Leukoencephalopathy with vanishing white matter 1

Summary

Leukoencephalopathy with vanishing white matter 1 (MONDO:0020507) is a disease caused by variants in EIF2B1, EIF2B2, EIF2B3, and 2 other genes, with 7 cohort genes. The dominant Reactome pathway is Recycling of eIF2:GDP (5 cohort genes).

At a glance

• Causal genes: EIF2B1 (GenCC Strong), EIF2B2 (GenCC Strong), EIF2B3 (GenCC Strong), EIF2B4 (GenCC Strong) (+1 more)
• Cohort genes: 7
• ClinVar variants: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with vanishing white matter 1
Mondo ID	MONDO:0020507
OMIM	603896
Orphanet	99854
DOID	DOID:0070374
UMLS	C5779972
MedGen	1830482
GARD	0016919
Is cancer (heuristic)	no

Also known as: CACH · childhood ataxia with central nervous system hypomyelinization · vanishing white matter leukodystrophy

Data availability: 40 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukoencephalopathy with vanishing white matter › leukoencephalopathy with vanishing white matter 1

Related subtypes (8): leukoencephalopathy, progressive, with ovarian failure, congenital or early infantile CACH syndrome, late infantile CACH syndrome, juvenile or adult CACH syndrome, leukoencephalopathy with vanishing white matter 2, leukoencephalopathy with vanishing white matter 3, leukoencephalopathy with vanishing white matter 4, leukoencephalopathy with vanishing white matter 5

