Fumaric aciduria

Summary

Fumaric aciduria (MONDO:0011730) is a disease caused by FH (GenCC Definitive), with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FH (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 378
• Phenotypes (HPO): 44
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0003536	Decreased fumarate hydratase activity	Very frequent (80-99%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001298	Encephalopathy	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000817	Reduced eye contact	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001901	Polycythemia	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0003191	Cleft ala nasi	Occasional (5-29%)
HP:0006808	Cerebral hypomyelination	Occasional (5-29%)
HP:0010804	Tented upper lip vermilion	Occasional (5-29%)
HP:0012402	Increased urine alpha-ketoglutarate concentration	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0025646	Bilateral polymicrogyria	Occasional (5-29%)
HP:0034648	Elevated urine fumaric acid level	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0001942	Metabolic acidosis	Very rare (<1-4%)
HP:0001943	Hypoglycemia	Very rare (<1-4%)
HP:0001987	Hyperammonemia	Very rare (<1-4%)
HP:0003128	Lactic acidosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	fumaric aciduria
Mondo ID	MONDO:0011730
MeSH	C538191
OMIM	606812
Orphanet	24
DOID	DOID:0111261
SNOMED CT	237983002
UMLS	C0342770
MedGen	87458
GARD	0006476
Is cancer (heuristic)	no

Also known as: FMRD · fumarase deficiency · fumarate hydratase deficiency · fumaric aciduria

Data availability: 378 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › fumaric aciduria

Related subtypes (13): oxoglutaricaciduria, multiple acyl-CoA dehydrogenase deficiency, inborn mitochondrial myopathy, HSD10 mitochondrial disease, histiocytoid cardiomyopathy, hypotonia-cystinuria syndrome, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, mitochondrial pyruvate carrier deficiency, mitochondrial oxidative phosphorylation disorder, mitochondrial membrane transport disorder, inherited lipoic acid biosynthesis defect, pyruvate dehydrogenase deficiency, OPA1-related optic atrophy with or without extraocular features

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

378 retrieved; paginated sample, class counts are floors:

163 uncertain significance, 108 conflicting classifications of pathogenicity, 44 pathogenic/likely pathogenic, 25 pathogenic, 16 benign/likely benign, 13 likely pathogenic, 6 likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
831714	NC_000001.10:g.(?241661108)(242431558_?)del	CHML	Pathogenic	criteria provided, single submitter
1066054	NM_000143.4(FH):c.563A>T (p.Asn188Ile)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067932	NM_000143.4(FH):c.1037G>A (p.Gly346Asp)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067933	NM_000143.4(FH):c.953A>T (p.His318Leu)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324399	NM_000143.4(FH):c.1358T>C (p.Leu453Pro)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141355	NM_000143.4(FH):c.697C>T (p.Arg233Cys)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142654	NM_000143.4(FH):c.557G>A (p.Ser186Asn)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16232	NM_000143.4(FH):c.301C>T (p.Arg101Ter)	FH	Pathogenic	criteria provided, multiple submitters, no conflicts
16235	NM_000143.4(FH):c.1027C>T (p.Arg343Ter)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16236	NM_000143.4(FH):c.698G>A (p.Arg233His)	FH	Pathogenic	criteria provided, multiple submitters, no conflicts
1771552	NM_000143.4(FH):c.1391-1G>T	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
184555	NM_000143.4(FH):c.700A>G (p.Thr234Ala)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185496	NM_000143.4(FH):c.786_806del (p.Lys263_Ile269del)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198391	NM_000143.4(FH):c.912_918del (p.Phe305fs)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208374	NM_000143.4(FH):c.905-1G>A	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214387	NM_000143.4(FH):c.1391-1G>C	FH	Pathogenic	criteria provided, multiple submitters, no conflicts
214389	NM_000143.4(FH):c.139C>T (p.Gln47Ter)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214399	NM_000143.4(FH):c.1083_1086del (p.Glu362fs)	FH	Pathogenic	criteria provided, multiple submitters, no conflicts
214405	NM_000143.4(FH):c.1370_1371insTCAC (p.Ala458fs)	FH	Pathogenic	criteria provided, multiple submitters, no conflicts
214412	NM_000143.4(FH):c.904+1G>A	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214419	NM_000143.4(FH):c.1097G>A (p.Ser366Asn)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214422	NM_000143.4(FH):c.1189G>A (p.Gly397Arg)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214423	NM_000143.4(FH):c.1391-2A>T	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573279	NM_000143.4(FH):c.490del (p.Met164fs)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265147	NM_000143.4(FH):c.668_669del (p.Lys223fs)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265150	NM_000143.4(FH):c.1390+1G>T	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675690	NM_000143.4(FH):c.839del (p.Gly280fs)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675693	NM_000143.4(FH):c.32C>A (p.Ser11Ter)	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2699515	NM_000143.4(FH):c.905-2A>C	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2762052	NM_000143.4(FH):c.738+1G>C	FH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · 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
FH	Definitive	Autosomal recessive	fumaric aciduria	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FH	Orphanet:24	Fumaric aciduria
FH	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
FH	Orphanet:523	Hereditary leiomyomatosis and renal cell cancer

