Inborn mitochondrial metabolism disorder

Summary

Inborn mitochondrial metabolism disorder (MONDO:0004069) is a disease (an umbrella term covering 14 Mondo subtypes) with 3 cohort genes and 103 clinical trials. Top therapeutic interventions include dextromethorphan, cysteamine bitartrate, and esflurbiprofen.

At a glance

• Umbrella term: 14 Mondo subtypes
• Cohort genes: 3
• Clinical trials: 103

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inborn mitochondrial metabolism disorder
Mondo ID	MONDO:0004069
MeSH	D028361
Orphanet	68380
DOID	DOID:700
UMLS	C1456275
MedGen	1778113
GARD	0018887
Is cancer (heuristic)	no

Also known as: mitochondrial disease · mitochondrial genetic disorders

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 14 Mondo subtypes.

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

Related subtypes (56): Neu-Laxova syndrome, Ehlers-Danlos syndrome, spondylodysplastic type, MGAT2-congenital disorder of glycosylation, ALDH18A1-related de Barsy syndrome, classic homocystinuria, Larsen-like syndrome, B3GAT3 type, Nijmegen breakage syndrome, Peters plus syndrome, Wiedemann-Rautenstrauch syndrome, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, SHORT syndrome, mucosulfatidosis, CHIME syndrome, creatine transporter deficiency, multiple congenital anomalies-hypotonia-seizures syndrome 2, SLC35A2-congenital disorder of glycosylation, SSR4-congenital disorder of glycosylation, Fabry disease, occipital horn syndrome, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, B4GALT1-congenital disorder of glycosylation, AICA-ribosiduria, COG7-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, Al-Gazali syndrome, COG1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, Nijmegen breakage syndrome-like disorder, multiple congenital anomalies-hypotonia-seizures syndrome 1, multiple congenital anomalies-hypotonia-seizures syndrome 3, autism spectrum disorder - epilepsy - arthrogryposis syndrome, cutis laxa, autosomal dominant 3, SLC39A8-CDG, transketolase deficiency, mucopolysaccharidosis-plus syndrome, Cockayne syndrome, pontocerebellar hypoplasia type 1, mandibuloacral dysplasia, hyperphosphatasia-intellectual disability syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, CADDS, XYLT1-congenital disorder of glycosylation, hypophosphatasia, sterol biosynthesis disorder, mucolipidosis, mucopolysaccharidosis, oligosaccharidosis, encephalopathy due to sulfite oxidase deficiency, Fanconi anemia, autosomal recessive cutis laxa type 2, Zellweger spectrum disorders, pseudohypoparathyroidism, developmental and epileptic encephalopathy, 77, glycosylphosphatidylinositol biosynthesis defect 15, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN

Subtypes (14): oxoglutaricaciduria, multiple acyl-CoA dehydrogenase deficiency, inborn mitochondrial myopathy, HSD10 mitochondrial disease, histiocytoid cardiomyopathy, hypotonia-cystinuria syndrome, fumaric aciduria, 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 0 · 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
GATB	Moderate	Autosomal recessive	inborn mitochondrial metabolism disorder
GATC	Limited	Autosomal recessive	inborn mitochondrial metabolism disorder	2
SLIRP	Limited	Autosomal recessive	inborn mitochondrial metabolism disorder	2

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
SLIRP	HGNC:20495	ENSG00000119705	Q9GZT3	SRA stem-loop-interacting RNA-binding protein, mitochondrial	gencc
GATC	HGNC:25068	ENSG00000257218	O43716	Glutamyl-tRNA(Gln) amidotransferase subunit C, mitochondrial	gencc
GATB	HGNC:8849	ENSG00000059691	O75879	Glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLIRP	SRA stem-loop-interacting RNA-binding protein, mitochondrial	RNA-binding protein that acts as a nuclear receptor corepressor.
GATC	Glutamyl-tRNA(Gln) amidotransferase subunit C, mitochondrial	Allows the formation of correctly charged Gln-tRNA(Gln) through the transamidation of misacylated Glu-tRNA(Gln) in the mitochondria.
GATB	Glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial	Allows the formation of correctly charged Gln-tRNA(Gln) through the transamidation of misacylated Glu-tRNA(Gln) in the mitochondria.

