mucopolysaccharidosis type 4A

Summary

mucopolysaccharidosis type 4A (MONDO:0009659) is a disease caused by GALNS (GenCC Definitive), with 4 cohort genes and 20 clinical trials. Top therapeutic interventions include elosulfase alfa, laronidase, and losartan.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: GALNS (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,243
• Clinical trials: 20

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	15	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.15	Canada	Validated
Point prevalence	1-9 / 1 000 000	0.12	Germany	Validated
Point prevalence	1-9 / 1 000 000	0.46	United Arab Emirates	Validated
Point prevalence	1-9 / 1 000 000	0.153	Australia	Validated
Point prevalence	<1 / 1 000 000	0.029	United States	Validated
Point prevalence	<1 / 1 000 000	0.0848	Brazil	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	Germany	Validated
Prevalence at birth	1-9 / 100 000	1.4	United Arab Emirates	Validated
Prevalence at birth	1-9 / 1 000 000	0.497	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.48	Canada	Validated
Prevalence at birth	1-9 / 1 000 000	0.29	Sweden	Validated
Prevalence at birth	1-9 / 1 000 000	0.11	United States	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mucopolysaccharidosis type 4A
Mondo ID	MONDO:0009659
OMIM	253000
Orphanet	309297
DOID	DOID:0111391
ICD-10-CM	E76.210
ICD-11	1919173641
NCIT	C84901
SNOMED CT	7259005
UMLS	C0086651
MedGen	43375
GARD	0003785
Is cancer (heuristic)	no

Also known as: galactosamine-6-sulfatase deficiency · GALNS deficiency · Morquio A disease · Morquio disease type A · Morquio syndrome A · MPS IV A · MPS IVA · MPS4A · MPSIVA · mucopolysaccharidosis type 4A · mucopolysaccharidosis type IVA · mucopolysaccharidosis, type IVA · N-acetylgalactosamine-6-sulfate sulfatase deficiency

Data availability: 1,243 ClinVar variants · 5 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › mucopolysaccharidosis type 4 › mucopolysaccharidosis type 4A

Related subtypes (2): Morquio syndrome C, mucopolysaccharidosis type 4B

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:

223 uncertain significance, 92 conflicting classifications of pathogenicity, 92 likely benign, 80 likely pathogenic, 66 pathogenic, 35 pathogenic/likely pathogenic, 10 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048378	NM_000512.5(GALNS):c.[1140-730_1365-1530del;121-2779_567-248del]		Pathogenic	criteria provided, single submitter
1048365	NC_000016.10:g.88770428_88832724del	APRT	Pathogenic	criteria provided, single submitter
1048367	NC_000016.10:g.(88810557_88811549)_(88841972_88842705)del	APRT	Pathogenic	criteria provided, single submitter
1021451	NM_000512.5(GALNS):c.602G>A (p.Gly201Glu)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030834	NM_000512.5(GALNS):c.1365-1G>C	GALNS	Pathogenic	criteria provided, multiple submitters, no conflicts
1048177	NM_000512.5(GALNS):c.281G>T (p.Arg94Leu)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048185	NM_000512.5(GALNS):c.319G>A (p.Ala107Thr)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048188	NM_000512.5(GALNS):c.319+2T>C	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048189	NM_000512.5(GALNS):c.320-1G>T	GALNS	Pathogenic	criteria provided, multiple submitters, no conflicts
1048200	NM_000512.5(GALNS):c.697G>A (p.Asp233Asn)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048204	NM_000512.5(GALNS):c.708del (p.His236fs)	GALNS	Pathogenic	criteria provided, single submitter
1048206	NM_000512.5(GALNS):c.719A>G (p.Tyr240Cys)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048209	NM_000512.5(GALNS):c.751C>T (p.Arg251Ter)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048210	NM_000512.5(GALNS):c.752G>A (p.Arg251Gln)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048222	NM_000512.5(GALNS):c.938C>T (p.Thr313Met)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048228	NM_000512.5(GALNS):c.1142del (p.Pro381fs)	GALNS	Pathogenic	criteria provided, multiple submitters, no conflicts
1048230	NM_000512.5(GALNS):c.1155C>A (p.Tyr385Ter)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048234	NM_000512.5(GALNS):c.1162G>A (p.Asp388Asn)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048237	NM_000512.5(GALNS):c.1420C>T (p.Gln474Ter)	GALNS	Pathogenic	criteria provided, single submitter
1048248	NM_000512.5(GALNS):c.29G>A (p.Trp10Ter)	GALNS	Pathogenic	criteria provided, multiple submitters, no conflicts
1048253	NM_000512.5(GALNS):c.85C>T (p.Gln29Ter)	GALNS	Pathogenic	criteria provided, single submitter
1048261	NM_000512.5(GALNS):c.143T>G (p.Val48Gly)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048272	NM_000512.5(GALNS):c.334del (p.Glu112fs)	GALNS	Pathogenic	criteria provided, single submitter
1048273	NM_000512.5(GALNS):c.347G>T (p.Gly116Val)	GALNS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048275	NM_000512.5(GALNS):c.376G>T (p.Glu126Ter)	GALNS	Pathogenic	criteria provided, single submitter
1048291	NM_000512.5(GALNS):c.551G>A (p.Trp184Ter)	GALNS	Pathogenic	criteria provided, single submitter
1048294	NM_000512.5(GALNS):c.758+1G>C	GALNS	Pathogenic	criteria provided, single submitter
1048316	NM_000512.5(GALNS):c.974G>A (p.Trp325Ter)	GALNS	Pathogenic	criteria provided, single submitter
1048321	NM_000512.5(GALNS):c.1168del (p.Thr389_Leu390insTer)	GALNS	Pathogenic	criteria provided, single submitter
1048322	NM_000512.5(GALNS):c.1177_1178insT (p.Ala393fs)	GALNS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
GALNS	Definitive	Autosomal recessive	mucopolysaccharidosis type 4A	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GALNS	Orphanet:309297	Mucopolysaccharidosis type 4A
IDUA	Orphanet:93473	Hurler syndrome
IDUA	Orphanet:93474	Scheie syndrome
IDUA	Orphanet:93476	Hurler-Scheie syndrome
APRT	Orphanet:976	Adenine phosphoribosyltransferase deficiency

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
GALNS	HGNC:4122	ENSG00000141012	P34059	N-acetylgalactosamine-6-sulfatase	gencc,clinvar
TRAPPC2L	HGNC:30887	ENSG00000167515	Q9UL33	Trafficking protein particle complex subunit 2-like protein	clinvar
IDUA	HGNC:5391	ENSG00000127415	P35475	Alpha-L-iduronidase	clinvar
APRT	HGNC:626	ENSG00000198931	P07741	Adenine phosphoribosyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRAPPC2L	Trafficking protein particle complex subunit 2-like protein	Plays a role in vesicular transport from endoplasmic reticulum to Golgi.
APRT	Adenine phosphoribosyltransferase	Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	21.0×	0.141
Antibody/Immunoglobulin	1	7.3×	0.195
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GALNS	Phosphatase	yes	3.1.6.12	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
TRAPPC2L	Other/Unknown	no		Sedlin, Longin-like_dom_sf, TRAPPC2L
IDUA	Antibody/Immunoglobulin	yes	3.2.1.76	Glyco_hydro_39, Ig-like_fold, GH_hydrolase_sf
APRT	Other/Unknown	no		PRTase_dom, Ade_phspho_trans, PRTase-like

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
male germ cell	1
right uterine tube	1
sperm	1
right adrenal gland	1
right adrenal gland cortex	1
right testis	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
lower esophagus mucosa	1
skin of abdomen	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GALNS	258	ubiquitous	marker	right uterine tube, sperm, male germ cell
TRAPPC2L	285	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, right testis
IDUA	209	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
APRT	287	ubiquitous	marker	skin of abdomen, skin of leg, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APRT	3,481
IDUA	1,927
GALNS	1,515
TRAPPC2L	1,387

Intra-cohort edges

A	B	Sources
APRT	GALNS	string_interaction
GALNS	IDUA	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APRT	P07741	16
IDUA	P35475	11
GALNS	P34059	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRAPPC2L	Q9UL33	92.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MPS IV - Morquio syndrome A	1	2855.0×	0.002	GALNS
MPS I - Hurler syndrome (HS-GAG degradation)	1	2855.0×	0.002	IDUA
Defective APRT disrupts adenine salvage	1	2855.0×	0.002	APRT
MPS I - Hurler syndrome (CS/DS degradation)	1	2855.0×	0.002	IDUA
Nucleotide salvage defects	1	1427.5×	0.002	APRT
Diseases of nucleotide metabolism	1	1427.5×	0.002	APRT
Nucleotide salvage	1	285.5×	0.010	APRT
Purine salvage	1	219.6×	0.011	APRT
Keratan sulfate degradation	1	178.4×	0.012	GALNS
CS/DS degradation	1	135.9×	0.015	IDUA
HS-GAG degradation	1	124.1×	0.015	IDUA
Neutrophil degranulation	2	11.5×	0.018	GALNS, APRT
Metabolism of nucleotides	1	75.1×	0.020	APRT
COPII-mediated vesicle transport	1	40.8×	0.035	TRAPPC2L
RAB GEFs exchange GTP for GDP on RABs	1	31.0×	0.042	TRAPPC2L
Diseases of metabolism	1	20.1×	0.061	APRT
Innate Immune System	1	6.4×	0.174	APRT
Disease	1	3.3×	0.289	APRT
Immune System	1	3.2×	0.289	APRT
Metabolism	1	2.9×	0.302	APRT