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

40 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 8 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
217281	NM_001414.4(EIF2B1):c.824A>G (p.Tyr275Cys)	EIF2B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2835749	NM_001414.4(EIF2B1):c.461_462del (p.Glu154fs)	EIF2B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2891124	NM_001414.4(EIF2B1):c.773_777dup (p.Ala260fs)	EIF2B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
995942	NM_001414.4(EIF2B1):c.439C>T (p.Arg147Ter)	EIF2B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4336	NM_014239.4(EIF2B2):c.638A>G (p.Glu213Gly)	EIF2B2	Pathogenic	criteria provided, multiple submitters, no conflicts
617677	NM_020365.5(EIF2B3):c.89T>C (p.Val30Ala)	EIF2B3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420062	NM_001034116.2(EIF2B4):c.728C>T (p.Pro243Leu)	EIF2B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195203	NM_003907.3(EIF2B5):c.318A>T (p.Leu106Phe)	EIF2B5	Pathogenic	criteria provided, multiple submitters, no conflicts
372361	NM_003907.3(EIF2B5):c.896G>A (p.Arg299His)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5946	NM_003907.3(EIF2B5):c.584G>A (p.Arg195His)	EIF2B5	Pathogenic	criteria provided, multiple submitters, no conflicts
942204	NM_003907.3(EIF2B5):c.806G>A (p.Arg269Gln)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382064	NM_001414.4(EIF2B1):c.521_522del (p.Pro174fs)	EIF2B1	Likely pathogenic	criteria provided, single submitter
1699333	NM_001034116.2(EIF2B4):c.631G>T (p.Gly211Cys)	EIF2B4	Likely pathogenic	criteria provided, single submitter
4123	NM_001414.4(EIF2B1):c.252+1G>A	EIF2B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1691306	NM_020365.5(EIF2B3):c.687T>G (p.Ile229Met)	EIF2B3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420063	NM_001034116.2(EIF2B4):c.626G>A (p.Arg209Gln)	EIF2B4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220101	NM_003119.4(SPG7):c.1948G>A (p.Asp650Asn)	SPG7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4277565	NM_024664.4(PPCS):c.302G>C (p.Trp101Ser)	CCDC30	Uncertain significance	criteria provided, single submitter
2176384	NM_001414.4(EIF2B1):c.13G>A (p.Glu5Lys)	EIF2B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584935	NM_001414.4(EIF2B1):c.875C>G (p.Thr292Arg)	EIF2B1	Uncertain significance	criteria provided, single submitter
2584983	NM_001414.4(EIF2B1):c.752A>G (p.Lys251Arg)	EIF2B1	Uncertain significance	criteria provided, single submitter
2689011	NM_001414.4(EIF2B1):c.385G>A (p.Ala129Thr)	EIF2B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3067917	NM_001414.4(EIF2B1):c.915_916del (p.Ter306ThrextTer?)	EIF2B1	Uncertain significance	criteria provided, single submitter
3068028	NM_001414.4(EIF2B1):c.392C>T (p.Ser131Phe)	EIF2B1	Uncertain significance	criteria provided, single submitter
3087894	NM_001414.4(EIF2B1):c.502C>G (p.Leu168Val)	EIF2B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779607	NM_001414.4(EIF2B1):c.503T>C (p.Leu168Pro)	EIF2B1	Uncertain significance	criteria provided, single submitter
4845344	NM_001414.4(EIF2B1):c.820G>A (p.Asp274Asn)	EIF2B1	Uncertain significance	criteria provided, single submitter
915406	NM_001414.4(EIF2B1):c.524T>A (p.Val175Asp)	EIF2B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
977417	NM_001414.4(EIF2B1):c.551G>A (p.Gly184Asp)	EIF2B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805642	NM_014239.4(EIF2B2):c.1A>G (p.Met1Val)	EIF2B2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 27 · 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
EIF2B2	Definitive	Autosomal recessive	leukoencephalopathy with vanishing white matter	6
EIF2B4	Definitive	Autosomal recessive	leukoencephalopathy with vanishing white matter 4	5
EIF2B5	Definitive	Autosomal recessive	leukoencephalopathy with vanishing white matter	6
EIF2B1	Strong	Autosomal recessive	leukoencephalopathy with vanishing white matter	5
EIF2B3	Strong	Autosomal recessive	leukoencephalopathy with vanishing white matter	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2B1	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B1	Orphanet:157716	Late infantile CACH syndrome
EIF2B1	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B1	Orphanet:99853	Ovarioleukodystrophy
EIF2B1	Orphanet:99854	Cree leukoencephalopathy
EIF2B2	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B2	Orphanet:157716	Late infantile CACH syndrome
EIF2B2	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B2	Orphanet:99853	Ovarioleukodystrophy
EIF2B2	Orphanet:99854	Cree leukoencephalopathy
EIF2B3	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B3	Orphanet:157716	Late infantile CACH syndrome
EIF2B3	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B3	Orphanet:99853	Ovarioleukodystrophy
EIF2B3	Orphanet:99854	Cree leukoencephalopathy
EIF2B4	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B4	Orphanet:157716	Late infantile CACH syndrome
EIF2B4	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B4	Orphanet:99853	Ovarioleukodystrophy
EIF2B4	Orphanet:99854	Cree leukoencephalopathy
EIF2B5	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B5	Orphanet:157716	Late infantile CACH syndrome
EIF2B5	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B5	Orphanet:99853	Ovarioleukodystrophy
EIF2B5	Orphanet:99854	Cree leukoencephalopathy
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EIF2B1	HGNC:3257	ENSG00000111361	Q14232	Translation initiation factor eIF2B subunit alpha	gencc,clinvar
EIF2B2	HGNC:3258	ENSG00000119718	P49770	Translation initiation factor eIF2B subunit beta	gencc,clinvar
EIF2B3	HGNC:3259	ENSG00000070785	Q9NR50	Translation initiation factor eIF2B subunit gamma	gencc,clinvar
EIF2B4	HGNC:3260	ENSG00000115211	Q9UI10	Translation initiation factor eIF2B subunit delta	gencc,clinvar
EIF2B5	HGNC:3261	ENSG00000145191	Q13144	Translation initiation factor eIF2B subunit epsilon	gencc,clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
CCDC30	HGNC:26103	ENSG00000186409	Q5VVM6	Coiled-coil domain-containing protein 30	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2B1	Translation initiation factor eIF2B subunit alpha	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
EIF2B2	Translation initiation factor eIF2B subunit beta	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
EIF2B3	Translation initiation factor eIF2B subunit gamma	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on the eukaryotic initiation factor 2 (eIF2) complex gamma subunit.
EIF2B4	Translation initiation factor eIF2B subunit delta	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
EIF2B5	Translation initiation factor eIF2B subunit epsilon	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.14

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
Protease	1	5.2×	0.176
Other/Unknown	6	1.5×	0.176

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EIF2B1	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, elF-2B_alpha_N
EIF2B2	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C
EIF2B3	Other/Unknown	no		NTP_transferase_dom, Nucleotide-diphossugar_trans, eIF2B_gamma
EIF2B4	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C
EIF2B5	Other/Unknown	no		W2_domain, Trimer_LpxA-like_sf, ARM-type_fold
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
CCDC30	Other/Unknown	no		DUF4686, CCD-Prefoldin_beta-like

