Hereditary recurrent myoglobinuria

Summary

Hereditary recurrent myoglobinuria (MONDO:0020504) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 3
• Phenotypes (HPO): 32

Clinical features

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0003652	Recurrent myoglobinuria	Obligate (100%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0030234	Highly elevated creatine kinase	Very frequent (80-99%)
HP:0040319	Dark urine	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003554	Type 2 muscle fiber atrophy	Frequent (30-79%)
HP:0003558	Viral infection-induced rhabdomyolysis	Frequent (30-79%)
HP:0003738	Exercise-induced myalgia	Frequent (30-79%)
HP:0008305	Exercise-induced myoglobinuria	Frequent (30-79%)
HP:0010969	Abnormality of glycolipid metabolism	Frequent (30-79%)
HP:0012544	Elevated circulating aldolase concentration	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0100614	Myositis	Frequent (30-79%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0000467	Neck muscle weakness	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0002153	Hyperkalemia	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0002905	Hyperphosphatemia	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0005216	Impaired mastication	Occasional (5-29%)
HP:0007340	Lower limb muscle weakness	Occasional (5-29%)
HP:0008997	Proximal muscle weakness in upper limbs	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0030195	Fatigable weakness of swallowing muscles	Occasional (5-29%)
HP:0045037	Abnormality of jaw muscles	Occasional (5-29%)
HP:0100520	Oliguria	Occasional (5-29%)
HP:0005521	Disseminated intravascular coagulation	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary recurrent myoglobinuria
Mondo ID	MONDO:0020504
Orphanet	99845
SNOMED CT	716721003
UMLS	C4274324
MedGen	901659
GARD	0016916
Is cancer (heuristic)	no

Also known as: genetic recurrent myoglobinuria

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › hereditary recurrent myoglobinuria

Related subtypes (92): thiopurine metabolic disease, hypercalcemia, infantile, hypermanganesemia with dystonia, abdominal obesity-metabolic syndrome, plasma protein metabolism disease, inherited lipid metabolism disorder, lysosomal storage disease, striatonigral degeneration, inborn metal metabolism disorder, inborn vitamin metabolic disorder, chondrocalcinosis 2, Ehlers-Danlos syndrome, spondylodysplastic type, fish eye disease, aromatase excess syndrome, spondyloepiphyseal dysplasia with congenital joint dislocations, hypertriglyceridemia 1, autosomal dominant myoglobinuria, diastrophic dysplasia, hemolytic anemia due to diphosphoglycerate mutase deficiency, multiple epiphyseal dysplasia type 4, atelosteogenesis type II, inherited threoninemia, inborn glycerol kinase deficiency, achondrogenesis type IB, diabetes mellitus, noninsulin-dependent, 1, diabetes mellitus, noninsulin-dependent, 2, renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, diabetes mellitus, noninsulin-dependent, 3, hypercholesterolemia, familial, 4, hypoalphalipoproteinemia, primary, 1, autosomal recessive proximal renal tubular acidosis, diabetes mellitus, noninsulin-dependent, 4, normophosphatemic familial tumoral calcinosis, apolipoprotein c-III deficiency, hypotonia-failure to thrive-microcephaly syndrome, chondrodysplasia with joint dislocations, gPAPP type, gluthathione peroxidase deficiency, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diabetes mellitus, noninsulin-dependent, 5, congenital disorder of glycosylation, monogenic diabetes, 2-hydroxyglutaric aciduria, familial hypoparathyroidism, familial intrahepatic cholestasis, inborn aminoacylase deficiency, disorder of lysosomal-related organelles, inborn disorder of porphyrin metabolism, disorder of metabolite absorption and transport, autosomal dominant proximal renal tubular acidosis, neurodegeneration with brain iron accumulation, ferro-cerebro-cutaneous syndrome, familial hypocalciuric hypercalcemia, hypophosphatasia, hereditary amyloidosis, peroxisomal disease, inborn disorder of amino acid and other organic acid metabolism, inborn carbohydrate metabolic disorder, inborn disorder of energy metabolism, inborn disorder of biogenic amine metabolism and transport, inborn disorder of purine or pyrimidine metabolism, spondyloepimetaphyseal dysplasia, PAPSS2 type, hereditary lipodystrophy, DNA repair disease, 4-hydroxyphenylacetic aciduria, 5-nucleotidase syndrome, antigen-peptide-transporter 2 deficiency, APO A-i deficiency, cardiomyopathy hypogonadism metabolic anomalies, deficiency of coenzyme q cytochrome c reductase, defective apolipoprotein b-100, sulfide quinone oxidoreductase deficiency, congenital disorder of deglycosylation, hypoalphalipoproteinemia, primary, 2, uridine-cytidineuria, NAD(P)HX dehydratase deficiency, inborn disorder of aspartate family metabolism, weinstein kliman scully syndrome, glycoprotein metabolism disease, inherited thyroid metabolism disease, tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 3, combined ApoA-I and ApoC-III deficiency, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, tumoral calcinosis, hyperphosphatemic, familial, 1, Waldenstrom macroglobulinemia, mucopolysaccharidosis or mucopolysaccharidosis-like disorder, disorder of peptide and amine metabolism, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis, Lane Hamilton syndrome, SQSTM1-related multisystem proteinopathy, hypertriglyceridemia 2, autosomal dominant dopa-responsive dystonia