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
disaccharide metabolic process	1	4213.0×	0.001	IDUA
adenine salvage	1	4213.0×	0.001	APRT
heparin proteoglycan catabolic process	1	4213.0×	0.001	IDUA
dermatan sulfate proteoglycan catabolic process	1	1053.2×	0.003	IDUA
IMP salvage	1	842.6×	0.003	APRT
chondroitin sulfate proteoglycan catabolic process	1	702.2×	0.003	GALNS
GMP salvage	1	702.2×	0.003	APRT
AMP salvage	1	702.2×	0.003	APRT
glycosaminoglycan catabolic process	1	601.9×	0.003	IDUA
purine ribonucleoside salvage	1	601.9×	0.003	APRT
heparan sulfate proteoglycan catabolic process	1	468.1×	0.003	IDUA
vesicle coat assembly	1	383.0×	0.003	TRAPPC2L
grooming behavior	1	280.9×	0.004	APRT
obsolete vesicle tethering	1	247.8×	0.005	TRAPPC2L
COPII vesicle coat assembly	1	175.5×	0.006	TRAPPC2L
endoplasmic reticulum to Golgi vesicle-mediated transport	1	34.0×	0.029	TRAPPC2L

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APRT	1	3
GALNS	0	0
TRAPPC2L	0	0
IDUA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	APRT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GALNS	15	Binding:15
IDUA	15	Binding:15
APRT	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GALNS	3.1.6.12, 3.1.6.4	N-acetylgalactosamine-4-sulfatase, N-acetylgalactosamine-6-sulfatase
IDUA	3.2.1.76	L-iduronidase

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)
CRENOLANIB	3	APRT

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	APRT
C	Druggable family + PDB, no drug	2	GALNS, IDUA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TRAPPC2L

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)
GALNS	15	APRT
TRAPPC2L	0	—
IDUA	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 20.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10
PHASE2	4
PHASE1/PHASE2	3
PHASE3	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01275066	PHASE3	COMPLETED	A Double-Blind Study to Evaluate the Efficacy and Safety of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT01415427	PHASE3	COMPLETED	Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT05845749	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of Voxzogo for Growth Deficits in MPS IVA and VI
NCT00884949	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety, Tolerability and Efficacy of BMN 110 in Subjects With Mucopolysaccharidosis IVA
NCT01242111	PHASE1/PHASE2	TERMINATED	A Study to Evaluate the Long-Term Efficacy and Safety of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT01515956	PHASE2	COMPLETED	Study of BMN 110 in Pediatric Patients < 5 Years of Age With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT01609062	PHASE2	TERMINATED	Safety and Exercise Study of Two Doses of BMN 110 for Morquio A Syndrome
NCT01697319	PHASE2	TERMINATED	Efficacy and Safety Study of BMN 110 for Morquio A Syndrome Patients Who Have Limited Ambulation
NCT03632213	PHASE2	UNKNOWN	Evaluation of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI
NCT04532047	PHASE1	RECRUITING	PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
NCT05284006	Not specified	RECRUITING	Non-invasive Functional Assessment and Pathogenesis of Morquio A
NCT07361536	Not specified	RECRUITING	Cardiac Structure and Function in MPS
NCT00787995	Not specified	TERMINATED	A Clinical Assessment Study of Subjects With Mucopolysaccharidosis IVA (Morquio Syndrome)
NCT01457456	Not specified	WITHDRAWN	Biomarker for Morquio Disease (BioMorquio)
NCT01733615	Not specified	TERMINATED	Discovering New Biomarkers For Monitoring Disease Progression in Patients With Mucopolysaccharidosis IVA
NCT01858103	Not specified	APPROVED_FOR_MARKETING	BMN 110 US Expanded Access Program
NCT01920828	Not specified	COMPLETED	Gait Analysis in MPS IVA
NCT01961518	Not specified	COMPLETED	Screening an Orthopedic Population for Mildly-affected Individuals With Morquio Syndrome A and Maroteaux-Lamy Syndrome
NCT02153255	Not specified	WITHDRAWN	Dynamic Gait Analysis in Children With Mucopolysaccharidosis Type IVa
NCT02294877	Not specified	COMPLETED	A Multicenter, Multinational, Observational Morquio A Registry Study (MARS)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELOSULFASE ALFA	4	6
LARONIDASE	4	1
LOSARTAN	4	1