Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy

Summary

Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy (MONDO:0014960) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy
Mondo ID	MONDO:0014960
EFO	EFO:0009158
OMIM	617186
GARD	0025040
Is cancer (heuristic)	no

Also known as: encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy · encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy; PEBEL · encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy; PEBEL · PEBEL

Data availability: 10 ClinVar variants.

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 › neurodegenerative disease › inherited neurodegenerative disorder › encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

Subtypes (2): encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, NAD(P)HX dehydratase deficiency

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

10 retrieved; paginated sample, class counts are floors:

7 pathogenic, 2 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
253145	NM_144772.3(NAXE):c.281C>A (p.Ala94Asp)	NAXE	Pathogenic	no assertion criteria provided
268116	NM_144772.3(NAXE):c.177C>A (p.Tyr59Ter)	NAXE	Pathogenic	no assertion criteria provided
268117	NM_144772.3(NAXE):c.196C>T (p.Gln66Ter)	NAXE	Pathogenic	no assertion criteria provided
268118	NM_144772.3(NAXE):c.516+1G>A	NAXE	Pathogenic	no assertion criteria provided
268120	NM_144772.3(NAXE):c.743del (p.Ala248fs)	NAXE	Pathogenic	no assertion criteria provided
268121	NM_144772.3(NAXE):c.653A>T (p.Asp218Val)	NAXE	Pathogenic	no assertion criteria provided
3381841	NAXE, (GGGCC)n REPEAT EXPANSION, PROMOTER	NAXE	Pathogenic	no assertion criteria provided
3773815	NM_144772.3(NAXE):c.664+2T>A	NAXE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
268119	NM_144772.3(NAXE):c.804_807delinsA (p.Lys270del)	NAXE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
634634	NM_144772.3(NAXE):c.326dup (p.Thr110fs)	NAXE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NAXE	Orphanet:555407	NAD(P)HX epimerase deficiency

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
NAXE	HGNC:18453	ENSG00000163382	Q8NCW5	NAD(P)H-hydrate epimerase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NAXE	NAD(P)H-hydrate epimerase	Catalyzes the epimerization of the S- and R-forms of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NAXE	Enzyme (other)	yes	5.1.99.6	YjeF_N_dom, YJEFN_prot_NAXE-like, YjeF_N_dom_sf

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
apex of heart	1
cardiac muscle of right atrium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NAXE	252	ubiquitous	marker	apex of heart, cardiac muscle of right atrium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NAXE	1,667

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NAXE	Q8NCW5	86.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
Nicotinate metabolism	1	393.8×	0.003	NAXE

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
nicotinamide nucleotide metabolic process	1	8426.0×	4e-04	NAXE
metabolite repair	1	8426.0×	4e-04	NAXE
membrane raft distribution	1	5617.3×	4e-04	NAXE
regulation of cholesterol efflux	1	2407.4×	7e-04	NAXE
sprouting angiogenesis	1	481.5×	0.003	NAXE
lipid transport	1	263.3×	0.004	NAXE
negative regulation of angiogenesis	1	168.5×	0.006	NAXE

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
NAXE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NAXE	5.1.99.6	NAD(P)H-hydrate epimerase

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	1	NAXE
E	Difficult family or no structure, no drug	0

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)
NAXE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.