Subtypes (2): myoglobinuria, acute recurrent, autosomal recessive, myoglobinuria, recurrent

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 10 · 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
LPIN1	Definitive	Autosomal recessive	myoglobinuria, acute recurrent, autosomal recessive	6
MT-CO1	Supportive	Autosomal dominant	hereditary recurrent myoglobinuria	4
MT-CO3	Supportive	Autosomal dominant	hereditary recurrent myoglobinuria	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LPIN1	Orphanet:99845	Genetic recurrent myoglobinuria
MT-CO1	Orphanet:104	Leber hereditary optic neuropathy
MT-CO1	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO1	Orphanet:550	MELAS
MT-CO1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-CO1	Orphanet:99845	Genetic recurrent myoglobinuria
MT-CO3	Orphanet:104	Leber hereditary optic neuropathy
MT-CO3	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO3	Orphanet:550	MELAS
MT-CO3	Orphanet:99845	Genetic recurrent myoglobinuria

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
LPIN1	HGNC:13345	ENSG00000134324	Q14693	Phosphatidate phosphatase LPIN1	gencc
MT-CO1	HGNC:7419	ENSG00000198804	P00395	Cytochrome c oxidase subunit 1	gencc
MT-CO3	HGNC:7422	ENSG00000198938	P00414	Cytochrome c oxidase subunit 3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LPIN1	Phosphatidate phosphatase LPIN1	Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis and therefore controls…
MT-CO1	Cytochrome c oxidase subunit 1	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-CO3	Cytochrome c oxidase subunit 3	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LPIN1	Enzyme (other)	yes	3.1.3.4	Lipin_N, LNS2, LIPIN
MT-CO1	Enzyme (other)	yes	7.1.1.9	Cyt_C_Oxase_1, Cyt_c_Oxase_su1_BS, Cyt_c_oxase-like_su1_dom
MT-CO3	Other/Unknown	no		Cyt_c_oxidase-like_su3, Cyt_c_oxidase_su3_a-hlx, Cyt_c/ubiquinol_Oxase_su3

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
rectum	2
lower esophagus mucosa	1
male germ cell	1
sperm	1
granulocyte	1
stromal cell of endometrium	1
endocervix	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LPIN1	297	ubiquitous	marker	sperm, male germ cell, lower esophagus mucosa
MT-CO1	134	ubiquitous	marker	granulocyte, stromal cell of endometrium, rectum
MT-CO3	134	ubiquitous	marker	zone of skin, endocervix, rectum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-CO1	3,547
LPIN1	1,992
MT-CO3	1,791

