Metachromatic leukodystrophy

disease

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Also known as arylsulfatase A deficiencyMLD

Summary

Metachromatic leukodystrophy (MONDO:0018868) is a disease caused by ARSA (GenCC Definitive), with 9 cohort genes and 37 clinical trials. The dominant Reactome pathway is Glycosphingolipid metabolism (3 cohort genes). Top therapeutic interventions include atidarsagene autotemcel, cyclophosphamide anhydrous, and alemtuzumab.

At a glance

Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
Causal gene: ARSA (GenCC Definitive)
Cohort genes: 9
ClinVar variants: 1,335
Phenotypes (HPO): 45
Clinical trials: 37

Clinical features

Epidemiology

Prevalence records

12 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000		Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.1	Europe	Validated
Prevalence at birth	1-9 / 100 000	1.47	Europe	Validated
Prevalence at birth	1-9 / 100 000	1.42	Netherlands	Validated
Prevalence at birth	1-9 / 100 000	1.85	Portugal	Validated
Prevalence at birth	1-9 / 1 000 000	0.6	Germany	Validated
Prevalence at birth	1-9 / 100 000	1.43	Turkey	Validated
Prevalence at birth	1-9 / 100 000	1.09	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.69	Czech Republic	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	Poland	Validated
Prevalence at birth	1-9 / 100 000	2.5	United States	Validated
Prevalence at birth	1-9 / 100 000	1.73	Sweden	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0006970	Periventricular leukomalacia	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002191	Progressive spasticity	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002922	Increased CSF protein concentration	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000751	Personality changes	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002311	Incoordination	Occasional (5-29%)
HP:0002607	Bowel incontinence	Occasional (5-29%)
HP:0009763	Limb pain	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012531	Pain	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0030858	Addictive behavior	Occasional (5-29%)
HP:0031064	Impaired continence	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)
HP:0002246	Abnormality of the duodenum	Very rare (<1-4%)
HP:0002576	Intussusception	Very rare (<1-4%)
HP:0002577	Abnormal stomach morphology	Very rare (<1-4%)
HP:0012437	Abnormal gallbladder morphology	Very rare (<1-4%)
HP:0025013	Decerebrate rigidity	Very rare (<1-4%)
HP:0100575	Neoplasm of the gallbladder	Very rare (<1-4%)
HP:0100762	Hemobilia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	metachromatic leukodystrophy
Mondo ID	MONDO:0018868
MeSH	D007966
Orphanet	512
DOID	DOID:10581
ICD-10-CM	E75.25
ICD-11	172326564
NCIT	C61251
SNOMED CT	238031009, 396338004, 66521008
UMLS	C0023522
MedGen	6071
GARD	0003230
MedDRA	10067609
NORD	1369
Is cancer (heuristic)	no

Also known as: arylsulfatase A deficiency · MLD

Data availability: 1,335 ClinVar variants · 1 GenCC gene-disease record · 19 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › hereditary dementia › metachromatic leukodystrophy

Subtypes (2): metachromatic leukodystrophy due to saposin B deficiency, metachromatic leukodystrophy, juvenile 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

600 retrieved; paginated sample, class counts are floors:

