Autosomal erythropoietic protoporphyria

Summary

Autosomal erythropoietic protoporphyria (MONDO:0019263) is a disease with 1 cohort gene and 4 clinical trials. Top therapeutic interventions include dersimelagon.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 10
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

22 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.012	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.92	Europe	Validated
Annual incidence	<1 / 1 000 000	0.006	France	Validated
Annual incidence	<1 / 1 000 000	0.007	Italy	Validated
Annual incidence	<1 / 1 000 000	0.018	Netherlands	Validated
Annual incidence	<1 / 1 000 000	0.036	Norway	Validated
Annual incidence	<1 / 1 000 000	0.003	Poland	Validated
Annual incidence	<1 / 1 000 000	0.003	Spain	Validated
Annual incidence	<1 / 1 000 000	0.018	Sweden	Validated
Annual incidence	<1 / 1 000 000	0.035	Switzerland	Validated
Annual incidence	<1 / 1 000 000	0.033	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000	0.46	France	Validated
Point prevalence	1-9 / 1 000 000	0.62	Ireland	Validated
Point prevalence	1-9 / 1 000 000	0.54	Italy	Validated
Point prevalence	1-9 / 100 000	1.39	Netherlands	Validated
Point prevalence	1-9 / 100 000	2.77	Norway	Validated
Point prevalence	1-9 / 1 000 000	0.15	Poland	Validated
Point prevalence	1-9 / 1 000 000	0.23	Spain	Validated
Point prevalence	1-9 / 100 000	1.39	Sweden	Validated
Point prevalence	1-9 / 100 000	2.7	Switzerland	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0000992	Cutaneous photosensitivity	Very frequent (80-99%)
HP:0010472	Abnormal circulating porphyrin concentration	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0001081	Cholelithiasis	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0001935	Microcytic anemia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal erythropoietic protoporphyria
Mondo ID	MONDO:0019263
Orphanet	79278
GARD	0004527
MedDRA	10015289
Is cancer (heuristic)	no

Also known as: EPP

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record · 4 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › hepatic porphyria › erythropoietic protoporphyria › autosomal erythropoietic protoporphyria

Related subtypes (1): X-linked erythropoietic protoporphyria

Subtypes (2): protoporphyria, erythropoietic, 1, protoporphyria, erythropoietic, 2

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500175	NM_000140.5(FECH):c.1049_1052dup (p.Glu351fs)	FECH	Pathogenic	no assertion criteria provided
930105	NM_000140.5(FECH):c.47del (p.Gly16fs)	FECH	Likely pathogenic	criteria provided, single submitter
562	NM_000140.5(FECH):c.315-48T>C	FECH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
FECH	Definitive	Autosomal recessive	protoporphyria, erythropoietic, 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FECH	Orphanet:79278	Autosomal erythropoietic protoporphyria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FECH	HGNC:3647	ENSG00000066926	P22830	Ferrochelatase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FECH	Ferrochelatase, mitochondrial	Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FECH	Enzyme (other)	yes	4.99.1.1	Ferrochelatase, Ferrochelatase_AS, Ferrochelatase_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FECH	269	ubiquitous	marker	trabecular bone tissue, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FECH	2,825

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FECH	P22830	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
Heme biosynthesis	1	761.3×	0.003	FECH
Mitochondrial protein degradation	1	114.2×	0.009	FECH

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of UV	1	16852.0×	6e-04	FECH
regulation of hemoglobin biosynthetic process	1	16852.0×	6e-04	FECH
obsolete protoporphyrinogen IX metabolic process	1	8426.0×	8e-04	FECH
response to platinum ion	1	4213.0×	0.001	FECH
response to insecticide	1	2808.7×	0.001	FECH
response to methylmercury	1	2407.4×	0.001	FECH
heme B biosynthetic process	1	1685.2×	0.002	FECH
heme A biosynthetic process	1	1532.0×	0.002	FECH
very-low-density lipoprotein particle assembly	1	1203.7×	0.002	FECH
response to arsenic-containing substance	1	1203.7×	0.002	FECH
response to lead ion	1	936.2×	0.002	FECH
response to light stimulus	1	887.0×	0.002	FECH
heme biosynthetic process	1	601.9×	0.002	FECH
multicellular organismal-level iron ion homeostasis	1	581.1×	0.002	FECH
cellular response to dexamethasone stimulus	1	581.1×	0.002	FECH
generation of precursor metabolites and energy	1	343.9×	0.004	FECH
erythrocyte differentiation	1	267.5×	0.004	FECH
cholesterol metabolic process	1	195.9×	0.006	FECH
response to ethanol	1	146.5×	0.007	FECH
response to xenobiotic stimulus	1	69.1×	0.014	FECH

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
FECH	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FECH	34	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	FECH
LENVATINIB	4	FECH
AXITINIB	4	FECH
NERATINIB	4	FECH
PACRITINIB	4	FECH
CABOZANTINIB	4	FECH
NILOTINIB	4	FECH
RIBOCICLIB	4	FECH
TUCATINIB	4	FECH
ERLOTINIB	4	FECH
GEFITINIB	4	FECH
LINSITINIB	3	FECH
RIGOSERTIB	3	FECH
CRENOLANIB	3	FECH
MK-2206	2	FECH
CC-401	2	FECH
MK-2461	2	FECH
ZOTIRACICLIB	2	FECH
VARLITINIB	2	FECH
RABUSERTIB	2	FECH
OSI-027	2	FECH
BGT-226 FREE BASE	2	FECH
R-406	2	FECH
CP-724714	2	FECH
BI-2536	2	FECH
PELITINIB	2	FECH
GSK-1070916	1	FECH
AZD-8055	1	FECH
MK-8033	1	FECH
JNJ-26483327	1	FECH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FECH	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FECH	4.99.1.1	protoporphyrin ferrochelatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
VEMURAFENIB	4	FECH
LENVATINIB	4	FECH
AXITINIB	4	FECH
NERATINIB	4	FECH
PACRITINIB	4	FECH
CABOZANTINIB	4	FECH
NILOTINIB	4	FECH
RIBOCICLIB	4	FECH
TUCATINIB	4	FECH
ERLOTINIB	4	FECH
GEFITINIB	4	FECH
LINSITINIB	3	FECH
RIGOSERTIB	3	FECH
CRENOLANIB	3	FECH
MK-2206	2	FECH
CC-401	2	FECH
MK-2461	2	FECH
ZOTIRACICLIB	2	FECH
VARLITINIB	2	FECH
RABUSERTIB	2	FECH
OSI-027	2	FECH
BGT-226 FREE BASE	2	FECH
R-406	2	FECH
CP-724714	2	FECH
BI-2536	2	FECH
PELITINIB	2	FECH
GSK-1070916	1	FECH
AZD-8055	1	FECH
MK-8033	1	FECH
JNJ-26483327	1	FECH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FECH
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05005975	PHASE3	RECRUITING	Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)
NCT04402489	PHASE3	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria or X-Linked Protoporphyria
NCT01688895	Not specified	COMPLETED	Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact
NCT02979249	Not specified	COMPLETED	Oral Iron for Erythropoietic Protoporphyrias

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DERSIMELAGON	3	1