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)
SLIRP	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, SLIRP_RRM
GATC	Enzyme (other)	yes	6.3.5.7	GatC, Asp/Glu-ADT_sf_sub_c
GATB	Enzyme (other)	yes	6.3.5.7	Asn/Gln_tRNA_amidoTrase-B-like, GatB, Asn/Gln-tRNA_Trfase_suB/E_cat

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
C1 segment of cervical spinal cord	2
hindlimb stylopod muscle	1
mucosa of transverse colon	1
globus pallidus	1
medial globus pallidus	1
tendon of biceps brachii	1
apex of heart	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLIRP	287	ubiquitous	marker	mucosa of transverse colon, hindlimb stylopod muscle, C1 segment of cervical spinal cord
GATC	258	ubiquitous	marker	tendon of biceps brachii, medial globus pallidus, globus pallidus
GATB	261	ubiquitous	marker	C1 segment of cervical spinal cord, apex of heart, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLIRP	3,455
GATB	2,294
GATC	1,044

Intra-cohort edges

A	B	Sources
GATB	GATC	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLIRP	Q9GZT3	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GATB	O75879	85.53
GATC	O43716	78.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Mitochondrial RNA degradation	1	1631.4×	0.001	SLIRP
Mitochondrial mRNA modification	1	1038.2×	0.001	SLIRP
Metabolism of RNA	1	41.7×	0.024	SLIRP

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
glutaminyl-tRNAGln biosynthesis via transamidation	2	3744.9×	6e-07	GATC, GATB
mitochondrial translation	2	115.8×	4e-04	GATC, GATB
negative regulation of mitochondrial mRNA catabolic process	1	2808.7×	0.001	SLIRP
mitochondrial mRNA polyadenylation	1	1404.3×	0.002	SLIRP
regulation of translational fidelity	1	1123.5×	0.002	GATC
single fertilization	1	61.1×	0.023	SLIRP
mitochondrion organization	1	50.6×	0.023	SLIRP
spermatid development	1	48.4×	0.023	SLIRP
flagellated sperm motility	1	39.0×	0.025	SLIRP

Therapeutics

Drugs indicated for this disease

1 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Valproic Acid	Approved (phase 4)
Ubidecarenone	Phase 3 (in late-stage trials)
Vatiquinone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bezafibrate, Elamipretide, Icatibant.

Drug target analysis

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

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
SLIRP	0	0
GATC	0	0
GATB	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
SLIRP	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GATC	6.3.5.7	glutaminyl-tRNA synthase (glutamine-hydrolysing)
GATB	6.3.5.7	glutaminyl-tRNA synthase (glutamine-hydrolysing)

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	0
D	Druggable family + AlphaFold only, no drug	2	GATC, GATB
E	Difficult family or no structure, no drug	1	SLIRP

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)
SLIRP	1	—
GATC	0	—
GATB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 103.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	68
PHASE2	16
PHASE1	10
PHASE3	3
PHASE1/PHASE2	3
PHASE4	1
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT01694940	Not specified	RECRUITING	North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT02000284	Not specified	ACTIVE_NOT_RECRUITING	Mitochondrial Dysfunction in Autism Spectrum Disorder
NCT04113447	Not specified	RECRUITING	Mitochondrial Donation: An 18 Month Outcome Study.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXTROMETHORPHAN	4	3
CYSTEAMINE BITARTRATE	4	1
ESFLURBIPROFEN	4	1
FLURBIPROFEN	4	1
ICATIBANT	4	1
METFORMIN	4	1
NIACINAMIDE	4	1
PROBUCOL	4	1
REPAGLINIDE	4	1
TRIGLYCERIDES, MEDIUM-CHAIN	4	1
URIDINE TRIACETATE	4	1
SONLICROMANOL	3	5
ELAMIPRETIDE	3	4
VATIQUINONE	3	4
BEZAFIBRATE	3	1
L-CITRULLINE	3	1
MEDIUM-CHAIN TRIGLYCERIDES	3	1
NICOTINAMIDE RIBOSIDE	3	1
NAPAZIMONE	2	4
DOXECITINE	2	1
CHEMBL3739769	0	1