mucopolysaccharidosis type 3A

Summary

mucopolysaccharidosis type 3A (MONDO:0009655) is a disease caused by SGSH (GenCC Definitive), with 5 cohort genes and 13 clinical trials. Top therapeutic interventions include rebisufligene etisparvovec and sobi-003.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: SGSH (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 1,169
• Clinical trials: 13

Clinical features

Epidemiology

Prevalence records

9 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1.4	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.32	Europe	Validated
Point prevalence	<1 / 1 000 000	0.052	United States	Validated
Prevalence at birth	1-9 / 100 000	1.16	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.88	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.47	Czech Republic	Validated
Prevalence at birth	1-9 / 100 000	1.62	Estonia	Validated
Prevalence at birth	1-9 / 1 000 000	0.62	Sweden	Validated
Prevalence at birth	1-9 / 1 000 000	0.19	United States	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mucopolysaccharidosis type 3A
Mondo ID	MONDO:0009655
OMIM	252900
Orphanet	79269
DOID	DOID:0111395
ICD-11	182200345
NCIT	C84897
SNOMED CT	41572006
UMLS	C0086647
MedGen	39264
GARD	0007071
Is cancer (heuristic)	no

Also known as: heparan sulfamidase deficiency · heparan sulphate sulfatase deficiency · heparane sulfamidase deficiency · MPS III A · MPS IIIA · MPS3A · MPSIIIA · mucopoly-saccharidosis type 3A · mucopolysaccharidosis type 3A · mucopolysaccharidosis type IIIA · mucopolysaccharidosis, type IIIA · Sanfilippo A · Sanfilippo syndrome a · Sanfilippo syndrome type A

Data availability: 1,169 ClinVar variants · 7 GenCC gene-disease records · 16 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › mucopolysaccharidosis type 3 › mucopolysaccharidosis type 3A

Related subtypes (3): mucopolysaccharidosis type 3B, mucopolysaccharidosis type 3C, mucopolysaccharidosis type 3D

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:

278 likely benign, 194 uncertain significance, 31 pathogenic/likely pathogenic, 31 likely pathogenic, 28 pathogenic, 23 conflicting classifications of pathogenicity, 9 benign, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
10486	NM_000202.8(IDS):c.1327C>T (p.Arg443Ter)	IDS	Pathogenic	criteria provided, multiple submitters, no conflicts
10497	NM_000202.8(IDS):c.1402C>T (p.Arg468Trp)	IDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1509031	NM_000202.8(IDS):c.1439C>T (p.Pro480Leu)	IDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460119	NM_000199.5(SGSH):c.2T>G (p.Met1Arg)	LOC130061900	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678724	NM_000199.5(SGSH):c.7_16del (p.Cys3fs)	LOC130061900	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066348	NM_000199.5(SGSH):c.268G>C (p.Gly90Arg)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068595	NC_000017.10:g.(?78194005)(78194132_?)del	SGSH	Pathogenic	criteria provided, single submitter
1069492	NM_000199.5(SGSH):c.757del (p.Val253fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071734	NM_000199.5(SGSH):c.545G>A (p.Arg182His)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072646	NM_000199.5(SGSH):c.630G>A (p.Trp210Ter)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073350	NM_000199.5(SGSH):c.1241_1242dup (p.Thr415fs)	SGSH	Pathogenic	criteria provided, multiple submitters, no conflicts
1075867	NM_000199.5(SGSH):c.466A>T (p.Lys156Ter)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075946	NM_000199.5(SGSH):c.1412G>A (p.Trp471Ter)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076318	NM_000199.5(SGSH):c.642del (p.Tyr215fs)	SGSH	Pathogenic	criteria provided, single submitter
1184569	NM_000199.5(SGSH):c.716A>G (p.Gln239Arg)	SGSH	Pathogenic	no assertion criteria provided
1297691	NM_000199.5(SGSH):c.1130G>A (p.Arg377His)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325064	NM_000199.5(SGSH):c.733C>T (p.Arg245Cys)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353938	NM_000199.5(SGSH):c.302T>C (p.Phe101Ser)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365580	NM_000199.5(SGSH):c.506+1G>A	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381871	NM_000199.5(SGSH):c.282_283dup (p.Val95fs)	SGSH	Pathogenic	criteria provided, single submitter
1383454	NM_000199.5(SGSH):c.250-289_463del	SGSH	Pathogenic	criteria provided, single submitter
1401367	NM_000199.5(SGSH):c.1345del (p.Gln449fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405407	NM_000199.5(SGSH):c.398del (p.Pro133fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1419099	NM_000199.5(SGSH):c.1295_1303del (p.Tyr432_Arg435delinsCys)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1437845	NM_000199.5(SGSH):c.909del (p.Lys303fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450886	NM_000199.5(SGSH):c.1091_1103del (p.Ser364fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452542	NM_000199.5(SGSH):c.693_705del (p.Ala232fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454739	NM_000199.5(SGSH):c.1426del (p.His476fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454978	NM_000199.5(SGSH):c.637dup (p.Gln213fs)	SGSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455207	NM_000199.5(SGSH):c.303C>A (p.Phe101Leu)	SGSH	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 7 · 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
SGSH	Definitive	Autosomal dominant	mucopolysaccharidosis type 3A	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SGSH	Orphanet:79269	Sanfilippo syndrome type A
RNF213	Orphanet:2573	Moyamoya disease
CARD14	Orphanet:2897	Pityriasis rubra pilaris
GNPTAB	Orphanet:423461	Mucolipidosis type III alpha/beta
GNPTAB	Orphanet:576	Mucolipidosis type II
IDS	Orphanet:217085	Mucopolysaccharidosis type 2, severe form
IDS	Orphanet:217093	Mucopolysaccharidosis type 2, attenuated form