282 likely benign, 152 uncertain significance, 58 pathogenic, 49 likely pathogenic, 24 pathogenic/likely pathogenic, 23 conflicting classifications of pathogenicity, 7 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2423149	NC_000022.10:g.(?50167881)(51066207_?)del	ADM2	Pathogenic	criteria provided, single submitter
1041453	NM_000487.6(ARSA):c.385G>A (p.Gly129Arg)	ARSA	Pathogenic	criteria provided, single submitter
1066073	NM_000487.6(ARSA):c.338T>C (p.Leu113Pro)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068641	NM_000487.6(ARSA):c.685-2A>G	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1070652	NM_000487.6(ARSA):c.1107+1G>T	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1072391	NC_000022.10:g.(?51063563)(51066217_?)del	ARSA	Pathogenic	criteria provided, single submitter
1072392	NC_000022.10:g.(?51064344)(51066227_?)del	ARSA	Pathogenic	criteria provided, single submitter
1098313	NM_000487.6(ARSA):c.582del (p.Trp195fs)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1177268	NM_000487.6(ARSA):c.1228_1229del (p.Thr410fs)	ARSA	Pathogenic	criteria provided, single submitter
1194838	NM_000487.6(ARSA):c.178C>T (p.Arg60Trp)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210332	NM_000487.6(ARSA):c.488G>C (p.Cys163Ser)	ARSA	Pathogenic	criteria provided, single submitter
1323434	NM_000487.6(ARSA):c.208_209del (p.Leu70fs)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1323930	NM_000487.6(ARSA):c.244C>T (p.Arg82Trp)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323931	NM_000487.6(ARSA):c.842C>T (p.Thr281Ile)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381264	NM_000487.6(ARSA):c.731C>A (p.Ser244Ter)	ARSA	Pathogenic	criteria provided, single submitter
1406153	NM_000487.6(ARSA):c.272del (p.Pro91fs)	ARSA	Pathogenic	criteria provided, single submitter
1410148	NM_000487.6(ARSA):c.1468T>C (p.Cys490Arg)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411564	NM_000487.6(ARSA):c.581C>G (p.Pro194Arg)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1421225	NM_000487.6(ARSA):c.270C>A (p.Tyr90Ter)	ARSA	Pathogenic	criteria provided, single submitter
1423789	NM_000487.6(ARSA):c.724G>T (p.Glu242Ter)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1436884	NM_000487.6(ARSA):c.157_164del (p.Gln53fs)	ARSA	Pathogenic	criteria provided, single submitter
1452278	NM_000487.6(ARSA):c.1136del (p.Pro379fs)	ARSA	Pathogenic	criteria provided, single submitter
1452818	NM_000487.6(ARSA):c.617dup (p.Ala207fs)	ARSA	Pathogenic	criteria provided, single submitter
1453841	NM_000487.6(ARSA):c.1107+1G>A	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455014	NC_000022.10:g.(?51065065)(51065595_?)del	ARSA	Pathogenic	criteria provided, single submitter
1455794	NM_000487.6(ARSA):c.302_303delinsTT (p.Gly101Val)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1457224	NM_000487.6(ARSA):c.1293T>A (p.Tyr431Ter)	ARSA	Pathogenic	criteria provided, single submitter
1460113	NM_000487.6(ARSA):c.13del (p.Ala5fs)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1460447	NM_000487.6(ARSA):c.185_186del (p.Thr62fs)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1476243	NM_000487.6(ARSA):c.393_425del (p.Pro132_Gly142del)	ARSA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 17 · 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
ARSA	Definitive	Autosomal recessive	metachromatic leukodystrophy, juvenile form	6

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
YARS1	Orphanet:100045	Autosomal dominant intermediate Charcot-Marie-Tooth disease type C
CLCN1	Orphanet:614	Thomsen and Becker disease
PYCR2	Orphanet:2512	Autosomal recessive primary microcephaly
PYCR2	Orphanet:481152	PYCR2-related microcephaly-progressive leukoencephalopathy
GFAP	Orphanet:363717	Alexander disease type I
GFAP	Orphanet:363722	Alexander disease type II
ARSB	Orphanet:276212	Mucopolysaccharidosis type 6, rapidly progressing
ARSB	Orphanet:276223	Mucopolysaccharidosis type 6, slowly progressing
PSAP	Orphanet:139406	Encephalopathy due to prosaposin deficiency
PSAP	Orphanet:206436	Infantile Krabbe disease
PSAP	Orphanet:309252	Atypical Gaucher disease due to saposin C deficiency
PSAP	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
PSAP	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
PSAP	Orphanet:309271	Metachromatic leukodystrophy, adult form

