Hurler syndrome

Summary

Hurler syndrome (MONDO:0011758) is a disease caused by IDUA (GenCC Strong), with 3 cohort genes and 18 clinical trials. Top therapeutic interventions include laronidase, cyclophosphamide anhydrous, and rimiducid.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: IDUA (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 280
• Phenotypes (HPO): 59
• Clinical trials: 18

Clinical features

Epidemiology

Prevalence records

11 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.5	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.7	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.76	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000		Denmark	Validated
Point prevalence	<1 / 1 000 000	0.07	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.64	Germany	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	Denmark	Validated
Prevalence at birth	1-9 / 100 000	1.05	Portugal	Validated
Prevalence at birth	<1 / 1 000 000	0.06	Taiwan, Province of China	Validated
Prevalence at birth	1-9 / 1 000 000	0.93	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.26	United States	Validated

Signs & symptoms

Clinical features (HPO)

59 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000293	Full cheeks	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000574	Thick eyebrow	Very frequent (80-99%)
HP:0000924	Abnormality of the skeletal system	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0001638	Cardiomyopathy	Very frequent (80-99%)
HP:0001654	Abnormal heart valve morphology	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002230	Generalized hirsutism	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0003468	Abnormal vertebral morphology	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0008155	Mucopolysacchariduria	Very frequent (80-99%)
HP:0012384	Rhinitis	Very frequent (80-99%)
HP:0100021	Cerebral palsy	Very frequent (80-99%)
HP:0100729	Large face	Very frequent (80-99%)
HP:0100765	Abnormality of the tonsils	Very frequent (80-99%)
HP:0100790	Hernia	Very frequent (80-99%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000488	Retinopathy	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000772	Abnormal rib morphology	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000889	Abnormality of the clavicle	Frequent (30-79%)
HP:0000940	Abnormal diaphysis morphology	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001522	Death in infancy	Frequent (30-79%)
HP:0002028	Chronic diarrhea	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003275	Narrow pelvis bone	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)
HP:0007957	Corneal opacity	Frequent (30-79%)
HP:0009811	Abnormality of the elbow	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Hurler syndrome
Mondo ID	MONDO:0011758
OMIM	607014
Orphanet	93473
DOID	DOID:0111390
NCIT	C61261
SNOMED CT	65327002
UMLS	C0086795
MedGen	39698
GARD	0012559
Is cancer (heuristic)	no

Also known as: Hurler disease · Hurler syndrome · MPS I H · MPS1-H · MPS1H · MPSIH · mucopolysaccharidosis IH · mucopolysaccharidosis type 1H · mucopolysaccharidosis type IH

Data availability: 280 ClinVar variants · 2 GenCC gene-disease records · 19 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › mucopolysaccharidosis type 1 › Hurler syndrome

Related subtypes (2): Hurler-Scheie syndrome, Scheie 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

280 retrieved; paginated sample, class counts are floors:

73 pathogenic, 62 likely pathogenic, 54 uncertain significance, 27 pathogenic/likely pathogenic, 25 likely benign, 18 conflicting classifications of pathogenicity, 17 benign, 3 benign/likely benign; other, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11911	NM_000203.3(IDUA):c.[1225G>C;1962A>T]		Pathogenic	no assertion criteria provided
1038439	NM_000203.5(IDUA):c.1862G>C (p.Arg621Pro)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065522	NM_000203.5(IDUA):c.1096_1099del (p.Thr366fs)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11908	NM_000203.5(IDUA):c.1205G>A (p.Trp402Ter)	IDUA	Pathogenic	reviewed by expert panel
11910	NM_000203.5(IDUA):c.1598C>G (p.Pro533Arg)	IDUA	Pathogenic	reviewed by expert panel
11914	NM_000203.5(IDUA):c.192C>A (p.Tyr64Ter)	IDUA	Pathogenic	criteria provided, multiple submitters, no conflicts
11916	NM_000203.5(IDUA):c.1096A>C (p.Thr366Pro)	IDUA	Pathogenic	no assertion criteria provided
11917	NM_000203.5(IDUA):c.1861C>T (p.Arg621Ter)	IDUA	Pathogenic	reviewed by expert panel
11919	NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11921	NM_000203.5(IDUA):c.613_617dup (p.Glu207fs)	IDUA	Pathogenic	reviewed by expert panel
11922	NM_000203.5(IDUA):c.266G>A (p.Arg89Gln)	IDUA	Pathogenic	reviewed by expert panel
11924	NM_000203.5(IDUA):c.1855C>G (p.Arg619Gly)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11925	NM_000203.5(IDUA):c.1091C>T (p.Thr364Met)	IDUA	Pathogenic	reviewed by expert panel
11927	NM_000203.5(IDUA):c.1037T>G (p.Leu346Arg)	IDUA	Pathogenic	criteria provided, multiple submitters, no conflicts
1323100	NM_000203.5(IDUA):c.603C>G (p.Tyr201Ter)	IDUA	Pathogenic	reviewed by expert panel
1339514	NM_000203.5(IDUA):c.1868T>C (p.Leu623Pro)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339515	NM_000203.5(IDUA):c.1496_1497del (p.Glu499fs)	IDUA	Pathogenic	criteria provided, multiple submitters, no conflicts
1454082	NM_000203.5(IDUA):c.1815dup (p.Val606fs)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526094	NM_000203.5(IDUA):c.589G>A (p.Gly197Ser)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167189	NM_000203.5(IDUA):c.164del (p.Pro55fs)	IDUA	Pathogenic	criteria provided, multiple submitters, no conflicts
167190	NM_000203.5(IDUA):c.979G>C (p.Ala327Pro)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167191	NM_000203.5(IDUA):c.1614del (p.His539fs)	IDUA	Pathogenic	reviewed by expert panel
193061	NM_000203.5(IDUA):c.152G>A (p.Gly51Asp)	IDUA	Pathogenic	reviewed by expert panel
195040	NM_000203.5(IDUA):c.191_192del (p.Tyr64fs)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2198440	NM_000203.5(IDUA):c.544G>A (p.Glu182Lys)	IDUA	Pathogenic	reviewed by expert panel
2203495	NM_000203.5(IDUA):c.532G>A (p.Glu178Lys)	IDUA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222993	NM_000203.5(IDUA):c.223G>A (p.Ala75Thr)	IDUA	Pathogenic	reviewed by expert panel
222994	NM_000203.5(IDUA):c.386-2A>G	IDUA	Pathogenic	reviewed by expert panel
222995	NM_000203.5(IDUA):c.653T>C (p.Leu218Pro)	IDUA	Pathogenic	reviewed by expert panel
222996	NM_000203.5(IDUA):c.590-7G>A	IDUA	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
IDUA	Strong	Autosomal recessive	Hurler syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IDUA	Orphanet:93473	Hurler syndrome
IDUA	Orphanet:93474	Scheie syndrome
IDUA	Orphanet:93476	Hurler-Scheie syndrome
PITX1	Orphanet:1275	Brachydactyly-elbow wrist dysplasia syndrome
PITX1	Orphanet:293144	Familial clubfoot due to 5q31 microdeletion
PITX1	Orphanet:293150	Familial clubfoot due to PITX1 point mutation
PITX1	Orphanet:498494	Mirror-image polydactyly

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IDUA	HGNC:5391	ENSG00000127415	P35475	Alpha-L-iduronidase	gencc,clinvar
SLC26A1	HGNC:10993	ENSG00000145217	Q9H2B4	Sulfate anion transporter 1	clinvar
PITX1	HGNC:9004	ENSG00000069011	P78337	Pituitary homeobox 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC26A1	Sulfate anion transporter 1	Sodium-independent sulfate anion transporter.
PITX1	Pituitary homeobox 1	Sequence-specific transcription factor that binds gene promoters and activates their transcription.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Transporter	1	25.9×	0.114
Antibody/Immunoglobulin	1	9.7×	0.149
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IDUA	Antibody/Immunoglobulin	yes	3.2.1.76	Glyco_hydro_39, Ig-like_fold, GH_hydrolase_sf
SLC26A1	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
PITX1	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left adrenal gland cortex	1
right adrenal gland cortex	1
right lobe of liver	1
esophagus mucosa	1
lower esophagus mucosa	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IDUA	209	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SLC26A1	156	tissue_specific	yes	right adrenal gland cortex, left adrenal gland cortex, right lobe of liver
PITX1	180	broad	marker	lower esophagus mucosa, esophagus mucosa, pharyngeal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IDUA	1,927
PITX1	1,884
SLC26A1	1,454

