Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1

Summary

Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 (MONDO:0020781) is a disease caused by NAXE (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NAXE (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 26

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

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1
Mondo ID	MONDO:0020781
OMIM	617186
Orphanet	555407
UMLS	C4310675
MedGen	934642
GARD	0017991
Is cancer (heuristic)	no

Also known as: encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy · encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy · NAD(P)HX epimerase deficiency · PEBEL1

Data availability: 26 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

26 retrieved; paginated sample, class counts are floors:

8 benign, 5 uncertain significance, 5 pathogenic, 5 likely pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1252042	NM_144772.3(NAXE):c.262G>T (p.Gly88Trp)	NAXE	Pathogenic	no assertion criteria provided
1320164	NM_144772.3(NAXE):c.229del (p.Gln77fs)	NAXE	Pathogenic	criteria provided, single submitter
1333657	NM_144772.3(NAXE):c.536dup (p.Tyr180fs)	NAXE	Pathogenic	criteria provided, single submitter
2506103	NM_144772.3(NAXE):c.128C>A (p.Ser43Ter)	NAXE	Pathogenic	criteria provided, multiple submitters, no conflicts
873152	NM_144772.3(NAXE):c.565G>A (p.Gly189Ser)	NAXE	Pathogenic	criteria provided, single submitter
1320163	NM_144772.3(NAXE):c.611T>C (p.Leu204Pro)	NAXE	Likely pathogenic	criteria provided, single submitter
1324778	NM_144772.3(NAXE):c.668G>A (p.Trp223Ter)	NAXE	Likely pathogenic	criteria provided, single submitter
3767216	NM_144772.3(NAXE):c.502dup (p.Glu168fs)	NAXE	Likely pathogenic	criteria provided, single submitter
3773815	NM_144772.3(NAXE):c.664+2T>A	NAXE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081529	NM_144772.3(NAXE):c.385C>T (p.Arg129Ter)	NAXE	Likely pathogenic	criteria provided, single submitter
268119	NM_144772.3(NAXE):c.804_807delinsA (p.Lys270del)	NAXE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
423273	NM_144772.3(NAXE):c.733A>C (p.Lys245Gln)	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
311103	NM_001846.4(COL4A2):c.549+5G>A	COL4A2	Uncertain significance	criteria provided, single submitter
1029165	NM_144772.3(NAXE):c.385C>G (p.Arg129Gly)	NAXE	Uncertain significance	criteria provided, single submitter
1029166	NM_144772.3(NAXE):c.430A>C (p.Lys144Gln)	NAXE	Uncertain significance	criteria provided, single submitter
2045406	NM_144772.3(NAXE):c.760C>T (p.Arg254Cys)	NAXE	Uncertain significance	criteria provided, multiple submitters, no conflicts
4813281	NM_144772.3(NAXE):c.235A>G (p.Ser79Gly)	NAXE	Uncertain significance	criteria provided, single submitter
1167010	NM_144772.3(NAXE):c.292-14G>A	NAXE	Benign	criteria provided, multiple submitters, no conflicts
1167828	NM_144772.3(NAXE):c.55G>C (p.Val19Leu)	NAXE	Benign	criteria provided, multiple submitters, no conflicts
1167829	NM_144772.3(NAXE):c.291+7G>A	NAXE	Benign	criteria provided, multiple submitters, no conflicts
1167830	NM_144772.3(NAXE):c.717A>C (p.Ile239=)	NAXE	Benign	criteria provided, multiple submitters, no conflicts
1167831	NM_144772.3(NAXE):c.804G>A (p.Glu268=)	NAXE	Benign	criteria provided, multiple submitters, no conflicts
1167832	NM_144772.3(NAXE):c.843C>T (p.Thr281=)	NAXE	Benign	criteria provided, multiple submitters, no conflicts
1192476	NM_144772.3(NAXE):c.664+28G>A	NAXE	Benign	criteria provided, multiple submitters, no conflicts
1192477	NM_144772.3(NAXE):c.*22T>C	NAXE	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · 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
NAXE	Strong	Autosomal recessive	encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NAXE	Orphanet:555407	NAD(P)HX epimerase deficiency
COL4A2	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A2	Orphanet:99810	Familial porencephaly

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
NAXE	HGNC:18453	ENSG00000163382	Q8NCW5	NAD(P)H-hydrate epimerase	gencc,clinvar
COL4A2	HGNC:2203	ENSG00000134871	P08572	Collagen alpha-2(IV) chain	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.
COL4A2	Collagen alpha-2(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.

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)
NAXE	Enzyme (other)	yes	5.1.99.6	YjeF_N_dom, YJEFN_prot_NAXE-like, YjeF_N_dom_sf
COL4A2	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold

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
apex of heart	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
decidua	1
placenta	1
saphenous vein	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
COL4A2	284	ubiquitous	marker	saphenous vein, decidua, placenta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A2	2,746
NAXE	1,667

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL4A2	P08572	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NAXE	Q8NCW5	86.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Anchoring fibril formation	1	380.7×	0.012	COL4A2
Scavenging by Class A Receptors	1	300.5×	0.012	COL4A2
Fibronectin matrix formation	1	285.5×	0.012	COL4A2
Crosslinking of collagen fibrils	1	285.5×	0.012	COL4A2
Attachment of bacteria to epithelial cells	1	248.3×	0.012	COL4A2
Nicotinate metabolism	1	196.9×	0.012	NAXE
Laminin interactions	1	190.3×	0.012	COL4A2
Collagen chain trimerization	1	129.8×	0.013	COL4A2
Signaling by PDGF	1	126.9×	0.013	COL4A2
NCAM1 interactions	1	124.1×	0.013	COL4A2
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.014	COL4A2
Collagen degradation	1	87.8×	0.014	COL4A2
Collagen biosynthesis and modifying enzymes	1	85.2×	0.014	COL4A2
Non-integrin membrane-ECM interactions	1	77.2×	0.014	COL4A2
ECM proteoglycans	1	75.1×	0.014	COL4A2
Integrin cell surface interactions	1	67.2×	0.015	COL4A2

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
negative regulation of angiogenesis	2	168.5×	5e-04	NAXE, COL4A2
nicotinamide nucleotide metabolic process	1	4213.0×	0.001	NAXE
metabolite repair	1	4213.0×	0.001	NAXE
membrane raft distribution	1	2808.7×	0.001	NAXE
regulation of cholesterol efflux	1	1203.7×	0.002	NAXE
collagen-activated tyrosine kinase receptor signaling pathway	1	648.1×	0.004	COL4A2
endodermal cell differentiation	1	247.8×	0.008	COL4A2
sprouting angiogenesis	1	240.7×	0.008	NAXE
response to activity	1	162.0×	0.010	COL4A2
cellular response to transforming growth factor beta stimulus	1	138.1×	0.010	COL4A2
lipid transport	1	131.7×	0.010	NAXE
DNA-templated transcription	1	112.3×	0.010	COL4A2
collagen fibril organization	1	112.3×	0.010	COL4A2
extracellular matrix organization	1	61.1×	0.017	COL4A2
angiogenesis	1	31.2×	0.032	COL4A2

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
NAXE	0	0
COL4A2	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: 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	1	NAXE
E	Difficult family or no structure, no drug	1	COL4A2

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)
NAXE	0	—
COL4A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.