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SGSH	HGNC:10818	ENSG00000181523	P51688	N-sulphoglucosamine sulphohydrolase	gencc,clinvar
RNF213	HGNC:14539	ENSG00000173821	Q63HN8	E3 ubiquitin-protein ligase RNF213	clinvar
CARD14	HGNC:16446	ENSG00000141527	Q9BXL6	Caspase recruitment domain-containing protein 14	clinvar
GNPTAB	HGNC:29670	ENSG00000111670	Q3T906	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta	clinvar
IDS	HGNC:5389	ENSG00000010404	P22304	Iduronate 2-sulfatase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SGSH	N-sulphoglucosamine sulphohydrolase	Catalyzes a step in lysosomal heparan sulfate degradation.
RNF213	E3 ubiquitin-protein ligase RNF213	Atypical E3 ubiquitin ligase that can catalyze ubiquitination of both proteins and lipids, and which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity.
CARD14	Caspase recruitment domain-containing protein 14	Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways.
GNPTAB	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta	Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus.
IDS	Iduronate 2-sulfatase	Lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.6

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	33.6×	0.006
Scaffold/PPI	1	3.5×	0.471
Enzyme (other)	1	2.4×	0.471
Transcription factor	1	1.6×	0.476

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SGSH	Phosphatase	yes	3.10.1.1	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
RNF213	Transcription factor	no		Znf_RING, AAA+_ATPase, Znf_RING/FYVE/PHD
CARD14	Scaffold/PPI	no		CARD, PDZ, Guanylate_kin-like_dom
GNPTAB	Enzyme (other)	yes	2.7.8.17	Notch_dom, EF_hand_dom, DMAP1-bd
IDS	Phosphatase	yes	3.1.6.13	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal cortex	1
left adrenal gland	1
left adrenal gland cortex	1
granulocyte	1
metanephros cortex	1
pancreatic ductal cell	1
lower esophagus mucosa	1
skin of abdomen	1
skin of leg	1
endothelial cell	1
sural nerve	1
tibia	1
cortical plate	1
descending thoracic aorta	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SGSH	272	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, adrenal cortex
RNF213	252	ubiquitous	marker	granulocyte, metanephros cortex, pancreatic ductal cell
CARD14	179	tissue_specific	yes	lower esophagus mucosa, skin of leg, skin of abdomen
GNPTAB	290	ubiquitous	marker	tibia, endothelial cell, sural nerve
IDS	238	ubiquitous	marker	right frontal lobe, cortical plate, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNF213	2,368
CARD14	1,902
GNPTAB	1,518
SGSH	1,151
IDS	1,123

