Encephalopathy due to mitochondrial and peroxisomal fission defect

Summary

Encephalopathy due to mitochondrial and peroxisomal fission defect (MONDO:0054865) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy due to mitochondrial and peroxisomal fission defect
Mondo ID	MONDO:0054865
OMIM	614388
Orphanet	527276
UMLS	C5681458
MedGen	1814479
GARD	0022192
Is cancer (heuristic)	no

Also known as: encephalopathy due to defective mitochondrial and peroxisomal fission · encephalopathy due to mitochondrial and peroxisomal fission defect

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (70): leukoencephalopathy, megalencephalic, encephalopathy, acute, infection-induced, diabetic encephalopathy, complex cortical dysplasia with other brain malformations, hydrocephalus, brain compression, cerebral sarcoidosis, hepatic encephalopathy, visual pathway disorder, central nervous system origin vertigo, cerebellar disorder, cerebritis, olfactory nerve disorder, thalamic disorder, pituitary gland disorder, disorder of optic chiasm, basal ganglia disorder, epilepsy, mental disorder, central nervous system cyst, migraine disorder, multiple sclerosis, prion disease, carbon monoxide-induced delayed encephalopathy, cerebral malaria, akinetic mutism, bulbar polio, Reye syndrome, brain edema, encephalomalacia, intracranial hypertension, intracranial hypotension, Wernicke encephalopathy, encephalopathy, recurrent, of childhood, XK aprosencephaly, progressive bulbar palsy, cerebrovascular disorder, glycine encephalopathy, autosomal recessive frontotemporal pachygyria, occipital pachygyria and polymicrogyria, insomnia, narcolepsy-cataplexy syndrome, megalencephaly, meningoencephalocele, cerebral cortical dysplasia, encephaloclastic disorder, bilirubin encephalopathy, autoimmune encephalopathy with parasomnia and obstructive sleep apnea, narcolepsy without cataplexy, hypothalamic hamartomas with gelastic seizures, encephalitis, cerebral lipidosis with dementia, brain neoplasm, colpocephaly, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cerebral degeneration, acute bilirubin encephalopathy, chronic bilirubin encephalopathy, atelencephaly, aprosencephaly, brain injury, traumatic encephalopathy, cluster headache syndrome, cerebral cortex disorder, midbrain disorder, brain malformations with or without urinary tract defects, encephalopathy, acute transient

Subtypes (2): encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, encephalopathy due to defective mitochondrial and peroxisomal fission 2

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3770240	NM_012062.5(DNM1L):c.223A>G (p.Lys75Glu)	DNM1L	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
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
DNM1L	Orphanet:330050	DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect
DNM1L	Orphanet:98673	Autosomal dominant optic atrophy, classic form

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
MFF	HGNC:24858	ENSG00000168958	Q9GZY8	Mitochondrial fission factor	gencc
DNM1L	HGNC:2973	ENSG00000087470	O00429	Dynamin-1-like protein	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.
DNM1L	Dynamin-1-like protein	Functions in mitochondrial and peroxisomal division.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MFF	Other/Unknown	no		Mff/Tango-11, Mff-like_dom
DNM1L	Enzyme (other)	yes	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, GED

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
sperm	2
left testis	1
right testis	1
lateral nuclear group of thalamus	1
substantia nigra pars compacta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFF	290	ubiquitous	marker	sperm, left testis, right testis
DNM1L	295	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, sperm

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNM1L	4,801
MFF	2,460

Intra-cohort edges

A	B	Sources
DNM1L	MFF	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNM1L	O00429	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MFF	Q9GZY8	64.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Apoptotic execution phase	1	475.8×	0.002	DNM1L

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
peroxisome fission	2	1532.0×	8e-06	MFF, DNM1L
mitochondrial fission	2	1053.2×	9e-06	MFF, DNM1L
positive regulation of mitochondrial fission	2	766.0×	1e-05	MFF, DNM1L
mitochondrion organization	2	151.8×	2e-04	MFF, DNM1L
mitochondrial membrane fission	1	4213.0×	8e-04	DNM1L
regulation of ATP metabolic process	1	4213.0×	8e-04	DNM1L
regulation of peroxisome organization	1	2808.7×	0.001	DNM1L
mitocytosis	1	1404.3×	0.002	DNM1L
intracellular distribution of mitochondria	1	1203.7×	0.002	DNM1L
mitochondrial fragmentation involved in apoptotic process	1	702.2×	0.003	DNM1L
protein localization to mitochondrion	1	648.1×	0.003	DNM1L
regulation of mitophagy	1	601.9×	0.003	DNM1L
heart contraction	1	383.0×	0.004	DNM1L
protein complex oligomerization	1	337.0×	0.004	DNM1L
positive regulation of neutrophil chemotaxis	1	324.1×	0.004	DNM1L
obsolete protein targeting to mitochondrion	1	290.6×	0.005	MFF
positive regulation of protein secretion	1	172.0×	0.007	DNM1L
rhythmic process	1	125.8×	0.009	DNM1L
calcium ion transport	1	90.6×	0.012	DNM1L
endocytosis	1	47.6×	0.022	DNM1L
regulation of gene expression	1	41.7×	0.024	DNM1L

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
MFF	0	0
DNM1L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DNM1L	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNM1L	3.6.5.5	dynamin GTPase

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	1	DNM1L
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MFF

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)
MFF	0	—
DNM1L	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.