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARSA	HGNC:713	ENSG00000100299	P15289	Arylsulfatase A	gencc,clinvar
YARS1	HGNC:12840	ENSG00000134684	P54577	Tyrosine–tRNA ligase, cytoplasmic	clinvar
MTCH1	HGNC:17586	ENSG00000137409	Q9NZJ7	Mitochondrial carrier homolog 1	clinvar
CLCN1	HGNC:2019	ENSG00000188037	P35523	Chloride channel protein 1	clinvar
ADM2	HGNC:28898	ENSG00000128165	Q7Z4H4	Protein ADM2	clinvar
PYCR2	HGNC:30262	ENSG00000143811	Q96C36	Pyrroline-5-carboxylate reductase 2	clinvar
GFAP	HGNC:4235	ENSG00000131095	P14136	Glial fibrillary acidic protein	clinvar
ARSB	HGNC:714	ENSG00000113273	P15848	Arylsulfatase B	clinvar
PSAP	HGNC:9498	ENSG00000197746	P07602	Prosaposin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARSA	Arylsulfatase A	Hydrolyzes cerebroside sulfate.
YARS1	Tyrosine–tRNA ligase, cytoplasmic	Tyrosine–tRNA ligase that catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).
MTCH1	Mitochondrial carrier homolog 1	Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane.
CLCN1	Chloride channel protein 1	Voltage-gated chloride channel involved in skeletal muscle excitability.
ADM2	Protein ADM2	Intermedin/ADM2 is a peptide hormone that plays a role as physiological regulator of gastrointestinal and cardiovascular bioactivities mediated by the CALCRL-RAMPs receptor complexes.
PYCR2	Pyrroline-5-carboxylate reductase 2	Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate to L-proline using NAD(P)H.
GFAP	Glial fibrillary acidic protein	GFAP, a class-III intermediate filament, is a cell-specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells.
ARSB	Arylsulfatase B	Removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation.
PSAP	Prosaposin	Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 6 · 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
Phosphatase	2	18.6×	0.014
Enzyme (other)	1	1.3×	0.543
Other/Unknown	6	1.2×	0.543

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARSA	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
YARS1	Enzyme (other)	yes	6.1.1.1	aa-tRNA-synth_Ic, Tyr-tRNA-ligase, tRNA-bd_dom
MTCH1	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf
CLCN1	Other/Unknown	no		ClC, Cl_channel-1, Cl-channel_core
ADM2	Other/Unknown	no		Adrenomedullin-reg_peptide
PYCR2	Other/Unknown	no		Pyrroline-COOH_reductase, 6-PGluconate_DH-like_C_sf, P5C_Rdtase_cat_N
GFAP	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
ARSB	Phosphatase	yes	3.1.6.1	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
PSAP	Other/Unknown	no		SAP_A, SapB_1, SapB_2

Expression context

Cohort genes with no expression data: 0.

8 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
monocyte	2
mononuclear cell	2
granulocyte	1
right testis	1
islet of Langerhans	1
left adrenal gland	1
right adrenal gland	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
triceps brachii	1
body of pancreas	1
gluteal muscle	1
tendon of biceps brachii	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
dorsal motor nucleus of vagus nerve	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
YARS1	290	ubiquitous	marker	islet of Langerhans, right adrenal gland, left adrenal gland
MTCH1	288	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
CLCN1	108	tissue_specific	marker	hindlimb stylopod muscle, triceps brachii, skeletal muscle tissue of rectus abdominis
ADM2	122	ubiquitous	yes	tendon of biceps brachii, body of pancreas, gluteal muscle
PYCR2	251	ubiquitous	marker	cardiac muscle of right atrium, right uterine tube, left ventricle myocardium
GFAP	210	broad	marker	medulla oblongata, inferior olivary complex, dorsal motor nucleus of vagus nerve
ARSB	193	ubiquitous	marker	calcaneal tendon, monocyte, mononuclear cell
PSAP	295	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFAP	6,997
YARS1	4,793
PYCR2	1,728
MTCH1	1,570
ARSA	1,356
CLCN1	1,191
ARSB	972
ADM2	548
PSAP	217

