metachromatic leukodystrophy due to saposin B deficiency

Summary

metachromatic leukodystrophy due to saposin B deficiency (MONDO:0009590) is a disease caused by PSAP (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: PSAP (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 818

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	metachromatic leukodystrophy due to saposin B deficiency
Mondo ID	MONDO:0009590
MeSH	C562609
OMIM	249900
SNOMED CT	1003375005, 297278001, 68390005
UMLS	C0268262
MedGen	120624
GARD	0010674
Is cancer (heuristic)	no

Also known as: metachromatic leukodystrophy due to sap-B deficiency · metachromatic leukodystrophy due to saposin b deficiency

Data availability: 818 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › hereditary dementia › metachromatic leukodystrophy › metachromatic leukodystrophy due to saposin B deficiency

Related subtypes (1): 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:

355 likely benign, 170 uncertain significance, 27 pathogenic, 20 likely pathogenic, 10 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 7 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070932	NM_002778.4(PSAP):c.1120del (p.Glu374fs)	PSAP	Pathogenic	criteria provided, single submitter
1075794	NM_002778.4(PSAP):c.2T>G (p.Met1Arg)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330309	NM_002778.4(PSAP):c.1005+1G>A	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13361	NM_002778.4(PSAP):c.650C>T (p.Thr217Ile)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13363	NM_002778.4(PSAP):c.722G>C (p.Cys241Ser)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13365	NM_002778.4(PSAP):c.1A>T (p.Met1Leu)	PSAP	Pathogenic	criteria provided, multiple submitters, no conflicts
13366	NM_002778.4(PSAP):c.577-1G>T	PSAP	Pathogenic	criteria provided, multiple submitters, no conflicts
13367	NM_002778.4(PSAP):c.643A>C (p.Asn215His)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13374	NM_002778.4(PSAP):c.577-2A>G	PSAP	Pathogenic	criteria provided, single submitter
13375	NM_002778.4(PSAP):c.828_829del (p.Glu276fs)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1366889	NC_000010.10:g.(?73587761)(73588844_?)del	PSAP	Pathogenic	criteria provided, single submitter
1382238	NM_002778.4(PSAP):c.83del (p.Gly28fs)	PSAP	Pathogenic	criteria provided, single submitter
1399943	NM_002778.4(PSAP):c.299_315del (p.Pro100fs)	PSAP	Pathogenic	criteria provided, single submitter
1412783	NC_000010.10:g.(?73610929)(73610988_?)del	PSAP	Pathogenic	criteria provided, single submitter
1438752	NM_002778.4(PSAP):c.670G>T (p.Glu224Ter)	PSAP	Pathogenic	criteria provided, single submitter
1455040	NM_002778.4(PSAP):c.889G>T (p.Glu297Ter)	PSAP	Pathogenic	criteria provided, multiple submitters, no conflicts
1455762	NM_002778.4(PSAP):c.1204C>T (p.Gln402Ter)	PSAP	Pathogenic	criteria provided, single submitter
1676842	NM_002778.4(PSAP):c.721T>G (p.Cys241Gly)	PSAP	Pathogenic	criteria provided, single submitter
1989545	NM_002778.4(PSAP):c.1050dup (p.Lys351fs)	PSAP	Pathogenic	criteria provided, single submitter
1993070	NM_002778.4(PSAP):c.527dup (p.Leu177fs)	PSAP	Pathogenic	criteria provided, single submitter
2005872	NM_002778.4(PSAP):c.1340dup (p.Tyr447Ter)	PSAP	Pathogenic	criteria provided, single submitter
2007832	NM_002778.4(PSAP):c.555_556dup (p.Arg186fs)	PSAP	Pathogenic	criteria provided, single submitter
2026090	NM_002778.4(PSAP):c.457C>T (p.Gln153Ter)	PSAP	Pathogenic	criteria provided, single submitter
2095404	NM_002778.4(PSAP):c.722_723delinsAA (p.Cys241Ter)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2122068	NM_002778.4(PSAP):c.723_726del (p.Ile240_Cys241insTer)	PSAP	Pathogenic	criteria provided, single submitter
2126174	NM_002778.4(PSAP):c.100del (p.Gln34fs)	PSAP	Pathogenic	criteria provided, single submitter
2424541	NC_000010.10:g.(?73578585)(73581640_?)del	PSAP	Pathogenic	criteria provided, single submitter
2694009	NM_002778.4(PSAP):c.785_788del (p.Lys262fs)	PSAP	Pathogenic	criteria provided, single submitter
2709568	NM_002778.4(PSAP):c.202del (p.Asp68fs)	PSAP	Pathogenic	criteria provided, single submitter
2735420	NM_002778.4(PSAP):c.148C>T (p.Gln50Ter)	PSAP	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 36 · Orphanet: 13 · 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
MTCH1	Definitive	Autosomal recessive	Krabbe disease due to saposin A deficiency	18
PSAP	Definitive	Autosomal recessive	Krabbe disease due to saposin A deficiency	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CDH23	Orphanet:231169	Usher syndrome type 1
CDH23	Orphanet:2965	Prolactinoma
CDH23	Orphanet:314777	Familial isolated pituitary adenoma
CDH23	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:91347	TSH-secreting pituitary adenoma
CDH23	Orphanet:96253	Cushing disease
ASCC1	Orphanet:486811	Prenatal-onset spinal muscular atrophy with congenital bone fractures