Intra-cohort edges

A	B	Sources
MT-CO1	MT-CO3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-CO1	P00395	3
MT-CO3	P00414	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LPIN1	Q14693	60.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. 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
Complex IV assembly	2	152.3×	0.001	MT-CO1, MT-CO3
Cytoprotection by HMOX1	2	122.8×	0.001	MT-CO1, MT-CO3
TP53 Regulates Metabolic Genes	2	86.5×	0.002	MT-CO1, MT-CO3
Mitochondrial translation termination	2	73.2×	0.002	MT-CO1, MT-CO3
Respiratory electron transport	2	63.4×	0.002	MT-CO1, MT-CO3
Synthesis of PE	1	292.8×	0.013	LPIN1
Depolymerization of the Nuclear Lamina	1	253.8×	0.013	LPIN1
Triglyceride biosynthesis	1	223.9×	0.013	LPIN1
Triglyceride metabolism	1	223.9×	0.013	LPIN1
Nuclear Envelope Breakdown	1	152.3×	0.017	LPIN1
Synthesis of PC	1	135.9×	0.017	LPIN1
Mitotic Prophase	1	122.8×	0.018	LPIN1
Glycerophospholipid biosynthesis	1	112.0×	0.018	LPIN1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	71.8×	0.025	LPIN1
Phospholipid metabolism	1	66.8×	0.025	LPIN1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	65.6×	0.025	LPIN1
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.030	LPIN1
Mitochondrial protein degradation	1	38.1×	0.038	MT-CO1
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.049	LPIN1
Epigenetic regulation of gene expression	1	23.8×	0.054	LPIN1
M Phase	1	22.0×	0.055	LPIN1
Cell Cycle, Mitotic	1	16.1×	0.072	LPIN1
Cell Cycle	1	12.0×	0.092	LPIN1
Metabolism of lipids	1	10.5×	0.100	LPIN1
Gene expression (Transcription)	1	6.0×	0.165	LPIN1
Metabolism	1	3.9×	0.237	LPIN1

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
mitochondrial electron transport, cytochrome c to oxygen	2	510.7×	1e-04	MT-CO1, MT-CO3
cellular respiration	2	288.1×	2e-04	MT-CO1, MT-CO3
negative regulation of phosphatidic acid biosynthetic process	1	5617.3×	0.001	LPIN1
triglyceride mobilization	1	1404.3×	0.004	LPIN1
phosphatidylethanolamine metabolic process	1	1123.5×	0.004	LPIN1
phosphatidic acid metabolic process	1	936.2×	0.004	LPIN1
respiratory chain complex IV assembly	1	802.5×	0.004	MT-CO3
mitotic nuclear membrane disassembly	1	624.1×	0.004	LPIN1
negative regulation of myelination	1	624.1×	0.004	LPIN1
response to copper ion	1	510.7×	0.004	MT-CO1
fatty acid catabolic process	1	432.1×	0.005	LPIN1
respiratory electron transport chain	1	280.9×	0.007	MT-CO1
triglyceride biosynthetic process	1	244.2×	0.007	LPIN1
response to electrical stimulus	1	216.1×	0.007	MT-CO1
animal organ regeneration	1	200.6×	0.007	LPIN1
cerebellum development	1	119.5×	0.011	MT-CO1
aerobic respiration	1	82.6×	0.016	MT-CO1
cellular response to insulin stimulus	1	56.7×	0.021	LPIN1
positive regulation of cold-induced thermogenesis	1	54.5×	0.021	LPIN1
response to oxidative stress	1	43.5×	0.025	MT-CO1
response to hypoxia	1	31.9×	0.032	MT-CO1
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	LPIN1

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
LPIN1	0	0
MT-CO1	0	0
MT-CO3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
MT-CO1	19	Binding:12, Functional:4, ADMET:2, Toxicity:1
MT-CO3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LPIN1	3.1.3.4	phosphatidate phosphatase
MT-CO1	7.1.1.9	cytochrome-c oxidase

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	MT-CO1
D	Druggable family + AlphaFold only, no drug	1	LPIN1
E	Difficult family or no structure, no drug	1	MT-CO3

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)
LPIN1	0	—
MT-CO1	19	—
MT-CO3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.