Structural data

PDB: 8 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSAP	P07602	20
ARSA	P15289	10
CLCN1	P35523	9
YARS1	P54577	8
ADM2	Q7Z4H4	2
PYCR2	Q96C36	2
GFAP	P14136	1
ARSB	P15848	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTCH1	Q9NZJ7	76.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid metabolism	3	112.7×	4e-05	ARSA, ARSB, PSAP
Glycosphingolipid catabolism	3	109.8×	4e-05	ARSA, ARSB, PSAP
Sphingolipid metabolism	3	63.0×	2e-04	ARSA, ARSB, PSAP
The activation of arylsulfatases	2	219.6×	4e-04	ARSA, ARSB
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	2	105.7×	0.001	ARSA, ARSB
MPS VI - Maroteaux-Lamy syndrome	1	1427.5×	0.005	ARSB
Metabolism of lipids	3	11.8×	0.009	ARSA, ARSB, PSAP
Innate Immune System	3	9.6×	0.015	ARSA, ARSB, PSAP
Mucopolysaccharidoses	1	237.9×	0.018	ARSB
Neutrophil degranulation	3	8.7×	0.018	ARSA, ARSB, PSAP
GPCR ligand binding	2	16.0×	0.024	ADM2, PSAP
Calcitonin-like ligand receptors	1	129.8×	0.027	ADM2
Chondroitin sulfate/dermatan sulfate metabolism	1	119.0×	0.027	ARSB
Diseases of carbohydrate metabolism	1	102.0×	0.027	ARSB
Glutamate and glutamine metabolism	1	102.0×	0.027	PYCR2
CS/DS degradation	1	68.0×	0.035	ARSB
Chaperone Mediated Autophagy	1	62.1×	0.035	GFAP
GPCR downstream signalling	2	10.9×	0.035	ADM2, PSAP
Signaling by GPCR	2	10.0×	0.035	ADM2, PSAP
Cytosolic tRNA aminoacylation	1	54.9×	0.038	YARS1
Immune System	3	4.9×	0.038	ARSA, ARSB, PSAP
Metabolism of proteins	3	4.6×	0.041	ARSA, YARS1, ARSB
Nuclear signaling by ERBB4	1	43.3×	0.042	GFAP
Metabolism	3	4.4×	0.045	ARSA, ARSB, PSAP
tRNA Aminoacylation	1	35.7×	0.047	YARS1
Glycosaminoglycan metabolism	1	27.4×	0.058	ARSB
Class B/2 (Secretin family receptors)	1	23.8×	0.064	ADM2
Response to elevated platelet cytosolic Ca2+	1	20.4×	0.072	PSAP
Stimuli-sensing channels	1	17.0×	0.083	CLCN1
Post-translational protein modification	2	4.8×	0.086	ARSA, ARSB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lysosomal transport	2	156.0×	0.004	ARSB, PSAP
tyrosyl-tRNA aminoacylation	1	1872.4×	0.006	YARS1
positive regulation of Schwann cell proliferation	1	1872.4×	0.006	GFAP
colon epithelial cell migration	1	1872.4×	0.006	ARSB
ganglioside GM1 transport to membrane	1	1872.4×	0.006	PSAP
Schwann cell proliferation	1	624.1×	0.011	GFAP
neuronal ion channel clustering	1	624.1×	0.011	MTCH1
regulation of neurotransmitter uptake	1	624.1×	0.011	GFAP
neuron projection regeneration	1	468.1×	0.011	GFAP
epithelial cell differentiation involved in prostate gland development	1	374.5×	0.011	PSAP
D-aspartate import across plasma membrane	1	374.5×	0.011	GFAP
regulation of chaperone-mediated autophagy	1	374.5×	0.011	GFAP
adrenomedullin receptor signaling pathway	1	374.5×	0.011	ADM2
response to pH	1	312.1×	0.011	ARSB
regulation of epithelial cell migration	1	312.1×	0.011	ARSB
chondroitin sulfate proteoglycan catabolic process	1	312.1×	0.011	ARSB
L-proline biosynthetic process	1	312.1×	0.011	PYCR2
response to methylmercury	1	267.5×	0.012	ARSB
prostate gland growth	1	234.1×	0.013	PSAP
gene expression	2	17.8×	0.016	GFAP, PSAP
Bergmann glial cell differentiation	1	170.2×	0.016	GFAP
neuronal action potential propagation	1	156.0×	0.017	CLCN1
protein insertion into mitochondrial outer membrane	1	144.0×	0.018	MTCH1
astrocyte development	1	124.8×	0.020	GFAP
regulation of systemic arterial blood pressure	1	117.0×	0.020	ADM2
sphingolipid metabolic process	1	110.1×	0.020	PSAP
enteric nervous system development	1	110.1×	0.020	GFAP
regulation of protein-containing complex assembly	1	81.4×	0.026	GFAP
positive regulation of heart rate	1	78.0×	0.026	ADM2
negative regulation of blood pressure	1	72.0×	0.027	ADM2

