Megalencephalic leukoencephalopathy with subcortical cysts

Summary

Megalencephalic leukoencephalopathy with subcortical cysts (MONDO:0011391) is a disease with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 201
• Phenotypes (HPO): 18
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002333	Motor deterioration	Frequent (30-79%)
HP:0005490	Postnatal macrocephaly	Frequent (30-79%)
HP:0007341	Diffuse swelling of cerebral white matter	Frequent (30-79%)
HP:6000461	Cerebral subcortical cyst	Frequent (30-79%)
HP:0000717	Autism	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002133	Status epilepticus	Occasional (5-29%)
HP:0002305	Athetosis	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0012762	Cerebral white matter atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephalic leukoencephalopathy with subcortical cysts
Mondo ID	MONDO:0011391
MeSH	C536141
Orphanet	2478
DOID	DOID:0080315
SNOMED CT	703536004
UMLS	C1858854
MedGen	347006
GARD	0003445
Is cancer (heuristic)	no

Also known as: megalencephalic leukodystrophy · megalencephalic leukoencephalopathy with subcortical cysts 1 · megalencephalic leukoencephalopathy with subcortical cysts type 1 · megalencephaly-cystic leukodystrophy · megalencephaly-cystic leukodystrophy syndrome · MLC · MLC1 · Vacuolating megalencephalic leukoencephalopathy with subcortical cysts · Van der Knaap syndrome

Data availability: 201 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › leukoencephalopathy, megalencephalic › megalencephalic leukoencephalopathy with subcortical cysts

Related subtypes (2): megalencephalic leukoencephalopathy with subcortical cysts 3, megalencephalic leukoencephalopathy with subcortical cysts 4, remitting

Subtypes (3): megalencephalic leukoencephalopathy with subcortical cysts 2A, megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability, megalencephalic leukoencephalopathy with subcortical cysts 1

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

201 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 25 benign, 21 pathogenic/likely pathogenic, 21 likely pathogenic, 19 conflicting classifications of pathogenicity, 18 likely benign, 12 benign/likely benign, 11 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1331500	NM_015166.4(MLC1):c.251G>A (p.Arg84His)	LOC125446261	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21522	NM_015166.4(MLC1):c.178-10T>A	LOC125446261	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
646457	NM_015166.4(MLC1):c.218G>A (p.Gly73Glu)	LOC125446261	Pathogenic	criteria provided, multiple submitters, no conflicts
1067995	NM_015166.4(MLC1):c.423+1G>T	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455282	NM_015166.4(MLC1):c.881C>T (p.Pro294Leu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702863	NM_015166.4(MLC1):c.908_918delinsGCA (p.Val303fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
188980	NM_015166.4(MLC1):c.714+1G>A	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138459	NM_015166.4(MLC1):c.597+1G>A	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138460	NM_015166.4(MLC1):c.135del (p.Cys46fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2441418	NM_015166.4(MLC1):c.849del (p.Ile283_Met284insTer)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676562	NM_015166.4(MLC1):c.177+1del	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676575	NM_015166.4(MLC1):c.772-1G>C	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2737054	NM_015166.4(MLC1):c.359C>T (p.Ala120Val)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31622	NM_015166.4(MLC1):c.206C>T (p.Ser69Leu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370408	NM_015166.4(MLC1):c.973C>T (p.Gln325Ter)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370785	NM_015166.4(MLC1):c.136del (p.Cys46fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
371207	NM_015166.4(MLC1):c.449_455del (p.Leu150fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4714	NM_015166.4(MLC1):c.278C>T (p.Ser93Leu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4719	NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4720	NM_015166.4(MLC1):c.594_597del (p.Ser197_Tyr198insTer)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4721	NM_015166.4(MLC1):c.176G>A (p.Gly59Glu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4722	NM_015166.4(MLC1):c.135dup (p.Cys46fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4815819	NM_015166.4(MLC1):c.772-2_772-1inv	MLC1	Pathogenic	criteria provided, single submitter
4815820	NM_015166.4(MLC1):c.976T>C (p.Cys326Arg)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554164	NM_015166.4(MLC1):c.824C>A (p.Ala275Asp)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
660628	NM_015166.4(MLC1):c.299_423+108del	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68794	NM_015166.4(MLC1):c.634G>A (p.Gly212Arg)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68797	NM_015166.4(MLC1):c.959C>A (p.Thr320Lys)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
843939	NM_015166.4(MLC1):c.701G>A (p.Trp234Ter)	MLC1	Pathogenic	criteria provided, single submitter
857173	NM_015166.4(MLC1):c.353C>T (p.Thr118Met)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
MLC1	Definitive	Autosomal recessive	megalencephalic leukoencephalopathy with subcortical cysts 1	6
HEPACAM	Strong	Autosomal recessive	megalencephalic leukoencephalopathy with subcortical cysts 2A	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MLC1	Orphanet:2478	Megalencephalic leukoencephalopathy with subcortical cysts
HEPACAM	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
HEPACAM	Orphanet:2478	Megalencephalic leukoencephalopathy with subcortical cysts

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
MLC1	HGNC:17082	ENSG00000100427	Q15049	Membrane protein MLC1	gencc,clinvar
HEPACAM	HGNC:26361	ENSG00000165478	Q14CZ8	Hepatic and glial cell adhesion molecule	gencc,clinvar
HEPN1	HGNC:34400	ENSG00000221932	Q6WQI6	Protein HEPN1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MLC1	Membrane protein MLC1	Transmembrane protein mainly expressed in brain astrocytes that may play a role in transport across the blood-brain and brain-cerebrospinal fluid barriers.
HEPACAM	Hepatic and glial cell adhesion molecule	Involved in regulating cell motility and cell-matrix interactions.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MLC1	Other/Unknown	no		Membrane_MLC1
HEPACAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
HEPN1	Other/Unknown	no

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
caudate nucleus	1
nucleus accumbens	1
ventricular zone	1
lateral globus pallidus	1
medial globus pallidus	1
substantia nigra pars reticulata	1
amygdala	1
male germ line stem cell (sensu Vertebrata) in testis	1
temporal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MLC1	192	broad	marker	nucleus accumbens, ventricular zone, caudate nucleus
HEPACAM	167	broad	marker	lateral globus pallidus, substantia nigra pars reticulata, medial globus pallidus
HEPN1	117		marker	male germ line stem cell (sensu Vertebrata) in testis, amygdala, temporal lobe

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HEPACAM	661
MLC1	630
HEPN1	449

Intra-cohort edges

A	B	Sources
HEPACAM	HEPN1	string_interaction
HEPACAM	MLC1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HEPACAM	Q14CZ8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MLC1	Q15049	71.29
HEPN1	Q6WQI6	54.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

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
regulation of response to osmotic stress	1	4213.0×	0.002	MLC1
caveolin-mediated endocytosis	1	1685.2×	0.003	MLC1
protein localization to cell-cell junction	1	936.2×	0.003	HEPACAM
positive regulation of intracellular transport	1	842.6×	0.003	MLC1
cellular response to cholesterol	1	421.3×	0.005	MLC1
vesicle-mediated transport	1	48.1×	0.034	MLC1
regulation of cell cycle	1	37.3×	0.038	HEPACAM
immune response	1	23.5×	0.050	HEPACAM
protein transport	1	21.9×	0.050	MLC1
cell adhesion	1	18.7×	0.053	HEPACAM

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
MLC1	0	0
HEPACAM	0	0
HEPN1	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
MLC1	1	Binding:1

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	HEPACAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MLC1, HEPN1

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)
MLC1	1	—
HEPACAM	0	—
HEPN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies