Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy

Summary

Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy (MONDO:0020714) is a disease caused by FDX2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FDX2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
Mondo ID	MONDO:0020714
OMIM	251900
UMLS	C5193223
MedGen	1679560
GARD	0025221
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, mitochondrial encephalomyopathy, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, autosomal dominant mitochondrial myopathy with exercise intolerance, fatal infantile encephalocardiomyopathy, mitochondrial myopathy-lactic acidosis-deafness syndrome, mitochondrial neurogastrointestinal encephalomyopathy, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial complex II deficiency, nuclear type, mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome, X-linked recessive mitochondrial myopathy, mitochondrial complex I deficiency, nuclear type 1, COX deficiency, benign infantile mitochondrial myopathy

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

5 retrieved; paginated sample, class counts are floors:

2 benign, 1 conflicting classifications of pathogenicity, 1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9715	NC_012920.1(MT-ND3):m.10197G>A	MT-ND3	Pathogenic	reviewed by expert panel
143059	NM_001397406.1(FDX2):c.1A>T (p.Met1Leu)	FDX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2920671	NM_001397406.1(FDX2):c.200+4A>G	FDX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
380037	NM_001397406.1(FDX2):c.45A>G (p.Leu15=)	FDX2	Benign	criteria provided, multiple submitters, no conflicts
380038	NM_001397406.1(FDX2):c.159T>G (p.Ala53=)	FDX2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
FDX2	Strong	Autosomal recessive	mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MT-ND3	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND3	Orphanet:2609	Isolated complex I deficiency
MT-ND3	Orphanet:99718	Leber plus disease

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
FDX2	HGNC:30546	ENSG00000267673	Q6P4F2	Ferredoxin-2, mitochondrial	gencc,clinvar
MT-ND3	HGNC:7458	ENSG00000198840	P03897	NADH-ubiquinone oxidoreductase chain 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FDX2	Ferredoxin-2, mitochondrial	Electron donor, of the core iron-sulfur cluster (ISC) assembly complex, that acts to reduce the persulfide into sulfide during [2Fe-2S] clusters assembly on the scaffolding protein ISCU.
MT-ND3	NADH-ubiquinone oxidoreductase chain 3	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FDX2	Other/Unknown	no		2Fe-2S_ferredoxin-type, Adrenodoxin-like, Beta-grasp_dom_sf
MT-ND3	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su3, NDAH_ubi_oxred_su3_sf

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
anterior cingulate cortex	1
frontal cortex	1
prefrontal cortex	1
adipose tissue	1
granulocyte	1
left lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FDX2	134	ubiquitous	marker	prefrontal cortex, frontal cortex, anterior cingulate cortex
MT-ND3	134	ubiquitous	marker	granulocyte, adipose tissue, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-ND3	2,923
FDX2	2,374

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FDX2	Q6P4F2	5
MT-ND3	P03897	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Electron transport from NADPH to Ferredoxin	1	1427.5×	0.004	FDX2
Defective CYP11A1 causes AICSR	1	1142.0×	0.004	FDX2
Mitochondrial iron-sulfur cluster biogenesis	1	407.9×	0.005	FDX2
Pregnenolone biosynthesis	1	407.9×	0.005	FDX2
Endogenous sterols	1	196.9×	0.008	FDX2
Complex I biogenesis	1	82.8×	0.016	MT-ND3
Mitochondrial translation termination	1	54.9×	0.021	MT-ND3
Respiratory electron transport	1	47.6×	0.021	MT-ND3

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
P450-containing electron transport chain	1	2808.7×	0.003	FDX2
[4Fe-4S] cluster assembly	1	1685.2×	0.003	FDX2
response to light intensity	1	1053.2×	0.003	MT-ND3
electron transport chain	1	766.0×	0.003	FDX2
[2Fe-2S] cluster assembly	1	702.2×	0.003	FDX2
ubiquinone biosynthetic process	1	468.1×	0.004	FDX2
cellular response to glucocorticoid stimulus	1	312.1×	0.005	MT-ND3
iron-sulfur cluster assembly	1	300.9×	0.005	FDX2
mitochondrial electron transport, NADH to ubiquinone	1	179.3×	0.007	MT-ND3
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.009	MT-ND3
aerobic respiration	1	123.9×	0.009	MT-ND3
response to oxidative stress	1	65.3×	0.015	MT-ND3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FDX2	0	0
MT-ND3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MT-ND3	4	Binding:4

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

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	0
E	Difficult family or no structure, no drug	2	FDX2, MT-ND3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FDX2	0	—
MT-ND3	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.