Constitutional megaloblastic anemia with severe neurologic disease

Summary

Constitutional megaloblastic anemia with severe neurologic disease (MONDO:0013456) is a disease caused by DHFR (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DHFR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	constitutional megaloblastic anemia with severe neurologic disease
Mondo ID	MONDO:0013456
MeSH	C565095
OMIM	613839
Orphanet	319651
SNOMED CT	124178006
UMLS	C3151205
MedGen	462555
GARD	0011000
Is cancer (heuristic)	no

Also known as: DHFR deficiency · dihydrofolate reductase deficiency · megaloblastic anaemia due to dihydrofolate reductase deficiency

Data availability: 8 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › macrocytic anemia › megaloblastic anemia › constitutional megaloblastic anemia with severe neurologic disease

Related subtypes (5): pernicious anemia, hereditary folate malabsorption, formiminoglutamic aciduria, Imerslund-Grasbeck syndrome, vitamin B12- and folate-independent constitutional megaloblastic anemia

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

8 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 2 pathogenic, 2 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
29673	NM_000791.4(DHFR):c.238C>T (p.Leu80Phe)	DHFR	Pathogenic	no assertion criteria provided
29674	NM_000791.4(DHFR):c.458A>T (p.Asp153Val)	DHFR	Pathogenic	no assertion criteria provided
3381823	NM_000791.4(DHFR):c.77C>T (p.Pro26Leu)	DHFR	Likely pathogenic	no assertion criteria provided
3381824	NM_000791.4(DHFR):c.53G>T (p.Gly18Val)	DHFR	Likely pathogenic	no assertion criteria provided
1709841	NM_000791.4(DHFR):c.335T>G (p.Met112Arg)	DHFR	Uncertain significance	criteria provided, single submitter
1803197	NM_000261.2(MYOC):c.1349A>G (p.Asn450Ser)	MYOC	Uncertain significance	reviewed by expert panel
710203	NM_000791.4(DHFR):c.-406CGCTGCAGC[1]	DHFR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
790792	NM_000791.4(DHFR):c.-418GGCCGCTGC[1]	DHFR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
DHFR	Definitive	Autosomal recessive	constitutional megaloblastic anemia with severe neurologic disease	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DHFR	Orphanet:319651	Constitutional megaloblastic anemia with severe neurologic disease
MYOC	Orphanet:98976	Congenital glaucoma
MYOC	Orphanet:98977	Juvenile glaucoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DHFR	HGNC:2861	ENSG00000228716	P00374	Dihydrofolate reductase	gencc,clinvar
MYOC	HGNC:7610	ENSG00000034971	Q99972	Myocilin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHFR	Dihydrofolate reductase	Catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate in a NADPH-dependent manner.
MYOC	Myocilin	Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHFR	Enzyme (other)	yes	1.5.1.3	DHFR_dom, DHFR, DHFR_CS
MYOC	Other/Unknown	no		Olfac-like_dom, Olfactomedin-like_domain

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
ganglionic eminence	1
ventricular zone	1
calcaneal tendon	1
esophagogastric junction muscularis propria	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHFR	290	ubiquitous	marker	buccal mucosa cell, ventricular zone, ganglionic eminence
MYOC	201	tissue_specific	marker	calcaneal tendon, mucosa of stomach, esophagogastric junction muscularis propria

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHFR	4,152
MYOC	1,272

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DHFR	P00374	89
MYOC	Q99972	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	1142.0×	0.002	DHFR
Metabolism of folate and pterines	1	634.4×	0.002	DHFR
G1/S-Specific Transcription	1	356.9×	0.003	DHFR

