Metachromatic leukodystrophy, late infantile form

Summary

Metachromatic leukodystrophy, late infantile form (MONDO:0017729) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 36

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000		Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002415	Leukodystrophy	Frequent (30-79%)
HP:0002922	Increased CSF protein concentration	Frequent (30-79%)
HP:0003444	EMG: chronic denervation signs	Frequent (30-79%)
HP:0007133	Progressive peripheral neuropathy	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0030051	Tip-toe gait	Frequent (30-79%)
HP:0030081	Punctate periventricular T2 hyperintense foci	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0000746	Delusion	Occasional (5-29%)
HP:0001082	Cholecystitis	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001939	Abnormality of metabolism/homeostasis	Occasional (5-29%)
HP:0002371	Loss of speech	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0008619	Bilateral sensorineural hearing impairment	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0012433	Abnormal social behavior	Occasional (5-29%)
HP:0025013	Decerebrate rigidity	Very rare (<1-4%)
HP:0031358	Vegetative state	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	metachromatic leukodystrophy, late infantile form
Mondo ID	MONDO:0017729
Orphanet	309256
SNOMED CT	47683004
UMLS	C0751278
MedGen	155529
GARD	0021328
Is cancer (heuristic)	no

Also known as: arylsulfatase A deficiency, late infantile form · MLD, late infantile form

Data availability: 6 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › hereditary dementia › metachromatic leukodystrophy › metachromatic leukodystrophy, juvenile form › metachromatic leukodystrophy, late infantile form

Related subtypes (1): metachromatic leukodystrophy, adult form

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

6 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
189073	NM_000487.6(ARSA):c.304del (p.Leu102fs)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
198735	NM_000487.6(ARSA):c.1408_1418del (p.Ala470fs)	ARSA	Pathogenic	criteria provided, single submitter
3054	NM_000487.6(ARSA):c.293C>T (p.Ser98Phe)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3091	NM_000487.6(ARSA):c.763G>A (p.Glu255Lys)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
3093	NM_000487.6(ARSA):c.905G>T (p.Cys302Phe)	ARSA	Pathogenic	no assertion criteria provided
3060	NM_000487.6(ARSA):c.931G>A (p.Gly311Ser)	ARSA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARSA	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
ARSA	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
ARSA	Orphanet:309271	Metachromatic leukodystrophy, adult form

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
ARSA	HGNC:713	ENSG00000100299	P15289	Arylsulfatase A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARSA	Arylsulfatase A	Hydrolyzes cerebroside sulfate.

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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARSA	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS

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
granulocyte	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARSA	177	ubiquitous	marker	right uterine tube, right testis, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARSA	1,356

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARSA	P15289	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
The activation of arylsulfatases	1	878.5×	0.010	ARSA
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	423.0×	0.010	ARSA
Glycosphingolipid metabolism	1	300.5×	0.010	ARSA
Glycosphingolipid catabolism	1	292.8×	0.010	ARSA
Sphingolipid metabolism	1	167.9×	0.014	ARSA
Metabolism of lipids	1	31.6×	0.063	ARSA
Innate Immune System	1	25.5×	0.065	ARSA
Neutrophil degranulation	1	23.1×	0.065	ARSA
Post-translational protein modification	1	19.2×	0.069	ARSA
Immune System	1	13.0×	0.086	ARSA
Metabolism of proteins	1	12.4×	0.086	ARSA
Metabolism	1	11.6×	0.086	ARSA

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
lipid metabolic process	1	91.6×	0.011	ARSA

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
ARSA	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
ARSA	4	Binding:3, Functional: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	1	ARSA
D	Druggable family + AlphaFold only, no drug	0
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)
ARSA	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.