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTCH1	HGNC:17586	ENSG00000137409	Q9NZJ7	Mitochondrial carrier homolog 1	gencc,clinvar
PSAP	HGNC:9498	ENSG00000197746	P07602	Prosaposin	gencc,clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	clinvar
ASCC1	HGNC:24268	ENSG00000138303	Q8N9N2	Activating signal cointegrator 1 complex subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTCH1	Mitochondrial carrier homolog 1	Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane.
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).
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
ASCC1	Activating signal cointegrator 1 complex subunit 1	Plays a role in DNA damage repair as component of the ASCC complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTCH1	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf
PSAP	Other/Unknown	no		SAP_A, SapB_1, SapB_2
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
ASCC1	Other/Unknown	no		KH_dom_type_1, Cyclic_Pdiesterase, ASCC1

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
leukocyte	1
monocyte	1
mononuclear cell	1
left ovary	1
right ovary	1
calcaneal tendon	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTCH1	288	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
PSAP	295	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary
ASCC1	282	ubiquitous	marker	calcaneal tendon, ventricular zone, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH23	1,575
MTCH1	1,570
ASCC1	1,500
PSAP	217

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSAP	P07602	20
CDH23	Q9H251	6
ASCC1	Q8N9N2	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: 27. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ALKBH3 mediated reversal of alkylation damage	1	951.7×	0.017	ASCC1
DNA Damage Reversal	1	543.8×	0.017	ASCC1
Reversal of alkylation damage by DNA dioxygenases	1	543.8×	0.017	ASCC1
Sensory processing of sound	1	102.9×	0.046	CDH23
Glycosphingolipid metabolism	1	100.2×	0.046	PSAP
Glycosphingolipid catabolism	1	97.6×	0.046	PSAP
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.049	CDH23
Sphingolipid metabolism	1	56.0×	0.049	PSAP
Response to elevated platelet cytosolic Ca2+	1	54.4×	0.049	PSAP
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.049	CDH23
Platelet activation, signaling and aggregation	1	35.2×	0.065	PSAP
DNA Repair	1	32.8×	0.065	ASCC1
Sensory Perception	1	31.7×	0.065	CDH23
Platelet degranulation	1	29.3×	0.065	PSAP
Class A/1 (Rhodopsin-like receptors)	1	24.7×	0.067	PSAP
Peptide ligand-binding receptors	1	24.7×	0.067	PSAP
GPCR ligand binding	1	21.4×	0.073	PSAP
GPCR downstream signalling	1	14.5×	0.101	PSAP
Signaling by GPCR	1	13.4×	0.101	PSAP
G alpha (i) signalling events	1	13.0×	0.101	PSAP
Hemostasis	1	12.0×	0.104	PSAP
Metabolism of lipids	1	10.5×	0.113	PSAP
Innate Immune System	1	8.5×	0.133	PSAP
Neutrophil degranulation	1	7.7×	0.140	PSAP
Immune System	1	4.3×	0.231	PSAP
Metabolism	1	3.9×	0.246	PSAP
Signal Transduction	1	3.4×	0.267	PSAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ganglioside GM1 transport to membrane	1	4213.0×	0.008	PSAP
neuronal ion channel clustering	1	1404.3×	0.011	MTCH1
epithelial cell differentiation involved in prostate gland development	1	842.6×	0.011	PSAP
equilibrioception	1	601.9×	0.011	CDH23
prostate gland growth	1	526.6×	0.011	PSAP
sensory perception of light stimulus	1	468.1×	0.011	CDH23
DNA alkylation repair	1	383.0×	0.012	ASCC1
protein insertion into mitochondrial outer membrane	1	324.1×	0.012	MTCH1
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	280.9×	0.013	CDH23
sphingolipid metabolic process	1	247.8×	0.013	PSAP
auditory receptor cell stereocilium organization	1	210.7×	0.014	CDH23
lysosomal transport	1	175.5×	0.015	PSAP
calcium-dependent cell-cell adhesion	1	120.4×	0.019	CDH23
cochlea development	1	117.0×	0.019	CDH23
regulation of lipid metabolic process	1	108.0×	0.020	PSAP
regulation of cytosolic calcium ion concentration	1	95.8×	0.021	CDH23
photoreceptor cell maintenance	1	89.6×	0.021	CDH23
regulation of signal transduction	1	66.9×	0.026	MTCH1
regulation of autophagy	1	60.2×	0.028	PSAP
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	54.7×	0.029	PSAP
calcium ion transport	1	45.3×	0.032	CDH23
locomotory behavior	1	44.8×	0.032	CDH23
DNA replication	1	41.3×	0.033	ASCC1
homophilic cell-cell adhesion	1	35.1×	0.038	CDH23
neuron projection development	1	30.5×	0.041	CDH23
sensory perception of sound	1	25.2×	0.048	CDH23
gene expression	1	20.0×	0.056	PSAP
visual perception	1	19.9×	0.056	CDH23
cell migration	1	15.4×	0.070	CDH23
positive regulation of apoptotic process	1	14.2×	0.073	MTCH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSAP	1	3
MTCH1	0	0
CDH23	0	0
ASCC1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FENRETINIDE	3	PSAP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSAP	12	Binding:8, ADMET:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
FENRETINIDE	3	PSAP

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	PSAP
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	MTCH1, CDH23, ASCC1

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)
MTCH1	0	—
CDH23	0	—
ASCC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.