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	3
left lobe of thyroid gland	2
gastrocnemius	2
monocyte	1
oocyte	1
secondary oocyte	1
right lobe of thyroid gland	1
thyroid gland	1
gluteal muscle	1
triceps brachii	1
body of pancreas	1
left testis	1
lower esophagus mucosa	1
tendon of biceps brachii	1
primordial germ cell in gonad	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2B1	279	ubiquitous	marker	oocyte, secondary oocyte, monocyte
EIF2B2	298	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland
EIF2B3	271	ubiquitous	marker	triceps brachii, gluteal muscle, gastrocnemius
EIF2B4	290	ubiquitous	marker	lower esophagus mucosa, body of pancreas, left testis
EIF2B5	286	ubiquitous	marker	sural nerve, tendon of biceps brachii, gastrocnemius
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
CCDC30	181	broad	marker	right uterine tube, sural nerve, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPG7	3,970
EIF2B3	3,212
EIF2B5	2,989
EIF2B2	2,800
EIF2B4	2,747
EIF2B1	2,548
CCDC30	857

Intra-cohort edges

A	B	Sources
EIF2B1	EIF2B2	biogrid_interaction, intact, string_interaction
EIF2B1	EIF2B3	biogrid_interaction, intact, string_interaction
EIF2B1	EIF2B4	biogrid_interaction, intact, string_interaction
EIF2B1	EIF2B5	biogrid_interaction, intact, string_interaction
EIF2B2	EIF2B3	biogrid_interaction, intact, string_interaction
EIF2B2	EIF2B4	biogrid_interaction, intact, string_interaction
EIF2B2	EIF2B5	biogrid_interaction, intact, string_interaction
EIF2B3	EIF2B4	biogrid_interaction, string_interaction
EIF2B3	EIF2B5	biogrid_interaction, string_interaction
EIF2B4	EIF2B5	biogrid_interaction, string_interaction

Structural data

PDB: 6 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2B1	Q14232	27
EIF2B2	P49770	27
EIF2B4	Q9UI10	27
EIF2B3	Q9NR50	26
EIF2B5	Q13144	26
SPG7	Q9UQ90	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCDC30	Q5VVM6	70.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 7 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recycling of eIF2:GDP	5	1057.4×	3e-15	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
Processing of SMDT1	1	105.7×	0.022	SPG7
Mitochondrial calcium ion transport	1	90.6×	0.022	SPG7
Mitochondrial protein degradation	1	19.0×	0.077	SPG7
Transport of small molecules	1	4.2×	0.259	SPG7
Metabolism of proteins	1	2.1×	0.397	SPG7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytoplasmic translational initiation	5	1170.3×	1e-14	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
oligodendrocyte development	5	501.6×	7e-13	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
response to heat	5	351.1×	3e-12	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
response to peptide hormone	5	326.6×	3e-12	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
translational initiation	5	298.8×	4e-12	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
response to glucose	5	212.8×	2e-11	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
T cell receptor signaling pathway	5	126.5×	2e-10	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5
ovarian follicle development	3	195.9×	1e-06	EIF2B2, EIF2B4, EIF2B5
myelination	3	125.8×	3e-06	EIF2B2, EIF2B4, EIF2B5
mitochondrial outer membrane permeabilization involved in programmed cell death	1	1404.3×	0.002	SPG7
regulation of calcium import into the mitochondrion	1	936.2×	0.002	SPG7
mitochondrial protein processing	1	468.1×	0.004	SPG7
regulation of mitochondrial membrane permeability	1	234.1×	0.008	SPG7
astrocyte development	1	187.2×	0.010	EIF2B5
positive regulation of translational initiation	1	140.4×	0.012	EIF2B5
astrocyte differentiation	1	127.7×	0.012	EIF2B5
anterograde axonal transport	1	96.8×	0.015	SPG7
regulation of translational initiation	1	78.0×	0.018	EIF2B2
hippocampus development	1	38.5×	0.034	EIF2B5
regulation of translation	1	36.5×	0.034	EIF2B4
response to endoplasmic reticulum stress	1	27.8×	0.042	EIF2B5
central nervous system development	1	19.2×	0.058	EIF2B2
positive regulation of apoptotic process	1	9.5×	0.110	EIF2B5
nervous system development	1	7.7×	0.129	SPG7
proteolysis	1	5.7×	0.163	SPG7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 5 of 7 evidence-associated genes (71%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2B5	1	2
EIF2B1	0	0
EIF2B2	0	0
EIF2B3	0	0
EIF2B4	0	0
SPG7	0	0
CCDC30	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	EIF2B5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EIF2B3	9	Binding:9
EIF2B5	7	Binding:7
EIF2B1	1	Binding:1
EIF2B2	1	Binding:1
EIF2B4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPG7	3.4.24.B18

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	EIF2B5

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	1	EIF2B5
C	Druggable family + PDB, no drug	1	SPG7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	EIF2B1, EIF2B2, EIF2B3, EIF2B4, CCDC30

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EIF2B1	1	EIF2B5
EIF2B2	1	EIF2B5
EIF2B3	9	EIF2B5
EIF2B4	1	EIF2B5
SPG7	0	—
CCDC30	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.