Encephalopathy due to defective mitochondrial and peroxisomal fission 2

Summary

Encephalopathy due to defective mitochondrial and peroxisomal fission 2 (MONDO:0014905) is a disease caused by MFF (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MFF (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 20
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0040288	Nasogastric tube feeding	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000544	External ophthalmoplegia	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0000758	Impaired use of nonverbal behaviors	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0005484	Secondary microcephaly	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012087	Abnormal mitochondrial shape	Frequent (30-79%)
HP:0012696	Abnormal thalamic MRI signal intensity	Frequent (30-79%)
HP:0012736	Profound global developmental delay	Frequent (30-79%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Frequent (30-79%)
HP:0025112	Sound sensitivity	Frequent (30-79%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0011097	Epileptic spasm	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy due to defective mitochondrial and peroxisomal fission 2
Mondo ID	MONDO:0014905
OMIM	617086
Orphanet	485421
DOID	DOID:0060994
UMLS	C4310726
MedGen	934693
GARD	0017881
Is cancer (heuristic)	no

Also known as: EMPF2 · encephalopathy due to defective mitochondrial and peroxisomal fission 2 · encephalopathy due to defective mitochondrial and peroxisomal fission type 2 · Leigh-like basal ganglia disease-optic atrophy-peripheral neuropathy syndrome · MFF-associated encephalopathy due to peroxisomal and mitochondrial fission defect

Data availability: 20 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › encephalopathy due to mitochondrial and peroxisomal fission defect › encephalopathy due to defective mitochondrial and peroxisomal fission 2

Related subtypes (1): encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

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

20 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 pathogenic, 5 likely pathogenic, 2 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
253268	NM_001277062.2(MFF):c.106dup (p.Leu36fs)	MFF	Pathogenic	no assertion criteria provided
253269	NM_001277062.2(MFF):c.739C>T (p.Arg247Ter)	MFF	Pathogenic	no assertion criteria provided
253270	NM_001277062.2(MFF):c.375_376del (p.Glu127fs)	MFF	Pathogenic	criteria provided, single submitter
39831	NM_001277062.2(MFF):c.112C>T (p.Gln38Ter)	MFF	Pathogenic/Likely pathogenic	no assertion criteria provided
545568	NM_001277062.2(MFF):c.284del (p.Thr95fs)	MFF	Pathogenic	criteria provided, single submitter
996025	NM_001277062.2(MFF):c.355C>T (p.Arg119Ter)	MFF	Pathogenic	no assertion criteria provided
3065870	NM_001277062.2(MFF):c.-40-841T>G	MFF	Likely pathogenic	criteria provided, single submitter
3065879	NM_001277062.2(MFF):c.-40-842dup	MFF	Likely pathogenic	criteria provided, single submitter
4073431	NM_001277062.2(MFF):c.159del (p.Pro54fs)	MFF	Likely pathogenic	no assertion criteria provided
4073432	NM_001277062.2(MFF):c.352-2A>C	MFF	Likely pathogenic	no assertion criteria provided
4689263	NM_001277062.2(MFF):c.-40-842G>T	MFF	Likely pathogenic	criteria provided, single submitter
2176257	NM_001277062.2(MFF):c.403G>A (p.Val135Ile)	MFF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029745	NM_001277062.2(MFF):c.749T>G (p.Ile250Ser)	MFF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030331	NM_001277062.2(MFF):c.856T>C (p.Trp286Arg)	MFF	Uncertain significance	criteria provided, single submitter
1033937	NM_001277062.2(MFF):c.678A>G (p.Ile226Met)	MFF	Uncertain significance	criteria provided, single submitter
2510850	NM_001277062.2(MFF):c.223G>A (p.Asp75Asn)	MFF	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891660	NM_001277062.2(MFF):c.351_351+1insATCC	MFF	Uncertain significance	criteria provided, single submitter
634511	NM_001277062.2(MFF):c.337C>A (p.Pro113Thr)	MFF	Uncertain significance	criteria provided, single submitter
1577363	NM_001277062.2(MFF):c.92C>T (p.Pro31Leu)	MFF	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
382150	NM_001277062.2(MFF):c.630C>A (p.Ala210=)	MFF	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
MFF	Definitive	Autosomal recessive	encephalopathy due to defective mitochondrial and peroxisomal fission 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MFF	Orphanet:485421	MFF-related encephalopathy due to mitochondrial and peroxisomal fission defect

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MFF	HGNC:24858	ENSG00000168958	Q9GZY8	Mitochondrial fission factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MFF	Mitochondrial fission factor	Plays a role in mitochondrial and peroxisomal fission.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MFF	Other/Unknown	no		Mff/Tango-11, Mff-like_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFF	290	ubiquitous	marker	sperm, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFF	2,460

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MFF	Q9GZY8	64.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peroxisome fission	1	1532.0×	0.002	MFF
mitochondrial fission	1	1053.2×	0.002	MFF
positive regulation of mitochondrial fission	1	766.0×	0.002	MFF
obsolete protein targeting to mitochondrion	1	581.1×	0.002	MFF
mitochondrion organization	1	151.8×	0.007	MFF

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
MFF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	MFF

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MFF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.