Galactosialidosis

Summary

Galactosialidosis (MONDO:0009737) is a disease caused by CTSA (GenCC Definitive), with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: CTSA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 524
• Phenotypes (HPO): 9
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.14	Sweden	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000925	Abnormality of the vertebral column	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0003468	Abnormal vertebral morphology	Very frequent (80-99%)
HP:0007957	Corneal opacity	Very frequent (80-99%)
HP:0010729	Cherry red spot of the macula	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	galactosialidosis
Mondo ID	MONDO:0009737
MeSH	C536411
OMIM	256540
Orphanet	351
DOID	DOID:0080540
ICD-11	1838660035
NCIT	C129928
SNOMED CT	35691006
UMLS	C0268233
MedGen	82779
GARD	0003953
Is cancer (heuristic)	no

Also known as: cathepsin A deficiency of · galactosialidosis · Goldberg syndrome · GSL · lysosomal protective protein deficiency of · neuraminidase deficiency with beta-galactosidase deficiency

Data availability: 524 ClinVar variants · 5 GenCC gene-disease records · 13 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › galactosialidosis

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

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

524 retrieved; paginated sample, class counts are floors:

290 likely benign, 124 uncertain significance, 34 pathogenic, 21 likely pathogenic, 20 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 12 benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3248233	NC_000020.10:g.(?44519965)(44751017_?)del	CD40	Pathogenic	criteria provided, single submitter
100724	NM_000308.4(CTSA):c.230del (p.Pro77fs)	CTSA	Pathogenic	criteria provided, single submitter
1068984	NM_000308.4(CTSA):c.1123C>T (p.Arg375Ter)	CTSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073864	NM_000308.4(CTSA):c.991del (p.Cys331fs)	CTSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1098801	NM_000308.4(CTSA):c.60del (p.Ser21fs)	CTSA	Pathogenic	criteria provided, single submitter
1180709	NM_000308.4(CTSA):c.946C>T (p.Gln316Ter)	CTSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322173	NM_000308.4(CTSA):c.1104dup (p.Gln369fs)	CTSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1452908	NM_000308.4(CTSA):c.130C>T (p.Gln44Ter)	CTSA	Pathogenic	criteria provided, single submitter
1456631	NM_000308.4(CTSA):c.1-2A>G	CTSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698376	NM_000308.4(CTSA):c.580G>A (p.Asp194Asn)	CTSA	Pathogenic	criteria provided, single submitter
1705554	NM_000308.4(CTSA):c.1294del (p.Asp432fs)	CTSA	Pathogenic	criteria provided, single submitter
2071782	NM_000308.4(CTSA):c.1005del (p.Ala336fs)	CTSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2101801	NM_000308.4(CTSA):c.143del (p.Arg48fs)	CTSA	Pathogenic	criteria provided, multiple submitters, no conflicts
2114494	NM_000308.4(CTSA):c.376del (p.Leu126fs)	CTSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225877	NM_000308.4(CTSA):c.833_834del (p.Tyr278fs)	CTSA	Pathogenic	criteria provided, multiple submitters, no conflicts
2425514	NM_000308.4(CTSA):c.1019dup (p.Tyr340Ter)	CTSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2727241	NM_000308.4(CTSA):c.518del (p.Phe173fs)	CTSA	Pathogenic	criteria provided, single submitter
2747132	NM_000308.4(CTSA):c.275_278del (p.Asp92fs)	CTSA	Pathogenic	criteria provided, single submitter
2748967	NM_000308.4(CTSA):c.15_19dup (p.Pro7fs)	CTSA	Pathogenic	criteria provided, single submitter
2753341	NM_000308.4(CTSA):c.463G>T (p.Glu155Ter)	CTSA	Pathogenic	criteria provided, single submitter
2755044	NM_000308.4(CTSA):c.253_254dup (p.Pro86fs)	CTSA	Pathogenic	criteria provided, single submitter
2777941	NM_000308.4(CTSA):c.843T>A (p.Cys281Ter)	CTSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2797688	NM_000308.4(CTSA):c.242G>A (p.Trp81Ter)	CTSA	Pathogenic	criteria provided, single submitter
2827278	NM_000308.4(CTSA):c.1215_1216insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGAGGGGCTCCTCACTTCCCAGAAGGGGCGGCCGGGCAGAGGCGCCCCTCACCTCCCAGACGGGGCGGCTGGCATGGCCTGCAATTTC (p.Phe405_Met406insPhePhePhePhePhePheXaaXaaXaaXaaGluGlyLeuLeuThrSerGlnLysGlyArgProGlyArgGlyAlaProHisLeuProAspGlyAlaAlaGlyMetAlaCysAsnPhe)	CTSA	Pathogenic	criteria provided, single submitter
2836788	NM_000308.4(CTSA):c.1106del (p.Gln369fs)	CTSA	Pathogenic	criteria provided, single submitter
2841707	NM_000308.4(CTSA):c.94C>T (p.Gln32Ter)	CTSA	Pathogenic	criteria provided, single submitter
2845062	NM_000308.4(CTSA):c.873T>G (p.Tyr291Ter)	CTSA	Pathogenic	criteria provided, single submitter
2888905	NM_000308.4(CTSA):c.31_34del (p.Leu11fs)	CTSA	Pathogenic	criteria provided, single submitter
2901872	NM_000308.4(CTSA):c.1063C>T (p.Gln355Ter)	CTSA	Pathogenic	criteria provided, single submitter
2968562	NM_000308.4(CTSA):c.350G>A (p.Trp117Ter)	CTSA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
CTSA	Definitive	Autosomal recessive	galactosialidosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTSA	Orphanet:351	Galactosialidosis
CTSA	Orphanet:575553	Cathepsin A-related arteriopathy-strokes-leukoencephalopathy
CD40	Orphanet:101090	Hyper-IgM syndrome type 3

