Fatal multiple mitochondrial dysfunctions syndrome

Summary

Fatal multiple mitochondrial dysfunctions syndrome (MONDO:0017338) is a disease (an umbrella term covering 9 Mondo subtypes) with 2 cohort genes and 1 clinical trial.

At a glance

• Umbrella term: 9 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	fatal multiple mitochondrial dysfunctions syndrome
Mondo ID	MONDO:0017338
MeSH	C565304
OMIM	605711
Orphanet	289573
DOID	DOID:0070330
SNOMED CT	720827002
UMLS	C3502075
MedGen	502474
GARD	0012632
Is cancer (heuristic)	no

Also known as: fatal multiple mitochondrial dysfunction syndrome · MMDS · multiple mitochondrial dysfunctions syndrome

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › inherited lipoic acid biosynthesis defect › fatal multiple mitochondrial dysfunctions syndrome

Related subtypes (5): pyruvate dehydrogenase E3 deficiency, lipoic acid synthetase deficiency, lipoyl transferase 1 deficiency, spasticity-ataxia-gait anomalies syndrome, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities

Subtypes (9): multiple mitochondrial dysfunctions syndrome 1, multiple mitochondrial dysfunctions syndrome 2, multiple mitochondrial dysfunctions syndrome 3, multiple mitochondrial dysfunctions syndrome 4, multiple mitochondrial dysfunctions syndrome 5, multiple mitochondrial dysfunctions syndrome 6, multiple mitochondrial dysfunctions syndrome 7, multiple mitochondrial dysfunctions syndrome 9b, multiple mitochondrial dysfunctions syndrome 10

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
183353	NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)	ISCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375415	NM_030940.4(ISCA1):c.259G>A (p.Glu87Lys)	ISCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ISCA2	Orphanet:457406	Multiple mitochondrial dysfunctions syndrome type 4
ISCA1	Orphanet:569274	Multiple mitochondrial dysfunctions syndrome type 5

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
ISCA2	HGNC:19857	ENSG00000165898	Q86U28	Iron-sulfur cluster assembly 2 homolog, mitochondrial	clinvar
ISCA1	HGNC:28660	ENSG00000135070	Q9BUE6	Iron-sulfur cluster assembly 1 homolog, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ISCA2	Iron-sulfur cluster assembly 2 homolog, mitochondrial	Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway.
ISCA1	Iron-sulfur cluster assembly 1 homolog, mitochondrial	Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway.

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)
ISCA2	Other/Unknown	no		ATAP_core_dom, ATAP, FeS_cluster_insertion_CS
ISCA1	Other/Unknown	no		ATAP_core_dom, ATAP, FeS_cluster_insertion_CS

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
cardiac muscle of right atrium	1
deltoid	1
left ventricle myocardium	1
biceps brachii	1
endothelial cell	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ISCA2	257	ubiquitous	marker	left ventricle myocardium, deltoid, cardiac muscle of right atrium
ISCA1	296	ubiquitous	marker	endothelial cell, biceps brachii, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ISCA1	1,689
ISCA2	1,444

Intra-cohort edges

A	B	Sources
ISCA1	ISCA2	intact, string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ISCA1	Q9BUE6	90.18
ISCA2	Q86U28	77.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Mitochondrial iron-sulfur cluster biogenesis	2	815.7×	7e-06	ISCA2, ISCA1
Maturation of TCA enzymes and regulation of TCA cycle	2	571.0×	7e-06	ISCA2, ISCA1
Citric acid cycle (TCA cycle)	2	423.0×	9e-06	ISCA2, ISCA1
Aerobic respiration and respiratory electron transport	2	88.5×	2e-04	ISCA2, ISCA1
Metabolism	2	11.6×	0.007	ISCA2, ISCA1

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
iron-sulfur cluster assembly	2	601.9×	5e-06	ISCA2, ISCA1
protein maturation	2	163.6×	4e-05	ISCA2, ISCA1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ISCA2	0	0
ISCA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	ISCA2, ISCA1

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)
ISCA2	0	—
ISCA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01439854	Not specified	COMPLETED	Study of Dapagliflozin on Mitochondrial Dysfunction and Impaired Insulin Signaling/Action

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHEMBL4281478	0	1