GM1 gangliosidosis type 1

Summary

GM1 gangliosidosis type 1 (MONDO:0009260) is a disease caused by GLB1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: GLB1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 227
• Phenotypes (HPO): 53

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0008166	Decreased beta-galactosidase activity	Obligate (100%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000618	Blindness	Very frequent (80-99%)
HP:0000707	Abnormality of the nervous system	Very frequent (80-99%)
HP:0000924	Abnormality of the skeletal system	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001433	Hepatosplenomegaly	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0003541	Urinary glycosaminoglycan excretion	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0410346	Increased urinary galactosylated oligosaccharide	Very frequent (80-99%)
HP:0000943	Dysostosis multiplex	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Frequent (30-79%)
HP:0002267	Exaggerated startle response	Frequent (30-79%)
HP:0002506	Diffuse cerebral atrophy	Frequent (30-79%)
HP:0002652	Skeletal dysplasia	Frequent (30-79%)
HP:0007204	Diffuse white matter abnormalities	Frequent (30-79%)
HP:0010729	Cherry red spot of the macula	Frequent (30-79%)
HP:0011951	Aspiration pneumonia	Frequent (30-79%)
HP:0012753	T2 hypointense basal ganglia	Frequent (30-79%)
HP:0000455	Broad nasal tip	Occasional (5-29%)
HP:0000768	Pectus carinatum	Occasional (5-29%)
HP:0000926	Platyspondyly	Occasional (5-29%)
HP:0001007	Hirsutism	Occasional (5-29%)
HP:0001072	Thickened skin	Occasional (5-29%)
HP:0001230	Broad metacarpals	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001789	Hydrops fetalis	Occasional (5-29%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0000212	Gingival overgrowth	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002684	Thickened calvaria	Occasional (5-29%)
HP:0002690	Large sella turcica	Occasional (5-29%)
HP:0002869	Flared iliac wings	Occasional (5-29%)
HP:0003026	Short long bone	Occasional (5-29%)
HP:0004562	Beaking of vertebral bodies T12-L3	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0006371	Broad long bone diaphyses	Occasional (5-29%)
HP:0008479	Hypoplastic vertebral bodies	Occasional (5-29%)
HP:0008807	Acetabular dysplasia	Occasional (5-29%)
HP:0008812	Flattened femoral head	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012307	Spatulate ribs	Occasional (5-29%)
HP:0025013	Decerebrate rigidity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	GM1 gangliosidosis type 1
Mondo ID	MONDO:0009260
OMIM	230500
Orphanet	79255
DOID	DOID:0080502
ICD-11	466200180
SNOMED CT	238026007
UMLS	C0268271
MedGen	75665
GARD	0006479
Is cancer (heuristic)	no

Also known as: Beta galactosidase deficiency type 1 · gangliosidosis generalised GM1 infantile form · gangliosidosis generalised GM1 type 1 · gangliosidosis generalized GM1 infantile form · gangliosidosis generalized GM1 type 1 · gangliosidosis, generalised GM1, infantile form · gangliosidosis, generalised GM1, type 1 · gangliosidosis, generalised GM1, type I, with Cardiac involvement · GLB deficiency type 1 · infantile GM1 gangliosidosis · Norman-Landing disease

Data availability: 227 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic dyslipidemia › GM1 gangliosidosis type 1

Related subtypes (28): familial apolipoprotein C-II deficiency, sitosterolemia, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata type 1, apparent mineralocorticoid excess, familial lipoprotein lipase deficiency, sea-blue histiocyte syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, CHIME syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, Barth syndrome, CHILD syndrome, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, Krabbe disease due to saposin A deficiency, lipoprotein glomerulopathy, hereditary spastic paraplegia 39, PHARC syndrome, congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome, hyperlipoproteinemia, type 1D, intellectual disability, autosomal recessive 53, hyperphosphatasia-intellectual disability syndrome, mevalonate kinase deficiency, fatty acid hydroxylase-associated neurodegeneration, nephrotic syndrome 14, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction, peroxisome biogenesis disorder due to PEX5 defect in the PEX7-binding domain, lysosomal acid lipase 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

227 retrieved; paginated sample, class counts are floors:

62 pathogenic/likely pathogenic, 55 likely pathogenic, 47 pathogenic, 28 uncertain significance, 17 conflicting classifications of pathogenicity, 9 benign, 6 benign/likely benign, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
424779	NM_000404.3(GLB1):c.[245C>T];[367G>A]		Pathogenic	criteria provided, single submitter
100725	NM_000404.4(GLB1):c.1188dup (p.Pro397fs)	GLB1	Pathogenic	no assertion criteria provided
100726	NM_000404.2:c.672_673delAT	GLB1	Pathogenic	no assertion criteria provided
100727	NM_000404.4(GLB1):c.922T>C (p.Phe308Leu)	GLB1	Pathogenic	no assertion criteria provided
1063917	NM_000404.4(GLB1):c.107A>G (p.Tyr36Cys)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069817	NM_000404.4(GLB1):c.1324C>T (p.Arg442Ter)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071414	NM_000404.4(GLB1):c.994G>A (p.Asp332Asn)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1251981	NM_000404.4(GLB1):c.1010T>C (p.Leu337Pro)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301844	NM_000404.4(GLB1):c.998A>G (p.Tyr333Cys)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332777	NM_000404.4(GLB1):c.425_428del (p.Lys142fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1332778	NM_000404.4(GLB1):c.266A>T (p.His89Leu)	GLB1	Pathogenic	criteria provided, single submitter
1332869	NM_000404.4(GLB1):c.75+4dup	GLB1	Pathogenic	criteria provided, single submitter
1353182	NM_000404.4(GLB1):c.569G>A (p.Gly190Asp)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449094	NM_000404.4(GLB1):c.591dup (p.Asp198Ter)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1454377	NM_000404.4(GLB1):c.1142del (p.Lys381fs)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1473187	NM_000404.4(GLB1):c.435TCT[1] (p.Leu147del)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167146	NM_000404.4(GLB1):c.1077del (p.Val360fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1683247	NM_000404.4(GLB1):c.1598_1601dup (p.His534fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685330	NM_000404.4(GLB1):c.553-2A>T	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1810758	NM_000404.4(GLB1):c.1122T>G (p.Tyr374Ter)	GLB1	Pathogenic	criteria provided, single submitter
194596	NM_000404.4(GLB1):c.1768C>T (p.Arg590Cys)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
195074	NM_000404.4(GLB1):c.203G>A (p.Arg68Gln)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198077	NM_000404.4(GLB1):c.602G>A (p.Arg201His)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202191	NM_000404.4(GLB1):c.1577dup (p.Trp527fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
2043978	NM_000404.4(GLB1):c.833del (p.Gly278fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
2164182	NM_000404.4(GLB1):c.1147A>T (p.Lys383Ter)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2507026	NM_000404.4(GLB1):c.562G>T (p.Glu188Ter)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
252985	NM_000404.4(GLB1):c.1733A>G (p.Lys578Arg)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585128	NM_000404.4(GLB1):c.1071_1073delinsGG (p.Phe357fs)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264673	NM_000404.4(GLB1):c.276G>A (p.Trp92Ter)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 4 · 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
GLB1	Definitive	Autosomal recessive	GM1 gangliosidosis	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLB1	Orphanet:309310	Mucopolysaccharidosis type 4B
GLB1	Orphanet:79255	GM1 gangliosidosis type 1
GLB1	Orphanet:79256	GM1 gangliosidosis type 2
GLB1	Orphanet:79257	GM1 gangliosidosis type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLB1	HGNC:4298	ENSG00000170266	P16278	Beta-galactosidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLB1	Beta-galactosidase	Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLB1	Other/Unknown	no		Glycoside_Hdrlase_35, Galactose-bd-like_sf, GH_hydrolase_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	1
mononuclear cell	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLB1	258	ubiquitous	marker	monocyte, mononuclear cell, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLB1	1,578

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLB1	P16278	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 1 evidence-associated genes (1 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 1 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 B (Keratin metabolism)	1	5710.0×	0.003	GLB1
MPS IV - Morquio syndrome B (CS/DS degradation)	1	5710.0×	0.003	GLB1
Defective NEU1 causes sialidosis	1	2855.0×	0.004	GLB1
Mucopolysaccharidoses	1	1903.3×	0.004	GLB1
Diseases of carbohydrate metabolism	1	815.7×	0.005	GLB1
Keratan sulfate degradation	1	713.8×	0.005	GLB1
Diseases associated with N-glycosylation of proteins	1	634.4×	0.005	GLB1
Heparan sulfate/heparin (HS-GAG) metabolism	1	543.8×	0.005	GLB1
CS/DS degradation	1	543.8×	0.005	GLB1
Keratan sulfate/keratin metabolism	1	496.5×	0.005	GLB1
HS-GAG degradation	1	496.5×	0.005	GLB1
Sialic acid metabolism	1	326.3×	0.007	GLB1
Glycosphingolipid metabolism	1	300.5×	0.007	GLB1
Synthesis of substrates in N-glycan biosythesis	1	292.8×	0.007	GLB1
Glycosphingolipid catabolism	1	292.8×	0.007	GLB1
Glycosaminoglycan metabolism	1	219.6×	0.008	GLB1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	207.6×	0.008	GLB1
Sphingolipid metabolism	1	167.9×	0.010	GLB1
Diseases of glycosylation	1	131.3×	0.012	GLB1
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.012	GLB1
Diseases of metabolism	1	80.4×	0.018	GLB1
Asparagine N-linked glycosylation	1	60.1×	0.023	GLB1
Metabolism of lipids	1	31.6×	0.041	GLB1
Innate Immune System	1	25.5×	0.049	GLB1
Neutrophil degranulation	1	23.1×	0.052	GLB1
Post-translational protein modification	1	19.2×	0.060	GLB1
Disease	1	13.1×	0.083	GLB1
Immune System	1	13.0×	0.083	GLB1
Metabolism of proteins	1	12.4×	0.084	GLB1
Metabolism	1	11.6×	0.086	GLB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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 cortisone	1	8426.0×	4e-04	GLB1
keratan sulfate proteoglycan catabolic process	1	5617.3×	4e-04	GLB1
response to Thyroglobulin triiodothyronine	1	5617.3×	4e-04	GLB1
galactose catabolic process	1	2808.7×	6e-04	GLB1
ganglioside catabolic process	1	1872.4×	7e-04	GLB1
glycoprotein catabolic process	1	1053.2×	0.001	GLB1
carbohydrate metabolic process	1	135.9×	0.007	GLB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
GLB1	MIGALASTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLB1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGALASTAT	4	GLB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GLB1	124	Binding:123, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GLB1	124

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
MIGALASTAT	4	GLB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GLB1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.