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IDUA	P35475	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC26A1	Q9H2B4	83.13
PITX1	P78337	62.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MPS I - Hurler syndrome (HS-GAG degradation)	1	5710.0×	0.001	IDUA
MPS I - Hurler syndrome (CS/DS degradation)	1	5710.0×	0.001	IDUA
Transport and metabolism of PAPS	1	815.7×	0.006	SLC26A1
Inorganic anion exchange by SLC26 transporters	1	634.4×	0.006	SLC26A1
CS/DS degradation	1	271.9×	0.009	IDUA
Cytosolic sulfonation of small molecules	1	259.6×	0.009	SLC26A1
HS-GAG degradation	1	248.3×	0.009	IDUA
Phase II - Conjugation of compounds	1	139.3×	0.013	SLC26A1
Glycosaminoglycan metabolism	1	109.8×	0.015	SLC26A1
Biological oxidations	1	64.9×	0.021	SLC26A1
R-HSA-425393	1	64.9×	0.021	SLC26A1
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.021	SLC26A1
SLC-mediated transmembrane transport	1	29.6×	0.039	SLC26A1
Transport of small molecules	1	12.6×	0.083	SLC26A1
Metabolism	1	5.8×	0.165	SLC26A1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
disaccharide metabolic process	1	5617.3×	0.002	IDUA
heparin proteoglycan catabolic process	1	5617.3×	0.002	IDUA
branchiomeric skeletal muscle development	1	1872.4×	0.003	PITX1
dermatan sulfate proteoglycan catabolic process	1	1404.3×	0.003	IDUA
myoblast fate commitment	1	1123.5×	0.003	PITX1
glycosaminoglycan catabolic process	1	802.5×	0.003	IDUA
oxalate transport	1	802.5×	0.003	SLC26A1
heparan sulfate proteoglycan catabolic process	1	624.1×	0.004	IDUA
sulfate transmembrane transport	1	401.2×	0.005	SLC26A1
pituitary gland development	1	216.1×	0.008	PITX1
embryonic hindlimb morphogenesis	1	193.7×	0.008	PITX1
chloride transport	1	151.8×	0.010	SLC26A1
cartilage development	1	83.8×	0.016	PITX1
chloride transmembrane transport	1	79.1×	0.016	SLC26A1
anatomical structure morphogenesis	1	46.4×	0.026	PITX1
skeletal system development	1	41.9×	0.027	PITX1
negative regulation of DNA-templated transcription	1	10.5×	0.098	PITX1
regulation of transcription by RNA polymerase II	1	3.9×	0.236	PITX1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IDUA	0	0
SLC26A1	0	0
PITX1	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
IDUA	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IDUA	3.2.1.76	L-iduronidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	IDUA
D	Druggable family + AlphaFold only, no drug	1	SLC26A1
E	Difficult family or no structure, no drug	1	PITX1

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)
IDUA	15	—
SLC26A1	0	—
PITX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 18.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	6
PHASE2	4
Not specified	4
PHASE1	3
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00258011	PHASE3	COMPLETED	Study of Aldurazyme® Replacement Therapy in Patients With Mucopolysaccharidosis I (MPS I) Disease
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT03488394	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant
NCT00146757	PHASE2	COMPLETED	A Study Evaluating the Safety and Pharmacokinetics of Aldurazyme® (Laronidase) in MPS I Patients Less Than 5 Years Old
NCT00176891	PHASE2	COMPLETED	Stem Cell Transplant w/Laronidase for Hurler
NCT00730314	PHASE1/PHASE2	COMPLETED	Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03580083	PHASE1/PHASE2	SUSPENDED	RGX-111 Gene Therapy in Patients With MPS I
NCT04284254	PHASE1/PHASE2	WITHDRAWN	MT2018-18: Sleeping Beauty Transposon-Engineered Plasmablasts for Hurler Syndrome Post Allo HSCT
NCT00638547	PHASE1	COMPLETED	Intrathecal Enzyme Replacement for Hurler Syndrome
NCT01173016	PHASE1	COMPLETED	Administration of IV Laronidase Post Bone Marrow Transplant in Hurler
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00286689	Not specified	WITHDRAWN	Effects of Growth Hormone in Chronically Ill Children
NCT01572636	Not specified	TERMINATED	Laronidase (Aldurazyme TM) Enzyme Replacement Therapy With Hematopoietic Stem Cell Transplant for Hurler Syndrome
NCT01873911	Not specified	COMPLETED	Neurobehavioral Phenotypes in MPS III
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

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LARONIDASE	4	2
CYCLOPHOSPHAMIDE ANHYDROUS	4	1
RIMIDUCID	2	1
RIVOGENLECLEUCEL	2	1