Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Summary

Leukoencephalopathy with mild cerebellar ataxia and white matter edema (MONDO:0014292) is a disease caused by CLCN2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CLCN2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 198

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with mild cerebellar ataxia and white matter edema
Mondo ID	MONDO:0014292
OMIM	615651
Orphanet	363540
NCIT	C171603
SNOMED CT	768663003
UMLS	C4554120
MedGen	1638681
GARD	0017565
Is cancer (heuristic)	no

Also known as: leukoencephalopathy with ataxia · LKPAT

Data availability: 198 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

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 mild cerebellar ataxia and white matter edema

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

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

198 retrieved; paginated sample, class counts are floors:

118 uncertain significance, 20 conflicting classifications of pathogenicity, 14 likely benign, 11 benign/likely benign, 10 pathogenic, 10 likely pathogenic, 8 not provided, 4 benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100629	NM_004366.6(CLCN2):c.1709G>A (p.Trp570Ter)	CLCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100630	NM_004366.6(CLCN2):c.430_435del (p.Leu144_Ile145del)	CLCN2	Pathogenic	no assertion criteria provided
100631	NM_004366.6(CLCN2):c.1499C>T (p.Ala500Val)	CLCN2	Pathogenic	no assertion criteria provided
100632	NM_004366.6(CLCN2):c.828dup (p.Arg277fs)	CLCN2	Pathogenic	criteria provided, single submitter
1032901	NM_004366.6(CLCN2):c.985_986del (p.Ile329fs)	CLCN2	Pathogenic	criteria provided, single submitter
1279936	NM_004366.6(CLCN2):c.668_672del (p.Leu223fs)	CLCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217787	NM_004366.6(CLCN2):c.1113delinsACTGCTCAT (p.Ser375fs)	CLCN2	Pathogenic	criteria provided, single submitter
217788	NM_004366.6(CLCN2):c.1143del (p.Gly382fs)	CLCN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2627936	NM_004366.6(CLCN2):c.1382_1386del (p.Pro461fs)	CLCN2	Pathogenic	criteria provided, single submitter
2724374	NM_004366.6(CLCN2):c.1828C>T (p.Arg610Ter)	CLCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068719	NM_004366.6(CLCN2):c.61dup (p.Leu21fs)	CLCN2	Pathogenic	criteria provided, single submitter
441164	NM_004366.6(CLCN2):c.515G>A (p.Arg172Gln)	CLCN2	Pathogenic	criteria provided, multiple submitters, no conflicts
813301	NM_004366.6(CLCN2):c.1397-1G>A	CLCN2	Pathogenic	criteria provided, single submitter
1194517	NM_004366.6(CLCN2):c.898+1G>A	CLCN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
217785	NM_004366.6(CLCN2):c.925C>T (p.Arg309Ter)	CLCN2	Likely pathogenic	criteria provided, single submitter
217791	NM_004366.6(CLCN2):c.1412G>A (p.Arg471His)	CLCN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
217796	NM_004366.6(CLCN2):c.2386C>T (p.Gln796Ter)	CLCN2	Likely pathogenic	criteria provided, single submitter
2671736	NM_004366.6(CLCN2):c.2068G>T (p.Glu690Ter)	CLCN2	Likely pathogenic	criteria provided, single submitter
3589028	NM_004366.6(CLCN2):c.1069del (p.Arg357fs)	CLCN2	Likely pathogenic	criteria provided, single submitter
3589053	NM_004366.6(CLCN2):c.221-2A>G	CLCN2	Likely pathogenic	criteria provided, single submitter
3589056	NM_004366.6(CLCN2):c.194del (p.Gly65fs)	CLCN2	Likely pathogenic	criteria provided, single submitter
3589059	NM_004366.6(CLCN2):c.64-1G>A	CLCN2	Likely pathogenic	criteria provided, single submitter
3779531	NM_004366.6(CLCN2):c.449del (p.Gly150fs)	CLCN2	Likely pathogenic	criteria provided, single submitter
1106292	NM_004366.6(CLCN2):c.1067A>G (p.Asn356Ser)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315588	NM_004366.6(CLCN2):c.1969A>C (p.Thr657Pro)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1394236	NM_004366.6(CLCN2):c.2174G>A (p.Arg725Gln)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1621558	NM_004366.6(CLCN2):c.2657G>A (p.Arg886Gln)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1958391	NM_004366.6(CLCN2):c.63+4A>G	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1959620	NM_004366.6(CLCN2):c.220+15G>A	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2040196	NM_004366.6(CLCN2):c.773-9C>G	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
CLCN2	Definitive	Autosomal recessive	leukoencephalopathy with mild cerebellar ataxia and white matter edema	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN2	Orphanet:307	Juvenile myoclonic epilepsy
CLCN2	Orphanet:363540	Leukoencephalopathy with mild cerebellar ataxia and white matter edema
CLCN2	Orphanet:404	Familial hyperaldosteronism type II

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
CLCN2	HGNC:2020	ENSG00000114859	P51788	Chloride channel protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN2	Chloride channel protein 2	Voltage-gated and osmosensitive chloride channel.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCN2	Other/Unknown	no		ClC, Cl-channel-2, Cl-channel_core

Expression context

Cohort genes with no expression data: 0.

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
mucosa of transverse colon	1
sural nerve	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN2	181	broad	yes	mucosa of transverse colon, tibial nerve, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN2	1,250

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN2	P51788	8

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
Stimuli-sensing channels	1	135.9×	0.007	CLCN2

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
regulation of aldosterone biosynthetic process	1	16852.0×	5e-04	CLCN2
cell differentiation involved in salivary gland development	1	8426.0×	5e-04	CLCN2
regulation of membrane depolarization during action potential	1	8426.0×	5e-04	CLCN2
stabilization of membrane potential	1	5617.3×	5e-04	CLCN2
acinar cell differentiation	1	3370.4×	7e-04	CLCN2
cellular hypotonic response	1	1404.3×	0.001	CLCN2
regulation of resting membrane potential	1	1296.3×	0.001	CLCN2
phagocytosis, engulfment	1	674.1×	0.002	CLCN2
positive regulation of oligodendrocyte differentiation	1	674.1×	0.002	CLCN2
chloride transport	1	455.5×	0.003	CLCN2
retina development in camera-type eye	1	255.3×	0.004	CLCN2
lung development	1	198.3×	0.005	CLCN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CLCN2	1	Binding:1

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	0
E	Difficult family or no structure, no drug	1	CLCN2

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)
CLCN2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.