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Atidarsagene Autotemcel	Approved (phase 4)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Busulfan.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 6 of 9 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
YARS1	CAPSAICIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
YARS1	2	4
PSAP	1	3
ARSA	0	0
MTCH1	0	0
CLCN1	0	0
ADM2	0	0
PYCR2	0	0
GFAP	0	0
ARSB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPSAICIN	4	YARS1
CRENOLANIB	3	YARS1
FENRETINIDE	3	PSAP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
YARS1	16	Binding:16
PSAP	12	Binding:8, ADMET:4
ARSA	4	Binding:3, Functional:1
PYCR2	2	Binding:2
ADM2	1	Binding:1
ARSB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YARS1	6.1.1.1	tyrosine-tRNA ligase
ARSB	3.1.6.1, 3.1.6.12	arylsulfatase (type I), N-acetylgalactosamine-4-sulfatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
CAPSAICIN	4	YARS1
CRENOLANIB	3	YARS1
FENRETINIDE	3	PSAP

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	YARS1
B	Phased (≥1) drug, not yet approved	1	PSAP
C	Druggable family + PDB, no drug	2	ARSA, ARSB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	MTCH1, CLCN1, ADM2, PYCR2, GFAP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARSA	4	—
MTCH1	0	—
CLCN1	0	—
ADM2	1	—
PYCR2	2	—
GFAP	0	—
ARSB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 37.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	21
PHASE2	6
PHASE1/PHASE2	6
PHASE1	2
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04283227	PHASE3	ACTIVE_NOT_RECRUITING	OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT03771898	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01303146	PHASE2	COMPLETED	Efficacy METAZYM for the Treatment Metachromatic Leukodystrophy Treated With Hematopoietic Stem Cell Transplantation
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT01510028	PHASE1/PHASE2	COMPLETED	Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)
NCT01560182	PHASE1/PHASE2	COMPLETED	Gene Therapy for Metachromatic Leukodystrophy (MLD)
NCT01801709	PHASE1/PHASE2	COMPLETED	Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy
NCT01887938	PHASE1/PHASE2	COMPLETED	An Efficacy and Safety Study of HGT-1110 in Participants With Metachromatic Leukodystrophy
NCT02559830	PHASE1/PHASE2	UNKNOWN	Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy
NCT03392987	PHASE2	COMPLETED	A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)
NCT00418561	PHASE1	COMPLETED	Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03725670	Not specified	RECRUITING	Direct Lentiviral Injection Gene Therapy for MLD
NCT04925349	Not specified	RECRUITING	Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT07046338	Not specified	RECRUITING	Lentiviral Hematopoietic Stem Cell Gene Therapy for MLD
NCT00004378	Not specified	COMPLETED	Stem Cell Transplantation (SCT) for Genetic Diseases
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT00639132	Not specified	WITHDRAWN	The Natural History of Metachromatic Leukodystrophy
NCT00683189	Not specified	COMPLETED	Effect of Warfarin in the Treatment of Metachromatic Leukodystrophy
NCT01963650	Not specified	TERMINATED	Natural History Study of Children With Metachromatic Leukodystrophy
NCT02021266	Not specified	NO_LONGER_AVAILABLE	Single Patient Expanded Access Protocol: Metabolic Boost
NCT02084121	Not specified	NO_LONGER_AVAILABLE	Allogeneic Stem Cell Transplantation for the Treatment of Multiple Sclerosis (Compassionate Use)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03639844	Not specified	NO_LONGER_AVAILABLE	BPX-501 T Cells Infused Post Stem Cell Transplant in Pediatrics With Non-Malignant Disorders Ineligible for BPU004 Study
NCT04628364	Not specified	COMPLETED	The Natural History of Metachromatic Leukodystrophy Study (HOME Study)
NCT05119764	Not specified	COMPLETED	Manual Lymphatic Drainage Before and After Total Knee Replacement, a Single-center Observer-blinded Randomized Controlled Trial
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05755568	Not specified	WITHDRAWN	A Study to Learn About Metachromatic Leukodystrophy (MLD) in Children in Spain

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ATIDARSAGENE AUTOTEMCEL	4	2
CYCLOPHOSPHAMIDE ANHYDROUS	4	2
ALEMTUZUMAB	4	1
BUSULFAN	4	1
CLOFARABINE	4	1
HYDROXYUREA	4	1
CEBSULFASE ALFA	2	3
RIMIDUCID	2	1
RIVOGENLECLEUCEL	2	1

Cohort genes: ARSA, YARS1, MTCH1, CLCN1, ADM2, PYCR2, GFAP, ARSB, PSAP
Drugs: Atidarsagene Autotemcel, Cyclophosphamide, Alemtuzumab, Busulfan, Clofarabine, Hydroxyurea