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
skeletal muscle hypertrophy	1	8426.0×	0.002	MYOC
response to methotrexate	1	8426.0×	0.002	DHFR
dihydrofolate metabolic process	1	2808.7×	0.003	DHFR
tetrahydrofolate biosynthetic process	1	1404.3×	0.003	DHFR
regulation of removal of superoxide radicals	1	1404.3×	0.003	DHFR
tetrahydrobiopterin biosynthetic process	1	1203.7×	0.003	DHFR
clustering of voltage-gated sodium channels	1	1203.7×	0.003	MYOC
tetrahydrofolate metabolic process	1	1203.7×	0.003	DHFR
ERBB2-ERBB3 signaling pathway	1	842.6×	0.004	MYOC
positive regulation of mitochondrial depolarization	1	842.6×	0.004	MYOC
one-carbon metabolic process	1	561.7×	0.004	DHFR
axon regeneration	1	561.7×	0.004	DHFR
folic acid metabolic process	1	561.7×	0.004	DHFR
negative regulation of cell-matrix adhesion	1	443.5×	0.005	MYOC
myelination in peripheral nervous system	1	443.5×	0.005	MYOC
negative regulation of Rho protein signal transduction	1	383.0×	0.005	MYOC
positive regulation of focal adhesion assembly	1	324.1×	0.005	MYOC
non-canonical Wnt signaling pathway	1	290.6×	0.005	MYOC
negative regulation of stress fiber assembly	1	290.6×	0.005	MYOC
regulation of MAPK cascade	1	227.7×	0.007	MYOC
positive regulation of substrate adhesion-dependent cell spreading	1	187.2×	0.008	MYOC
positive regulation of stress fiber assembly	1	156.0×	0.009	MYOC
bone development	1	138.1×	0.009	MYOC
negative regulation of translation	1	98.0×	0.013	DHFR
positive regulation of JNK cascade	1	81.8×	0.015	MYOC
neuron projection development	1	61.1×	0.018	MYOC
osteoblast differentiation	1	60.6×	0.018	MYOC
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.027	MYOC
positive regulation of cell migration	1	30.9×	0.033	MYOC
signal transduction	1	8.0×	0.121	MYOC

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DHFR	TRIMETREXATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DHFR	23	4
MYOC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRIMETREXATE	4	DHFR
PRALATREXATE	4	DHFR
LEUCOVORIN	4	DHFR
TRIMETHOPRIM	4	DHFR
RALTITREXED	4	DHFR
PEMETREXED	4	DHFR
METHOTREXATE	4	DHFR
PYRIMETHAMINE	4	DHFR
SULFADIAZINE	4	DHFR
SULFACETAMIDE	4	DHFR
GENTAMICIN	4	DHFR
MEFENAMIC ACID	4	DHFR
DIFLUNISAL	4	DHFR
TERIFLUNOMIDE	4	DHFR
ICLAPRIM	3	DHFR
DIAVERIDINE	2	DHFR
EPIROPRIM	2	DHFR
EDATREXATE	2	DHFR
AMINOPTERIN	2	DHFR
BREQUINAR	2	DHFR
CYCLOGUANIL	2	DHFR
PIRITREXIM	2	DHFR
FANOTAPRIM	1	DHFR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DHFR	457	Binding:426, ADMET:16, Functional:12, Toxicity:3
MYOC	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHFR	1.5.1.3	dihydrofolate reductase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
DHFR	457

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

23 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)
TRIMETREXATE	4	DHFR
PRALATREXATE	4	DHFR
LEUCOVORIN	4	DHFR
TRIMETHOPRIM	4	DHFR
RALTITREXED	4	DHFR
PEMETREXED	4	DHFR
METHOTREXATE	4	DHFR
PYRIMETHAMINE	4	DHFR
SULFADIAZINE	4	DHFR
SULFACETAMIDE	4	DHFR
GENTAMICIN	4	DHFR
MEFENAMIC ACID	4	DHFR
DIFLUNISAL	4	DHFR
TERIFLUNOMIDE	4	DHFR
ICLAPRIM	3	DHFR
DIAVERIDINE	2	DHFR
EPIROPRIM	2	DHFR
EDATREXATE	2	DHFR
AMINOPTERIN	2	DHFR
BREQUINAR	2	DHFR
CYCLOGUANIL	2	DHFR
PIRITREXIM	2	DHFR
FANOTAPRIM	1	DHFR

Druggability pyramid

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

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYOC	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.