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
FH	HGNC:3700	ENSG00000091483	P07954	Fumarate hydratase, mitochondrial	gencc,clinvar
OPN3	HGNC:14007	ENSG00000054277	Q9H1Y3	Opsin-3	clinvar
CHML	HGNC:1941	ENSG00000203668	P26374	Rab proteins geranylgeranyltransferase component A 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FH	Fumarate hydratase, mitochondrial	Catalyzes the reversible stereospecific interconversion of fumarate to L-malate.
OPN3	Opsin-3	G protein-coupled receptor which selectively activates G(i/o) proteins via ultraviolet A (UVA) light-mediated activation in the skin, thereby decreasing cellular cAMP.
CHML	Rab proteins geranylgeranyltransferase component A 2	Substrate-binding subunit (component A) of the Rab geranylgeranyltransferase (GGTase) complex.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
GPCR	1	8.0×	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)
FH	Enzyme (other)	yes	4.2.1.2	Fumarate_lyase_fam, Fum_hydII, L-Aspartase-like
OPN3	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM, Retinal_BS
CHML	Other/Unknown	no		Rab_escort, GDP_dissociation_inhibitor, FAD/NAD-bd_sf

Expression context

Cohort genes with no expression data: 0.

3 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
body of tongue	1
cardiac ventricle	1
heart right ventricle	1
middle temporal gyrus	1
placenta	1
tibia	1
cortical plate	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FH	292	ubiquitous	marker	heart right ventricle, body of tongue, cardiac ventricle
OPN3	273	ubiquitous	marker	middle temporal gyrus, placenta, tibia
CHML	251	broad	marker	sperm, cortical plate, male germ cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FH	3,709
CHML	916
OPN3	747

Intra-cohort edges

A	B	Sources
CHML	OPN3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FH	P07954	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OPN3	Q9H1Y3	80.71
CHML	P26374	79.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Opsins	1	423.0×	0.014	OPN3
Citric acid cycle (TCA cycle)	1	141.0×	0.021	FH
RAB geranylgeranylation	1	57.7×	0.031	CHML
RAB GEFs exchange GTP for GDP on RABs	1	41.4×	0.031	CHML
Mitochondrial protein degradation	1	38.1×	0.031	FH
G alpha (i) signalling events	1	13.0×	0.075	OPN3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fumarate metabolic process	1	5617.3×	0.003	FH
detection of light stimulus	1	5617.3×	0.003	OPN3
obsolete regulation of arginine metabolic process	1	2808.7×	0.004	FH
response to blue light	1	1123.5×	0.005	OPN3
protein geranylgeranylation	1	936.2×	0.005	CHML
arginine metabolic process	1	802.5×	0.005	FH
negative regulation of melanin biosynthetic process	1	802.5×	0.005	OPN3
positive regulation of eating behavior	1	802.5×	0.005	OPN3
malate metabolic process	1	624.1×	0.005	FH
positive regulation of cellular respiration	1	624.1×	0.005	OPN3
positive regulation of melanin biosynthetic process	1	468.1×	0.005	OPN3
cellular response to UV-A	1	468.1×	0.005	OPN3
urea cycle	1	432.1×	0.005	FH
cellular response to light stimulus	1	351.1×	0.006	OPN3
positive regulation of double-strand break repair via nonhomologous end joining	1	330.4×	0.006	FH
tricarboxylic acid cycle	1	170.2×	0.011	FH
phototransduction	1	165.2×	0.011	OPN3
positive regulation of D-glucose import across plasma membrane	1	151.8×	0.011	OPN3
homeostasis of number of cells within a tissue	1	147.8×	0.011	FH
regulation of circadian rhythm	1	86.4×	0.017	OPN3
keratinocyte differentiation	1	82.6×	0.017	OPN3
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	73.0×	0.019	OPN3
small GTPase-mediated signal transduction	1	61.1×	0.021	CHML
positive regulation of cold-induced thermogenesis	1	54.5×	0.023	FH
vesicle-mediated transport	1	32.1×	0.037	CHML
intracellular protein transport	1	21.6×	0.051	CHML
DNA repair	1	21.3×	0.051	FH
DNA damage response	1	17.8×	0.059	FH
G protein-coupled receptor signaling pathway	1	12.1×	0.083	OPN3
negative regulation of apoptotic process	1	11.6×	0.084	OPN3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FH	0	0
OPN3	0	0
CHML	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
OPN3	2	Binding:2
FH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FH	4.2.1.2	fumarate hydratase

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

0 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.

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	0
C	Druggable family + PDB, no drug	1	FH
D	Druggable family + AlphaFold only, no drug	1	OPN3
E	Difficult family or no structure, no drug	1	CHML

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FH	1	—
OPN3	2	—
CHML	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04387500	PHASE2	UNKNOWN	Sintilimab Injection Combined With Inlyta in Fumarate Hydratase- Deficient Renal Cell Carcinoma
NCT04623502	Not specified	RECRUITING	An Investigation of Kidney and Urothelial Tumor Metabolism in Patients Undergoing Surgical Resection and/or Biopsy