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
CTSA	HGNC:9251	ENSG00000064601	P10619	Lysosomal protective protein	gencc,clinvar
CD40	HGNC:11919	ENSG00000101017	P25942	Tumor necrosis factor receptor superfamily member 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTSA	Lysosomal protective protein	Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity.
CD40	Tumor necrosis factor receptor superfamily member 5	Receptor for TNFSF5/CD40LG.

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTSA	Protease	yes	3.4.16.5	Peptidase_S10, Ser_caboxypep_ser_AS, AB_hydrolase_fold
CD40	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_5, TNFRSF5_N

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
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
lymph node	1
right lung	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTSA	297	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
CD40	242	ubiquitous	marker	lymph node, right lung, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD40	3,765
CTSA	2,964

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD40	P25942	14
CTSA	P10619	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Defective NEU1 causes sialidosis	1	1427.5×	0.006	CTSA
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	335.9×	0.012	CD40
Sialic acid metabolism	1	163.1×	0.014	CTSA
Glycosphingolipid catabolism	1	146.4×	0.014	CTSA
TNFR2 non-canonical NF-kB pathway	1	90.6×	0.018	CD40
MHC class II antigen presentation	1	44.6×	0.026	CTSA
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.026	CD40
Neutrophil degranulation	1	11.5×	0.085	CTSA

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
response to cobalamin	1	4213.0×	0.003	CD40
positive regulation of protein kinase C signaling	1	2808.7×	0.003	CD40
positive regulation of interleukin-4-mediated signaling pathway	1	2808.7×	0.003	CD40
negative regulation of chaperone-mediated autophagy	1	2808.7×	0.003	CTSA
B cell mediated immunity	1	2106.5×	0.003	CD40
cellular response to erythropoietin	1	2106.5×	0.003	CD40
regulation of chaperone-mediated autophagy	1	1685.2×	0.003	CTSA
immune response-regulating cell surface receptor signaling pathway	1	936.2×	0.005	CD40
CD40 signaling pathway	1	842.6×	0.005	CD40
positive regulation of isotype switching to IgG isotypes	1	766.0×	0.005	CD40
positive regulation of endothelial cell apoptotic process	1	366.4×	0.009	CD40
defense response to protozoan	1	300.9×	0.010	CD40
response to type II interferon	1	263.3×	0.011	CD40
B cell proliferation	1	240.7×	0.011	CD40
B cell activation	1	227.7×	0.011	CD40
positive regulation of interleukin-12 production	1	195.9×	0.011	CD40
positive regulation of blood vessel endothelial cell migration	1	195.9×	0.011	CD40
positive regulation of B cell proliferation	1	172.0×	0.012	CD40
cell surface receptor signaling pathway via JAK-STAT	1	145.3×	0.013	CD40
cellular response to interleukin-1	1	140.4×	0.013	CD40
platelet activation	1	133.8×	0.013	CD40
cellular response to mechanical stimulus	1	108.0×	0.015	CD40
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	105.3×	0.015	CD40
cellular response to tumor necrosis factor	1	81.8×	0.018	CD40
intracellular calcium ion homeostasis	1	72.6×	0.020	CD40
regulation of protein stability	1	62.9×	0.022	CTSA
positive regulation of angiogenesis	1	57.7×	0.022	CD40
protein-containing complex assembly	1	56.9×	0.022	CD40
cellular response to lipopolysaccharide	1	49.0×	0.025	CD40
positive regulation of MAPK cascade	1	40.3×	0.030	CD40

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CTSA	ISOFLUROPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CTSA	2	4
CD40	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ISOFLUROPHATE	4	CTSA
BORTEZOMIB	4	CTSA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CTSA	19	Binding:13, ADMET:6
CD40	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CTSA	3.4.16.5	carboxypeptidase C

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

2 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)
ISOFLUROPHATE	4	CTSA
BORTEZOMIB	4	CTSA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CTSA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CD40

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)
CD40	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01416467	Not specified	COMPLETED	Characterization of the Patient Population With Galactosialidosis
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses
NCT04624789	Not specified	UNKNOWN	Registry Gangliosidoses