Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

Summary

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (MONDO:0013726) is a disease caused by DNM1L (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNM1L (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 62
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0012103	Abnormality of the mitochondrion	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0012707	Elevated brain lactate level by MRS	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001488	Bilateral ptosis	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002506	Diffuse cerebral atrophy	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0006801	Hyperactive deep tendon reflexes	Occasional (5-29%)
HP:0007359	Focal-onset seizure	Occasional (5-29%)
HP:0010553	Oculogyric crisis	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0012569	Delayed menarche	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1
Mondo ID	MONDO:0013726
OMIM	614388
Orphanet	330050
DOID	DOID:0070347
UMLS	C3280660
MedGen	482290
GARD	0017509
Is cancer (heuristic)	no

Also known as: DNM1L-associated encephalopathy due to peroxisomal and mitochondrial fission defect · EMPF · EMPF1 · encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission · encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 · lethal encephalopathy due to mitochondrial and peroxisomal fission defect

Data availability: 62 ClinVar variants · 7 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, lethal, due to defective mitochondrial peroxisomal fission 1

Related subtypes (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

62 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 16 likely pathogenic, 8 pathogenic, 5 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 4 benign/likely benign, 4 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1195874	NM_012062.5(DNM1L):c.176C>A (p.Thr59Asn)	DNM1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320222	NM_012062.5(DNM1L):c.1227_1228del (p.Glu410fs)	DNM1L	Pathogenic	criteria provided, single submitter
1506895	NM_012062.5(DNM1L):c.1674+1G>A	DNM1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136102	NM_012062.5(DNM1L):c.116G>A (p.Ser39Asn)	DNM1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214313	NM_012062.5(DNM1L):c.1207C>T (p.Arg403Cys)	DNM1L	Pathogenic	criteria provided, multiple submitters, no conflicts
253262	NM_012062.5(DNM1L):c.1084G>A (p.Gly362Ser)	DNM1L	Pathogenic	criteria provided, multiple submitters, no conflicts
253263	NM_001278464.2(DNM1L):c.261dup (p.Trp88fs)	DNM1L	Pathogenic	no assertion criteria provided
253264	NM_012062.5(DNM1L):c.346_347del (p.Glu116fs)	DNM1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3897542	NM_001278464.2(DNM1L):c.270C>G (p.Asn90Lys)	DNM1L	Pathogenic	criteria provided, single submitter
6015	NM_012062.5(DNM1L):c.1184C>A (p.Ala395Asp)	DNM1L	Pathogenic	no assertion criteria provided
619028	NM_012062.5(DNM1L):c.2072A>G (p.Tyr691Cys)	DNM1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689730	NM_012062.5(DNM1L):c.763_764dup (p.Lys256fs)	DNM1L	Pathogenic	criteria provided, single submitter
974819	NM_012062.5(DNM1L):c.115A>G (p.Ser39Gly)	DNM1L	Pathogenic	criteria provided, single submitter
1503004	NM_012062.5(DNM1L):c.1596+2T>A	DNM1L	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803023	NM_012062.5(DNM1L):c.1247T>C (p.Leu416Pro)	DNM1L	Likely pathogenic	criteria provided, single submitter
1803961	NM_012062.5(DNM1L):c.428C>G (p.Thr143Arg)	DNM1L	Likely pathogenic	criteria provided, single submitter
243096	NM_012062.5(DNM1L):c.1337G>T (p.Cys446Phe)	DNM1L	Likely pathogenic	no assertion criteria provided
2500693	NM_012062.5(DNM1L):c.115A>C (p.Ser39Arg)	DNM1L	Likely pathogenic	criteria provided, single submitter
253261	NM_012062.5(DNM1L):c.1085G>A (p.Gly362Asp)	DNM1L	Likely pathogenic	criteria provided, single submitter
2572009	NM_012062.5(DNM1L):c.2161C>T (p.Gln721Ter)	DNM1L	Likely pathogenic	criteria provided, single submitter
2572010	NM_012062.5(DNM1L):c.1049G>C (p.Gly350Ala)	DNM1L	Likely pathogenic	criteria provided, single submitter
2572539	NM_001278464.2(DNM1L):c.254del (p.Pro85fs)	DNM1L	Likely pathogenic	criteria provided, single submitter
2584374	NM_012062.5(DNM1L):c.176C>T (p.Thr59Ile)	DNM1L	Likely pathogenic	criteria provided, single submitter
374321	NM_012062.5(DNM1L):c.1135G>A (p.Glu379Lys)	DNM1L	Likely pathogenic	criteria provided, single submitter
3775615	NM_012062.5(DNM1L):c.729_733dup (p.Val245delinsGluTer)	DNM1L	Likely pathogenic	criteria provided, single submitter
4293670	NM_012062.5(DNM1L):c.1949T>G (p.Leu650Arg)	DNM1L	Likely pathogenic	criteria provided, single submitter
802833	NM_012062.5(DNM1L):c.1108T>C (p.Phe370Leu)	DNM1L	Likely pathogenic	criteria provided, single submitter
976414	NM_012062.5(DNM1L):c.1087G>A (p.Gly363Ser)	DNM1L	Likely pathogenic	criteria provided, single submitter
985169	NM_012062.5(DNM1L):c.1228G>A (p.Glu410Lys)	DNM1L	Likely pathogenic	criteria provided, single submitter
2062373	NM_012062.5(DNM1L):c.1393G>A (p.Val465Ile)	DNM1L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
DNM1L	Strong	Autosomal dominant	encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNM1L	Orphanet:330050	DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect
DNM1L	Orphanet:98673	Autosomal dominant optic atrophy, classic form
CEP55	Orphanet:500135	Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome

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
DNM1L	HGNC:2973	ENSG00000087470	O00429	Dynamin-1-like protein	gencc,clinvar
CEP55	HGNC:1161	ENSG00000138180	Q53EZ4	Centrosomal protein of 55 kDa	clinvar
OSBPL7	HGNC:16387	ENSG00000006025	Q9BZF2	Oxysterol-binding protein-related protein 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNM1L	Dynamin-1-like protein	Functions in mitochondrial and peroxisomal division.
CEP55	Centrosomal protein of 55 kDa	Plays a role in mitotic exit and cytokinesis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Scaffold/PPI	1	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNM1L	Enzyme (other)	yes	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, GED
CEP55	Other/Unknown	no		EABR, CEP55
OSBPL7	Scaffold/PPI	no		Oxysterol-bd, PH_domain, PH-like_dom_sf

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
lateral nuclear group of thalamus	1
sperm	1
substantia nigra pars compacta	1
primordial germ cell in gonad	1
secondary oocyte	1
ventricular zone	1
body of stomach	1
mucosa of transverse colon	1
transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNM1L	295	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, sperm
CEP55	189	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, secondary oocyte
OSBPL7	210	ubiquitous	marker	mucosa of transverse colon, body of stomach, transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNM1L	4,801
CEP55	2,662
OSBPL7	726

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNM1L	O00429	11
CEP55	Q53EZ4	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OSBPL7	Q9BZF2	72.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Apoptotic execution phase	1	237.9×	0.005	DNM1L
Synthesis of bile acids and bile salts	1	203.9×	0.005	OSBPL7

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
mitochondrial membrane fission	1	2808.7×	0.005	DNM1L
regulation of ATP metabolic process	1	2808.7×	0.005	DNM1L
regulation of peroxisome organization	1	1872.4×	0.005	DNM1L
mitocytosis	1	936.2×	0.007	DNM1L
intracellular distribution of mitochondria	1	802.5×	0.007	DNM1L
peroxisome fission	1	510.7×	0.007	DNM1L
mitochondrial fragmentation involved in apoptotic process	1	468.1×	0.007	DNM1L
protein localization to mitochondrion	1	432.1×	0.007	DNM1L
regulation of mitophagy	1	401.2×	0.007	DNM1L
mitochondrial fission	1	351.1×	0.007	DNM1L
positive regulation of proteasomal protein catabolic process	1	330.4×	0.007	OSBPL7
cranial skeletal system development	1	312.1×	0.007	CEP55
cellular response to cholesterol	1	280.9×	0.007	OSBPL7
heart contraction	1	255.3×	0.007	DNM1L
positive regulation of mitochondrial fission	1	255.3×	0.007	DNM1L
midbody abscission	1	244.2×	0.007	CEP55
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	234.1×	0.007	CEP55
protein complex oligomerization	1	224.7×	0.007	DNM1L
positive regulation of neutrophil chemotaxis	1	216.1×	0.007	DNM1L
bile acid biosynthetic process	1	208.1×	0.007	OSBPL7
establishment of protein localization	1	144.0×	0.010	CEP55
positive regulation of protein secretion	1	114.6×	0.011	DNM1L
mitotic cytokinesis	1	86.4×	0.014	CEP55
rhythmic process	1	83.8×	0.014	DNM1L
regulation of autophagy	1	80.2×	0.014	OSBPL7
calcium ion transport	1	60.4×	0.018	DNM1L
mitochondrion organization	1	50.6×	0.021	DNM1L
endocytosis	1	31.7×	0.032	DNM1L
regulation of gene expression	1	27.8×	0.036	DNM1L

Therapeutics

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
DNM1L	0	0
CEP55	0	0
OSBPL7	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: 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	1	DNM1L
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CEP55, OSBPL7

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)
DNM1L	4	—
CEP55	0	—
OSBPL7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.