Mucosulfatidosis

Summary

Mucosulfatidosis (MONDO:0010088) is a disease caused by SUMF1 (GenCC Definitive), with 4 cohort genes and 6 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SUMF1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 776
• Phenotypes (HPO): 30
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		154	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.2	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0003134	Abnormality of peripheral nerve conduction	Very frequent (80-99%)
HP:0007307	Rapid neurologic deterioration	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0008155	Mucopolysacchariduria	Very frequent (80-99%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000319	Smooth philtrum	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000574	Thick eyebrow	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0002208	Coarse hair	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0007957	Corneal opacity	Frequent (30-79%)
HP:0010059	Broad hallux phalanx	Frequent (30-79%)
HP:0011304	Broad thumb	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mucosulfatidosis
Mondo ID	MONDO:0010088
MeSH	D052517
OMIM	272200
Orphanet	585
DOID	DOID:0050441
ICD-11	848083807
NCIT	C84908
SNOMED CT	54898003
UMLS	C0268263
MedGen	75664
GARD	0005061
NORD	1471
Is cancer (heuristic)	no

Also known as: juvenile sulfatidosis · juvenile sulfatidosis, Austin type · MSD · mucosulfatidosis · Multiple Sulfatase Deficiency · multiple sulfatase deficiency · multiple sulfatase deficiency disease · sulfatidosis juvenile, Austin type · sulfatidosis, juvenile, Austin type

Data availability: 776 ClinVar variants · 5 GenCC gene-disease records · 7 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › mucosulfatidosis

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, autosomal dominant deafness - onychodystrophy syndrome, keratoderma hereditarium mutilans, Rombo syndrome, Sjogren-Larsson syndrome, ichthyosis prematurity syndrome, ANE syndrome, frontonasal dysplasia with alopecia and genital anomaly, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous syndrome

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:

304 likely benign, 153 uncertain significance, 60 pathogenic, 24 pathogenic/likely pathogenic, 23 likely pathogenic, 19 benign, 15 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068976	NM_182760.4(SUMF1):c.191del (p.Ser64fs)	LOC129936056	Pathogenic	criteria provided, single submitter
1069955	NM_182760.4(SUMF1):c.266del (p.His88_Ser89insTer)	LOC129936056	Pathogenic	criteria provided, single submitter
1354739	NM_182760.4(SUMF1):c.156C>A (p.Cys52Ter)	LOC129936056	Pathogenic	criteria provided, multiple submitters, no conflicts
1454207	NM_182760.4(SUMF1):c.150C>A (p.Cys50Ter)	LOC129936056	Pathogenic	criteria provided, single submitter
2032625	NM_182760.4(SUMF1):c.164_170del (p.Pro55fs)	LOC129936056	Pathogenic	criteria provided, single submitter
2670	NM_182760.4(SUMF1):c.243del (p.Gly82fs)	LOC129936056	Pathogenic	no assertion criteria provided
2700697	NM_182760.4(SUMF1):c.247G>T (p.Glu83Ter)	LOC129936056	Pathogenic	criteria provided, single submitter
2759355	NM_182760.4(SUMF1):c.250_251del (p.Arg84fs)	LOC129936056	Pathogenic	criteria provided, single submitter
2808494	NM_182760.4(SUMF1):c.166del (p.Gln56fs)	LOC129936056	Pathogenic	criteria provided, single submitter
2893418	NM_182760.4(SUMF1):c.103C>T (p.Gln35Ter)	LOC129936056	Pathogenic	criteria provided, single submitter
3366587	NM_182760.4(SUMF1):c.266C>A (p.Ser89Ter)	LOC129936056	Pathogenic	criteria provided, multiple submitters, no conflicts
1029322	NM_182760.4(SUMF1):c.818A>G (p.Asp273Gly)	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066911	NM_182760.4(SUMF1):c.445-1G>A	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067600	NM_182760.4(SUMF1):c.603-1G>C	SUMF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070279	NC_000003.11:g.(?4403818)(4494743_?)del	SUMF1	Pathogenic	criteria provided, single submitter
1070280	NC_000003.11:g.(?4403818)(4459826_?)del	SUMF1	Pathogenic	criteria provided, single submitter
1072766	NM_182760.4(SUMF1):c.43G>T (p.Glu15Ter)	SUMF1	Pathogenic	criteria provided, single submitter
1076175	NM_182760.4(SUMF1):c.511C>T (p.Gln171Ter)	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076822	NM_182760.4(SUMF1):c.451A>T (p.Lys151Ter)	SUMF1	Pathogenic	criteria provided, single submitter
1323658	NM_182760.4(SUMF1):c.706C>T (p.Arg236Ter)	SUMF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323659	NM_182760.4(SUMF1):c.445-2A>G	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1348585	NC_000003.11:g.(?4494540)(4494753_?)del	SUMF1	Pathogenic	criteria provided, single submitter
1366344	NM_182760.4(SUMF1):c.323del (p.Ile108fs)	SUMF1	Pathogenic	criteria provided, single submitter
1373777	NM_182760.4(SUMF1):c.896G>A (p.Trp299Ter)	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1378318	NM_182760.4(SUMF1):c.603-2A>T	SUMF1	Pathogenic	criteria provided, single submitter
1394842	NM_182760.4(SUMF1):c.537G>A (p.Trp179Ter)	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1402280	NM_182760.4(SUMF1):c.616_623del (p.Val206fs)	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1409518	NM_182760.4(SUMF1):c.903G>A (p.Trp301Ter)	SUMF1	Pathogenic	criteria provided, single submitter
1414033	NM_182760.4(SUMF1):c.358dup (p.Thr120fs)	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1422956	NM_182760.4(SUMF1):c.668del (p.Lys223fs)	SUMF1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
SUMF1	Definitive	Autosomal recessive	mucosulfatidosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SUMF1	Orphanet:585	Multiple sulfatase deficiency
ITPR1	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
ITPR1	Orphanet:208513	Spinocerebellar ataxia type 29
ITPR1	Orphanet:98769	Spinocerebellar ataxia type 15/16

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SUMF1	HGNC:20376	ENSG00000144455	Q8NBK3	Formylglycine-generating enzyme	gencc,clinvar
SUMF2	HGNC:20415	ENSG00000129103	Q8NBJ7	Inactive C-alpha-formylglycine-generating enzyme 2	clinvar
EGOT	HGNC:37129	ENSG00000235947		eosinophil granule ontogeny transcript	clinvar
ITPR1	HGNC:6180	ENSG00000150995	Q14643	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SUMF1	Formylglycine-generating enzyme	Oxidase that catalyzes the conversion of cysteine to 3-oxoalanine on target proteins, using molecular oxygen and an unidentified reducing agent. 3-oxoalanine modification, which is also named formylglycine (fGly), occurs in the maturation…
SUMF2	Inactive C-alpha-formylglycine-generating enzyme 2	Lacks formylglycine generating activity and is unable to convert newly synthesized inactive sulfatases to their active form.
ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel that, upon inositol 1,4,5-trisphosphate binding, mediates calcium release from the endoplasmic reticulum (ER).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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
Kinase	2	13.9×	0.022
Ion channel	1	27.9×	0.053
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SUMF1	Kinase	yes	1.8.3.7	SUMF_dom, CTDL_fold, SUMF_sf
SUMF2	Kinase	yes		SUMF_dom, CTDL_fold, SUMF_sf
EGOT	Other/Unknown	no
ITPR1	Ion channel	yes		InsP3_rcpt, RIH_dom, Ion_trans_dom

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
kidney epithelium	1
renal medulla	1
upper arm skin	1
body of pancreas	1
right uterine tube	1
stromal cell of endometrium	1
bone marrow cell	1
caput epididymis	1
metanephros cortex	1
Brodmann (1909) area 23	1
cauda epididymis	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SUMF1	258	ubiquitous	marker	kidney epithelium, renal medulla, upper arm skin
SUMF2	246	ubiquitous	marker	right uterine tube, stromal cell of endometrium, body of pancreas
EGOT	118	tissue_specific	yes	bone marrow cell, caput epididymis, metanephros cortex
ITPR1	284	ubiquitous	marker	cauda epididymis, Brodmann (1909) area 23, primary visual cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ITPR1	3,483
SUMF1	1,541
SUMF2	1,288
EGOT	0

Intra-cohort edges

A	B	Sources
ITPR1	SUMF1	string_interaction
SUMF1	SUMF2	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SUMF1	Q8NBK3	18
SUMF2	Q8NBJ7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ITPR1	Q14643

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. 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
The activation of arylsulfatases	2	585.6×	2e-04	SUMF1, SUMF2
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	2	282.0×	5e-04	SUMF1, SUMF2
Glycosphingolipid metabolism	2	200.3×	5e-04	SUMF1, SUMF2
Glycosphingolipid catabolism	2	195.2×	5e-04	SUMF1, SUMF2
Sphingolipid metabolism	2	112.0×	0.001	SUMF1, SUMF2
Metabolism	3	11.6×	0.006	SUMF1, SUMF2, ITPR1
CLEC7A (Dectin-1) induces NFAT activation	1	346.1×	0.021	ITPR1
Nitric oxide stimulates guanylate cyclase	1	271.9×	0.021	ITPR1
Elevation of cytosolic Ca2+ levels	1	237.9×	0.021	ITPR1
Platelet calcium homeostasis	1	237.9×	0.021	ITPR1
cGMP effects	1	237.9×	0.021	ITPR1
Metabolism of lipids	2	21.0×	0.021	SUMF1, SUMF2
VEGFR2 mediated cell proliferation	1	190.3×	0.021	ITPR1
Effects of PIP2 hydrolysis	1	152.3×	0.021	ITPR1
Role of phospholipids in phagocytosis	1	152.3×	0.021	ITPR1
Anti-inflammatory response favouring Leishmania parasite infection	1	131.3×	0.021	ITPR1
Leishmania parasite growth and survival	1	131.3×	0.021	ITPR1
FCERI mediated Ca+2 mobilization	1	119.0×	0.021	ITPR1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	119.0×	0.021	ITPR1
Signaling by the B Cell Receptor (BCR)	1	115.3×	0.021	ITPR1
G-protein mediated events	1	108.8×	0.021	ITPR1
DAG and IP3 signaling	1	105.7×	0.021	ITPR1
Beta-catenin independent WNT signaling	1	97.6×	0.021	ITPR1
FCGR3A-mediated IL10 synthesis	1	97.6×	0.021	ITPR1
Fcgamma receptor (FCGR) dependent phagocytosis	1	92.8×	0.021	ITPR1
Platelet homeostasis	1	92.8×	0.021	ITPR1
Fc epsilon receptor (FCERI) signaling	1	90.6×	0.021	ITPR1
Opioid Signalling	1	88.5×	0.021	ITPR1
PLC beta mediated events	1	88.5×	0.021	ITPR1
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	88.5×	0.021	ITPR1

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
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1	4213.0×	0.004	ITPR1
protein oxidation	1	2808.7×	0.004	SUMF1
voluntary musculoskeletal movement	1	1404.3×	0.004	ITPR1
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	1053.2×	0.004	ITPR1
epithelial fluid transport	1	1053.2×	0.004	ITPR1
negative regulation of calcium-mediated signaling	1	1053.2×	0.004	ITPR1
ligand-gated ion channel signaling pathway	1	936.2×	0.004	ITPR1
glycosphingolipid catabolic process	1	766.0×	0.004	SUMF1
calcium import into the mitochondrion	1	601.9×	0.004	ITPR1
regulation of calcium-mediated signaling	1	561.7×	0.004	ITPR1
endoplasmic reticulum calcium ion homeostasis	1	421.3×	0.005	ITPR1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	240.7×	0.009	ITPR1
post-translational protein modification	1	210.7×	0.009	SUMF1
regulation of cytosolic calcium ion concentration	1	191.5×	0.009	ITPR1
release of sequestered calcium ion into cytosol	1	172.0×	0.010	ITPR1
positive regulation of insulin secretion	1	127.7×	0.012	ITPR1
regulation of autophagy	1	120.4×	0.012	ITPR1
protein homotetramerization	1	118.7×	0.012	ITPR1
post-embryonic development	1	102.8×	0.013	ITPR1
single fertilization	1	91.6×	0.013	ITPR1
calcium ion transport	1	90.6×	0.013	ITPR1
cell morphogenesis	1	78.8×	0.014	ITPR1
response to hypoxia	1	47.9×	0.023	ITPR1
positive regulation of apoptotic process	1	28.4×	0.036	ITPR1
signal transduction	1	8.0×	0.121	ITPR1

Therapeutics

Drug target analysis

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

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
SUMF1	0	0
SUMF2	0	0
EGOT	0	0
ITPR1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ITPR1	13	Binding:12, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SUMF1	1.8.3.7	formylglycine-generating enzyme

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

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	2	SUMF1, SUMF2
D	Druggable family + AlphaFold only, no drug	1	ITPR1
E	Difficult family or no structure, no drug	1	EGOT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SUMF1	0	—
SUMF2	0	—
EGOT	0	—
ITPR1	13	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT06036693	Not specified	RECRUITING	MPS (RaDiCo Cohort) (RaDiCo-MPS)
NCT01841983	Not specified	COMPLETED	Project A: Integrated Approaches to Improving the Health and Safety of Health Care Workers
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03831737	Not specified	COMPLETED	Team-based Ergonomics Educational Model for Workplace WELLNESS Improvement: A Pilot Study