Fucosidosis

Summary

Fucosidosis (MONDO:0009254) is a disease caused by FUCA1 (GenCC Definitive), with 2 cohort genes and 9 clinical trials. Top therapeutic interventions include cyclophosphamide anhydrous and busulfan.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FUCA1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 423
• Phenotypes (HPO): 31
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		161	Worldwide	Validated
Point prevalence	<1 / 1 000 000	0.06	Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.1	Sweden	Validated
Prevalence at birth	1-9 / 1 000 000	0.63	Cuba	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000821	Hypothyroidism	Very frequent (80-99%)
HP:0000943	Dysostosis multiplex	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002808	Kyphosis	Very frequent (80-99%)
HP:0005595	Generalized hyperkeratosis	Very frequent (80-99%)
HP:0008155	Mucopolysacchariduria	Very frequent (80-99%)
HP:0008430	Anterior beaking of lumbar vertebrae	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011220	Prominent forehead	Very frequent (80-99%)
HP:0100578	Lipoatrophy	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001626	Abnormality of the cardiovascular system	Frequent (30-79%)
HP:0002510	Spastic tetraplegia	Frequent (30-79%)
HP:0003199	Decreased muscle mass	Frequent (30-79%)
HP:0005264	Abnormality of the gallbladder	Frequent (30-79%)
HP:0007957	Corneal opacity	Frequent (30-79%)
HP:0011276	Vascular skin abnormality	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0001063	Acrocyanosis	Occasional (5-29%)
HP:0001597	Abnormality of the nail	Occasional (5-29%)
HP:0001640	Cardiomegaly	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	fucosidosis
Mondo ID	MONDO:0009254
MeSH	D005645
OMIM	230000
Orphanet	349
DOID	DOID:14500
ICD-11	1470242510
NCIT	C61274
SNOMED CT	64716005
UMLS	C0016788
MedGen	5288
GARD	0006473
NORD	1168
Is cancer (heuristic)	no

Also known as: Alpha-L-fucosidase deficiency · fucosidosis · lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues

Data availability: 423 ClinVar variants · 6 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › oligosaccharidosis › fucosidosis

Related subtypes (6): aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, galactosialidosis, sialidosis, alpha-N-acetylgalactosaminidase deficiency

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

423 retrieved; paginated sample, class counts are floors:

178 likely benign, 120 uncertain significance, 58 pathogenic, 24 likely pathogenic, 18 conflicting classifications of pathogenicity, 10 benign, 9 pathogenic/likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100721	NM_000147.5(FUCA1):c.790C>T (p.Arg264Ter)	FUCA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324433	NM_000147.5(FUCA1):c.7del (p.Ala3fs)	FUCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328977	NM_000147.5(FUCA1):c.1285_1286insT (p.Asp429fs)	FUCA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457587	NM_000147.5(FUCA1):c.671del (p.Pro224fs)	FUCA1	Pathogenic	criteria provided, single submitter
1458099	NM_000147.5(FUCA1):c.551C>G (p.Ser184Ter)	FUCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1727210	NM_000147.5(FUCA1):c.577dup (p.Tyr193fs)	FUCA1	Pathogenic	criteria provided, single submitter
198046	NM_000147.5(FUCA1):c.1125G>A (p.Trp375Ter)	FUCA1	Pathogenic	criteria provided, multiple submitters, no conflicts
218428	NM_000147.5(FUCA1):c.1082G>A (p.Trp361Ter)	FUCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2185928	NM_000147.5(FUCA1):c.1206G>A (p.Trp402Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2202728	NM_000147.5(FUCA1):c.459G>A (p.Trp153Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2202729	NM_000147.5(FUCA1):c.194G>A (p.Gly65Asp)	FUCA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2422463	NC_000001.10:g.(?24172205)(24194776_?)del	FUCA1	Pathogenic	criteria provided, single submitter
2422464	NC_000001.10:g.(?24191961)(24194776_?)del	FUCA1	Pathogenic	criteria provided, single submitter
2445830	NM_000147.5(FUCA1):c.1289_1301del (p.Leu430fs)	FUCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627143	NM_000147.5(FUCA1):c.699G>A (p.Trp233Ter)	FUCA1	Pathogenic	criteria provided, multiple submitters, no conflicts
265438	NM_000147.5(FUCA1):c.393T>A (p.Tyr131Ter)	FUCA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2706835	NM_000147.5(FUCA1):c.1057G>T (p.Glu353Ter)	FUCA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2709717	NM_000147.5(FUCA1):c.610_614del (p.Gln204fs)	FUCA1	Pathogenic	criteria provided, single submitter
2711635	NM_000147.5(FUCA1):c.1131_1132delinsTT (p.Gln378Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2715395	NM_000147.5(FUCA1):c.698G>A (p.Trp233Ter)	FUCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2745354	NM_000147.5(FUCA1):c.679_683dup (p.Trp228Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2745555	NM_000147.5(FUCA1):c.355_364del (p.Glu119fs)	FUCA1	Pathogenic	criteria provided, single submitter
2749012	NM_000147.5(FUCA1):c.969+1G>T	FUCA1	Pathogenic	criteria provided, single submitter
2757124	NM_000147.5(FUCA1):c.293dup (p.Pro99fs)	FUCA1	Pathogenic	criteria provided, single submitter
2791475	NM_000147.5(FUCA1):c.679_683del (p.Ile227fs)	FUCA1	Pathogenic	criteria provided, single submitter
2824353	NM_000147.5(FUCA1):c.80C>A (p.Ser27Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2838100	NM_000147.5(FUCA1):c.563G>A (p.Trp188Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2839403	NM_000147.5(FUCA1):c.291C>G (p.Tyr97Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2849047	NM_000147.5(FUCA1):c.23C>A (p.Ser8Ter)	FUCA1	Pathogenic	criteria provided, single submitter
2873243	NM_000147.5(FUCA1):c.1260+2T>A	FUCA1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
FUCA1	Definitive	Autosomal recessive	fucosidosis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FUCA1	Orphanet:349	Fucosidosis
DCX	Orphanet:2148	Lissencephaly type 1 due to doublecortin gene mutation
DCX	Orphanet:99796	Subcortical band heterotopia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FUCA1	HGNC:4006	ENSG00000179163	P04066	Tissue alpha-L-fucosidase	gencc,clinvar
DCX	HGNC:2714	ENSG00000077279	O43602	Neuronal migration protein doublecortin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FUCA1	Tissue alpha-L-fucosidase	Alpha-L-fucosidase is responsible for hydrolyzing the alpha-1,6-linked fucose joined to the reducing-end N-acetylglucosamine of the carbohydrate moieties of glycoproteins.
DCX	Neuronal migration protein doublecortin	Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FUCA1	Enzyme (other)	yes	3.2.1.51	Glyco_hydro_29, Glyco_hydro_b, FUC_metazoa-typ
DCX	Other/Unknown	no		Doublecortin_dom, DCX_chordates, Doublecortin_dom_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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
ileal mucosa	1
mucosa of sigmoid colon	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FUCA1	286	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, ileal mucosa
DCX	114	broad	marker	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DCX	2,112
FUCA1	1,125

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DCX	O43602	14
FUCA1	P04066	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Neurofascin interactions	1	713.8×	0.003	DCX
Reactions specific to the complex N-glycan synthesis pathway	1	571.0×	0.003	FUCA1
Neutrophil degranulation	1	11.5×	0.085	FUCA1

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
glycolipid catabolic process	1	4213.0×	0.002	FUCA1
glycoside catabolic process	1	1404.3×	0.002	FUCA1
fucose metabolic process	1	1203.7×	0.002	FUCA1
axoneme assembly	1	271.8×	0.008	DCX
retina development in camera-type eye	1	127.7×	0.014	DCX
neuron migration	1	66.9×	0.022	DCX
central nervous system development	1	57.7×	0.022	DCX
nervous system development	1	23.0×	0.048	DCX
intracellular signal transduction	1	19.1×	0.052	DCX

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Busulfan.

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FUCA1	1	2
DCX	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DUVOGLUSTAT	2	FUCA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FUCA1	83	Binding:79, ADMET:4
DCX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FUCA1	3.2.1.51	alpha-L-fucosidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
DUVOGLUSTAT	2	FUCA1

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	FUCA1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DCX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DCX	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

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

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
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
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT07615400	Not specified	RECRUITING	A Long-Term Observational Study of Patients With Fucosidosis
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOPHOSPHAMIDE ANHYDROUS	4	3
BUSULFAN	4	1