Intra-cohort edges

A	B	Sources
IDS	SGSH	intact

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNPTAB	Q3T906	5
RNF213	Q63HN8	4
SGSH	P51688	2
IDS	P22304	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CARD14	Q9BXL6	75.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 5 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
HS-GAG degradation	2	331.0×	3e-04	SGSH, IDS
MPS II - Hunter syndrome (HS-GAG degradation)	1	3806.7×	0.002	IDS
MPS IIIA - Sanfilippo syndrome A	1	3806.7×	0.002	SGSH
MPS II - Hunter syndrome (CS/DS degradation)	1	3806.7×	0.002	IDS
Mucopolysaccharidoses	1	634.4×	0.008	SGSH
Suppression of apoptosis	1	543.8×	0.008	RNF213
Response of Mtb to phagocytosis	1	475.8×	0.008	RNF213
Infection with Mycobacterium tuberculosis	1	380.7×	0.008	RNF213
Diseases of carbohydrate metabolism	1	271.9×	0.010	SGSH
Heparan sulfate/heparin (HS-GAG) metabolism	1	181.3×	0.013	SGSH
CS/DS degradation	1	181.3×	0.013	IDS
Bacterial Infection Pathways	1	112.0×	0.019	RNF213
Signaling by ALK in cancer	1	90.6×	0.021	RNF213
Glycosaminoglycan metabolism	1	73.2×	0.024	SGSH
Disease	2	8.7×	0.028	SGSH, RNF213
Signaling by ALK fusions and activated point mutants	1	50.1×	0.031	RNF213
Metabolism of carbohydrates and carbohydrate derivatives	1	40.1×	0.036	SGSH
Diseases of metabolism	1	26.8×	0.051	SGSH
Class I MHC mediated antigen processing & presentation	1	23.4×	0.056	RNF213
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.065	RNF213
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.093	RNF213
Adaptive Immune System	1	9.9×	0.111	RNF213
Infectious disease	1	8.3×	0.126	RNF213
Immune System	1	4.3×	0.223	RNF213
Metabolism	1	3.9×	0.237	SGSH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycosaminoglycan catabolic process	2	963.0×	4e-05	SGSH, IDS
heparan sulfate proteoglycan catabolic process	2	749.0×	4e-05	SGSH, IDS
lipid ubiquitination	1	3370.4×	0.003	RNF213
N-glycan processing to lysosome	1	1685.2×	0.004	GNPTAB
dermatan sulfate proteoglycan catabolic process	1	842.6×	0.006	IDS
secretion of lysosomal enzymes	1	674.1×	0.006	GNPTAB
negative regulation of non-canonical Wnt signaling pathway	1	674.1×	0.006	RNF213
xenophagy	1	481.5×	0.008	RNF213
carbohydrate phosphorylation	1	421.3×	0.008	GNPTAB
activation of NF-kappaB-inducing kinase activity	1	337.0×	0.009	CARD14
lipid droplet formation	1	198.3×	0.014	RNF213
motor behavior	1	112.3×	0.022	SGSH
regulation of immune response	1	99.1×	0.022	CARD14
sprouting angiogenesis	1	96.3×	0.022	RNF213
determination of adult lifespan	1	86.4×	0.022	SGSH
regulation of lipid metabolic process	1	86.4×	0.022	RNF213
immune system process	1	78.4×	0.022	RNF213
tumor necrosis factor-mediated signaling pathway	1	66.1×	0.025	CARD14
lysosome organization	1	61.3×	0.026	GNPTAB
positive regulation of protein phosphorylation	1	55.2×	0.027	CARD14
protein K63-linked ubiquitination	1	53.5×	0.027	RNF213
protein autoubiquitination	1	46.8×	0.029	RNF213
obsolete positive regulation of NF-kappaB transcription factor activity	1	41.1×	0.031	CARD14
defense response to bacterium	1	21.6×	0.057	RNF213
ubiquitin-dependent protein catabolic process	1	14.8×	0.077	RNF213
positive regulation of canonical NF-kappaB signal transduction	1	14.5×	0.077	CARD14
angiogenesis	1	12.5×	0.086	RNF213
protein ubiquitination	1	8.3×	0.123	RNF213
negative regulation of apoptotic process	1	7.0×	0.141	CARD14
apoptotic process	1	5.7×	0.162	CARD14

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SGSH	0	0
RNF213	0	0
CARD14	0	0
GNPTAB	0	0
IDS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
RNF213	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SGSH	3.10.1.1	N-sulfoglucosamine sulfohydrolase
GNPTAB	2.7.8.17	UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase
IDS	3.1.6.13	iduronate-2-sulfatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	3	SGSH, GNPTAB, IDS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RNF213, CARD14

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SGSH	0	—
RNF213	1	—
CARD14	0	—
GNPTAB	0	—
IDS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	5
Not specified	4
PHASE2/PHASE3	2
PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02716246	PHASE2/PHASE3	RECRUITING	Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
NCT04360265	PHASE3	ENROLLING_BY_INVITATION	Follow-up Study of AAV-Mediated Gene Transfer (UX111; Previously Known as ABO-102) for MPS Type IIIA
NCT03612869	PHASE2/PHASE3	UNKNOWN	Study of AAVrh10-h.SGSH Gene Therapy in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIA)
NCT04201405	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Gene Therapy with Modified Autologous Hematopoietic Stem Cells for Patients with Mucopolysaccharidosis Type IIIA
NCT06181136	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of DNL126 in Pediatric Participants With Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome Type A)
NCT03423186	PHASE1/PHASE2	COMPLETED	A Study to Assess the Safety and Tolerability of SOBI003 in Pediatric MPS IIIA Patients
NCT03811028	PHASE1/PHASE2	COMPLETED	A Study to Assess the Safety, Tolerability, and Efficacy of Long-term SOBI003 Treatment in Pediatric MPS IIIA Patients
NCT04088734	PHASE1/PHASE2	TERMINATED	Gene Transfer Study of ABO-102 in Patients With Middle and Advanced Phases of MPS IIIA Disease
NCT06567769	PHASE1	RECRUITING	Phase 1 Study of GC1130A in Patients With Sanfilippo Syndrome Type A (MPS IIIA)
NCT01047306	Not specified	COMPLETED	A Study of Patients With Sanfilippo Syndrome Type A (MPS IIIA)
NCT01873911	Not specified	COMPLETED	Neurobehavioral Phenotypes in MPS III
NCT02037880	Not specified	COMPLETED	Natural History Studies of Mucopolysaccharidosis III
NCT04918641	Not specified	UNKNOWN	Natural History Observational Study of MPS IIIa in SMC

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
REBISUFLIGENE ETISPARVOVEC	1	2
SOBI-003	1	2