C (p.Trp59Ser)	MTHFR	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MTHFR	Definitive	Autosomal recessive	homocystinuria due to methylene tetrahydrofolate reductase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTHFR	Orphanet:395	Homocystinuria due to methylene tetrahydrofolate reductase deficiency
MTHFR	Orphanet:563609	Isolated anencephaly
MTHFR	Orphanet:563612	Isolated exencephaly
MYH9	Orphanet:182050	MYH9-related syndromic thrombocytopenia
MYH9	Orphanet:477742	Nodular fasciitis
MYH9	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTHFR	HGNC:7436	ENSG00000177000	P42898	Methylenetetrahydrofolate reductase (NADPH)	gencc,clinvar
C1orf167	HGNC:25262	ENSG00000215910	Q5SNV9	Uncharacterized protein C1orf167	clinvar
MYH9	HGNC:7579	ENSG00000100345	P35579	Myosin-9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTHFR	Methylenetetrahydrofolate reductase (NADPH)	Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.
MYH9	Myosin-9	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTHFR	Enzyme (other)	yes	1.5.1.20	Mehydrof_redctse-like, Fadh2_euk, FAD-linked_oxidoreductase-like
C1orf167	Other/Unknown	no		DUF4684
MYH9	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
corpus epididymis	1
sural nerve	1
left testis	1
right testis	1
testis	1
ascending aorta	1
stromal cell of endometrium	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTHFR	254	ubiquitous	marker	corpus epididymis, sural nerve, apex of heart
C1orf167	153	tissue_specific	yes	left testis, right testis, testis
MYH9	279	ubiquitous	marker	stromal cell of endometrium, ascending aorta, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH9	5,533
MTHFR	3,492
C1orf167	246

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYH9	P35579	8
MTHFR	P42898	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C1orf167	Q5SNV9	48.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CD163 mediating an anti-inflammatory response	1	571.0×	0.019	MYH9
Sema4D in semaphorin signaling	1	335.9×	0.019	MYH9
Metabolism of folate and pterines	1	317.2×	0.019	MTHFR
RHO GTPases activate CIT	1	300.5×	0.019	MYH9
RHO GTPases Activate ROCKs	1	300.5×	0.019	MYH9
Sema4D induced cell migration and growth-cone collapse	1	285.5×	0.019	MYH9
RHO GTPases activate PAKs	1	271.9×	0.019	MYH9
Semaphorin interactions	1	196.9×	0.019	MYH9
Anti-inflammatory response favouring Leishmania parasite infection	1	196.9×	0.019	MYH9
Leishmania parasite growth and survival	1	196.9×	0.019	MYH9
EPHA-mediated growth cone collapse	1	190.3×	0.019	MYH9
Parasite infection	1	173.0×	0.019	MYH9
Leishmania phagocytosis	1	173.0×	0.019	MYH9
RHO GTPases activate PKNs	1	158.6×	0.019	MYH9
Sensory processing of sound	1	154.3×	0.019	MYH9
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.019	MYH9
Signaling by ALK in cancer	1	135.9×	0.019	MYH9
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.022	MYH9
FCGR3A-mediated phagocytosis	1	93.6×	0.022	MYH9
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.022	MYH9
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.022	MTHFR
EPH-Ephrin signaling	1	82.8×	0.022	MYH9
Leishmania infection	1	81.6×	0.022	MYH9
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.022	MYH9
Parasitic Infection Pathways	1	81.6×	0.022	MYH9
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	77.2×	0.022	MYH9
Signaling by ALK fusions and activated point mutants	1	75.1×	0.022	MYH9
Metabolism of vitamins and cofactors	1	58.3×	0.027	MTHFR
Sensory Perception	1	47.6×	0.032	MYH9
RHO GTPase Effectors	1	34.0×	0.043	MYH9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
uropod organization	1	4213.0×	0.002	MYH9
response to vitamin B2	1	4213.0×	0.002	MTHFR
cortical granule exocytosis	1	4213.0×	0.002	MYH9
negative regulation of actin filament severing	1	4213.0×	0.002	MYH9
positive regulation of protein processing in phagocytic vesicle	1	4213.0×	0.002	MYH9
cytokinetic process	1	2808.7×	0.002	MYH9
S-adenosylmethionine metabolic process	1	2808.7×	0.002	MTHFR
regulation of plasma membrane repair	1	2808.7×	0.002	MYH9
establishment of meiotic spindle localization	1	2106.5×	0.002	MYH9
obsolete methionine biosynthetic process	1	1685.2×	0.002	MTHFR
cytoplasmic actin-based contraction involved in cell motility	1	1685.2×	0.002	MYH9
L-methionine metabolic process	1	1404.3×	0.003	MTHFR
meiotic spindle organization	1	1203.7×	0.003	MYH9
response to folic acid	1	1203.7×	0.003	MTHFR
establishment of T cell polarity	1	936.2×	0.003	MYH9
homocysteine metabolic process	1	936.2×	0.003	MTHFR
tetrahydrofolate interconversion	1	842.6×	0.003	MTHFR
blood vessel endothelial cell migration	1	702.2×	0.003	MYH9
heterochromatin organization	1	648.1×	0.004	MTHFR
response to amino acid	1	495.6×	0.004	MTHFR
regulated exocytosis	1	443.5×	0.005	MYH9
actin filament-based movement	1	401.2×	0.005	MYH9
monocyte differentiation	1	401.2×	0.005	MYH9
platelet formation	1	351.1×	0.005	MYH9
phagocytosis, engulfment	1	337.0×	0.005	MYH9
membrane protein ectodomain proteolysis	1	324.1×	0.005	MYH9
leukocyte migration	1	312.1×	0.005	MYH9
myoblast fusion	1	300.9×	0.005	MYH9
plasma membrane repair	1	290.6×	0.005	MYH9
actomyosin structure organization	1	280.9×	0.005	MYH9

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYH9	1	2
MTHFR	0	0
C1orf167	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MYH9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MYH9	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTHFR	1.5.1.20, 1.5.1.53	methylenetetrahydrofolate reductase [NAD(P)H], methylenetetrahydrofolate reductase (NADPH)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	MYH9

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	MYH9
C	Druggable family + PDB, no drug	1	MTHFR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	C1orf167

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MTHFR	0	—
C1orf167	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns