Tay-Sachs disease

Summary

Tay-Sachs disease (MONDO:0010100) is a disease caused by HEXA (GenCC Definitive), with 5 cohort genes and 18 clinical trials. Top therapeutic interventions include alemtuzumab, busulfan, and clofarabine.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: HEXA (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 1,275
• Phenotypes (HPO): 69
• Clinical trials: 18

Clinical features

Epidemiology

Prevalence records

12 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.28	Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.31	Europe	Validated
Prevalence at birth	1-5 / 10 000	27.8	Specific population	Validated
Prevalence at birth	1-9 / 100 000	3.13	Portugal	Validated
Prevalence at birth	1-9 / 1 000 000	0.3	Czech Republic	Validated
Prevalence at birth	1-9 / 1 000 000	0.5	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.41	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.29	Canada	Validated
Prevalence at birth	1-9 / 1 000 000	0.74	United Arab Emirates	Validated
Prevalence at birth	1-9 / 1 000 000	0.23	Turkey	Validated
Prevalence at birth	1-9 / 1 000 000	0.48	Sweden	Validated
Annual incidence	1-9 / 1 000 000	0.5	Specific population	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002191	Progressive spasticity	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003495	GM2-ganglioside accumulation	Very frequent (80-99%)
HP:0010969	Abnormality of glycolipid metabolism	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002171	Gliosis	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002311	Incoordination	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0007010	Poor fine motor coordination	Frequent (30-79%)
HP:0007103	Hypointensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0009050	Quadriceps muscle atrophy	Frequent (30-79%)
HP:0010729	Cherry red spot of the macula	Frequent (30-79%)
HP:0011951	Aspiration pneumonia	Frequent (30-79%)
HP:0012696	Abnormal thalamic MRI signal intensity	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001377	Limited elbow extension	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002267	Exaggerated startle response	Occasional (5-29%)
HP:0002283	Global brain atrophy	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Tay-Sachs disease
Mondo ID	MONDO:0010100
MeSH	D013661
OMIM	272800
Orphanet	845
DOID	DOID:3320
ICD-10-CM	E75.02
ICD-11	215008783
NCIT	C85184
SNOMED CT	111385000, 49562005
UMLS	C0039373
MedGen	11713
GARD	0007737
MedDRA	10043147
NORD	1761
Is cancer (heuristic)	no

Also known as: B variant GM2 gangliosidosis · disease, Tay-Sachs · gangliosidosis GM2, type 1 · GM2 gangliosidosis, B, B1 variant · GM2 gangliosidosis, type 1 · GM2-gangliosidosis, several forms · Hex A pseudodeficiency · hexosaminidase A deficiency · hexosaminidase alpha-subunit deficiency (variant B) · sphingolipidosis, Tay-Sachs · Tay Sachs Disease · Tay-Sachs disease · TSD

Data availability: 1,275 ClinVar variants · 5 GenCC gene-disease records · 46 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

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, galactosialidosis, 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, 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

Subtypes (4): Tay-Sachs disease, b variant, infantile form, Tay-Sachs disease, b variant, juvenile form, Tay-Sachs disease, B variant, adult form, Tay-Sachs disease, B1 variant

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:

277 likely benign, 224 uncertain significance, 42 pathogenic, 26 likely pathogenic, 20 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 3 benign, 1 conflicting classifications of pathogenicity; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
100728	NM_000405.5(GM2A):c.333del (p.Cys112fs)	GM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
100729	NM_000520.6(HEXA):c.1305C>T (p.Tyr435=)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100730	NM_000520.6(HEXA):c.718_719insT (p.Lys240fs)	HEXA	Pathogenic	no assertion criteria provided
1067655	NM_000520.6(HEXA):c.1171G>A (p.Val391Met)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068668	NM_000520.6(HEXA):c.1220del (p.Val407fs)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069429	NM_000520.6(HEXA):c.1098T>G (p.Tyr366Ter)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070611	NC_000015.9:g.(?_72662933)_72670877del	HEXA	Pathogenic	criteria provided, single submitter
1074825	NM_000520.6(HEXA):c.755G>A (p.Arg252His)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075193	NM_000520.6(HEXA):c.1258del (p.Trp420fs)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075310	NM_000520.6(HEXA):c.289_290del (p.Val97fs)	HEXA	Pathogenic	criteria provided, single submitter
1076289	NM_000520.6(HEXA):c.1073+1G>C	HEXA	Pathogenic	criteria provided, single submitter
1076944	NM_000520.6(HEXA):c.32del (p.Leu11fs)	HEXA	Pathogenic	criteria provided, single submitter
1184915	NM_000520.6(HEXA):c.743del (p.Leu248fs)	HEXA	Pathogenic	criteria provided, multiple submitters, no conflicts
1192227	NM_000520.6(HEXA):c.1525_1526+27del	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332717	NM_000520.6(HEXA):c.1429_1445del (p.Ala477fs)	HEXA	Pathogenic	criteria provided, single submitter
1368819	NM_000520.6(HEXA):c.938del (p.Pro313fs)	HEXA	Pathogenic	criteria provided, single submitter
1390393	NM_000520.6(HEXA):c.1330+2T>C	HEXA	Pathogenic	criteria provided, multiple submitters, no conflicts
1423338	NM_000520.6(HEXA):c.672+2T>C	HEXA	Pathogenic	criteria provided, single submitter
1435017	NM_000520.6(HEXA):c.492del (p.Arg166fs)	HEXA	Pathogenic	criteria provided, single submitter
1440029	NM_000520.6(HEXA):c.51_52insAGTTTTCGCTGCTGCTGGCGGCAGCGTTCGCA (p.Gly18fs)	HEXA	Pathogenic	criteria provided, single submitter
1440906	NM_000520.6(HEXA):c.917T>G (p.Leu306Ter)	HEXA	Pathogenic	criteria provided, single submitter
1449829	NM_000520.6(HEXA):c.118del (p.Tyr40fs)	HEXA	Pathogenic	criteria provided, single submitter
1450778	NM_000520.6(HEXA):c.395_398del (p.Val132fs)	HEXA	Pathogenic	criteria provided, single submitter
1451990	NM_000520.6(HEXA):c.1455G>A (p.Trp485Ter)	HEXA	Pathogenic	criteria provided, single submitter
1453002	NM_000520.6(HEXA):c.144C>G (p.Tyr48Ter)	HEXA	Pathogenic	criteria provided, single submitter
1453693	NM_000520.6(HEXA):c.1114del (p.Val372fs)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453891	NM_000520.6(HEXA):c.1168del (p.Gln390fs)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455050	NC_000015.9:g.(?72636408)(72636491_?)del	HEXA	Pathogenic	criteria provided, single submitter
1457426	NM_000520.6(HEXA):c.226_242del (p.Gly76fs)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459589	NM_000520.6(HEXA):c.1435del (p.Ala479fs)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
HEXA	Definitive	Autosomal recessive	Tay-Sachs disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HEXA	Orphanet:309178	Tay-Sachs disease, infantile form
HEXA	Orphanet:309185	Tay-Sachs disease, juvenile form
HEXA	Orphanet:309192	Tay-Sachs disease, adult form
GM2A	Orphanet:309246	GM2 gangliosidosis, AB variant
SETX	Orphanet:357043	Amyotrophic lateral sclerosis type 4
SETX	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2
MYO9A	Orphanet:98914	Presynaptic congenital myasthenic syndromes

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HEXA	HGNC:4878	ENSG00000213614	P06865	Beta-hexosaminidase subunit alpha	gencc,clinvar
ADPGK	HGNC:25250	ENSG00000159322	Q9BRR6	ADP-dependent glucokinase	clinvar
GM2A	HGNC:4367	ENSG00000196743	P17900	Ganglioside GM2 activator	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
MYO9A	HGNC:7608	ENSG00000066933	B2RTY4	Unconventional myosin-IXa	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HEXA	Beta-hexosaminidase subunit alpha	Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides.
ADPGK	ADP-dependent glucokinase	Catalyzes the phosphorylation of D-glucose to D-glucose 6-phosphate using ADP as the phosphate donor.
GM2A	Ganglioside GM2 activator	The large binding pocket can accommodate several single chain phospholipids and fatty acids, GM2A also exhibits some calcium-independent phospholipase activity.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
MYO9A	Unconventional myosin-IXa	Myosins are actin-based motor molecules with ATPase activity.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Kinase	1	5.5×	0.503
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HEXA	Enzyme (other)	yes	3.2.1.169	GH20_cat, GH_hydrolase_sf, GH20
ADPGK	Kinase	yes	2.7.1.147	ADP_PFK/GK, Ribokinase-like
GM2A	Other/Unknown	no		ML_dom, GM2-AP, GM2-AP_sf
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
MYO9A	Other/Unknown	no		IQ_motif_EF-hand-BS, RA_dom, RhoGAP_dom

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
gall bladder	1
stromal cell of endometrium	1
type B pancreatic cell	1
monocyte	1
mononuclear cell	1
oocyte	1
mammalian vulva	1
penis	1
placenta	1
left testis	1
right testis	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HEXA	293	ubiquitous	marker	type B pancreatic cell, gall bladder, stromal cell of endometrium
ADPGK	263	ubiquitous	marker	oocyte, monocyte, mononuclear cell
GM2A	284	ubiquitous	marker	mammalian vulva, penis, placenta
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis
MYO9A	280	ubiquitous	marker	calcaneal tendon, male germ cell, sperm

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETX	3,127
MYO9A	2,434
ADPGK	1,205
GM2A	1,074
HEXA	999

Intra-cohort edges

A	B	Sources
GM2A	HEXA	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GM2A	P17900	8
HEXA	P06865	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADPGK	Q9BRR6	91.36
MYO9A	B2RTY4	58.07
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 5 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
Glycosphingolipid catabolism	2	146.4×	0.001	HEXA, GM2A
Defective HEXA causes GM2G1 (Hyaluronan metabolism)	1	2855.0×	0.004	HEXA
Glucose metabolism	1	219.6×	0.025	ADPGK
Keratan sulfate degradation	1	178.4×	0.025	HEXA
Hyaluronan degradation	1	178.4×	0.025	HEXA
CS/DS degradation	1	135.9×	0.027	HEXA
Glycosphingolipid metabolism	1	75.1×	0.034	GM2A
Glycolysis	1	71.4×	0.034	ADPGK
RHOV GTPase cycle	1	71.4×	0.034	MYO9A
Sphingolipid metabolism	1	42.0×	0.051	GM2A
RHOB GTPase cycle	1	38.6×	0.051	MYO9A
Metabolism of carbohydrates and carbohydrate derivatives	1	30.1×	0.060	ADPGK
Metabolism	2	5.8×	0.067	ADPGK, GM2A
RHOA GTPase cycle	1	18.7×	0.083	MYO9A
RHO GTPase cycle	1	15.0×	0.095	MYO9A
Signaling by Rho GTPases	1	8.6×	0.148	MYO9A
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	8.4×	0.148	MYO9A
Metabolism of lipids	1	7.9×	0.148	GM2A
Innate Immune System	1	6.4×	0.171	GM2A
Neutrophil degranulation	1	5.8×	0.179	GM2A
Immune System	1	3.2×	0.288	GM2A
Signal Transduction	1	2.5×	0.339	MYO9A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ganglioside catabolic process	2	749.0×	1e-04	HEXA, GM2A
lipid storage	2	217.4×	8e-04	HEXA, GM2A
neuromuscular process controlling balance	2	132.2×	0.001	HEXA, GM2A
positive regulation of termination of DNA-templated transcription	1	3370.4×	0.003	SETX
glycolytic process through glucose-6-phosphate	1	3370.4×	0.003	ADPGK
positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled	1	1123.5×	0.007	SETX
dermatan sulfate proteoglycan catabolic process	1	842.6×	0.008	HEXA
regulation of neuron projection arborization	1	561.7×	0.010	MYO9A
glycosaminoglycan metabolic process	1	481.5×	0.010	HEXA
positive regulation of DNA-templated transcription initiation	1	374.5×	0.010	SETX
cell junction assembly	1	337.0×	0.010	MYO9A
DNA-templated transcription termination	1	306.4×	0.010	SETX
oligosaccharide catabolic process	1	306.4×	0.010	GM2A
glycosphingolipid catabolic process	1	306.4×	0.010	GM2A
cell morphogenesis involved in neuron differentiation	1	306.4×	0.010	HEXA
termination of RNA polymerase II transcription	1	259.3×	0.011	SETX
positive regulation of RNA splicing	1	210.7×	0.012	SETX
establishment of epithelial cell apical/basal polarity	1	210.7×	0.012	MYO9A
neuromuscular process controlling posture	1	210.7×	0.012	HEXA
hyaluronan catabolic process	1	198.3×	0.012	HEXA
glycosaminoglycan biosynthetic process	1	168.5×	0.013	HEXA
mRNA splice site recognition	1	160.5×	0.013	SETX
N-glycan processing	1	146.5×	0.014	HEXA
adult walking behavior	1	99.1×	0.020	HEXA
DNA recombination	1	67.4×	0.028	SETX
lysosome organization	1	61.3×	0.029	HEXA
lipid transport	1	52.7×	0.031	GM2A
glucose metabolic process	1	51.1×	0.031	ADPGK
myelination	1	50.3×	0.031	HEXA
circadian rhythm	1	48.9×	0.031	SETX

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Venglustat	Phase 3 (in late-stage trials)

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

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) 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
HEXA	PYRIMETHAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HEXA	1	4
ADPGK	0	0
GM2A	0	0
SETX	0	0
MYO9A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRIMETHAMINE	4	HEXA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
HEXA	58	Binding:58

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HEXA	3.2.1.169	protein O-GlcNAcase
ADPGK	2.7.1.147	ADP-specific glucose/glucosamine kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)	1	HEXA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADPGK
E	Difficult family or no structure, no drug	3	GM2A, SETX, MYO9A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADPGK	0	—
GM2A	0	—
SETX	0	—
MYO9A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 18.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE2	2
PHASE1/PHASE2	2
PHASE1	2
PHASE4	1
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02030015	PHASE4	TERMINATED	Synergistic Enteral Regimen for Treatment of the Gangliosidoses
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT04221451	PHASE3	TERMINATED	A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT01102686	PHASE1/PHASE2	COMPLETED	Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT03759665	PHASE2	COMPLETED	N-Acetyl-L-Leucine for GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease)
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT04669535	PHASE1	TERMINATED	A Dose-escalation and Safety & Efficacy Study of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease
NCT00668187	Not specified	RECRUITING	A Natural History Study of the Gangliosidoses
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT06614569	Not specified	ACTIVE_NOT_RECRUITING	Long-Term Follow-Up of Subjects Treated With AXO-AAV-GM2 for Tay-Sachs or Sandhoff Disease
NCT00006057	Not specified	COMPLETED	Diagnostic and Screening Study of Genetic Disorders
NCT01869270	Not specified	COMPLETED	Gene Therapy for Tay-Sachs Disease
NCT01999257	Not specified	COMPLETED	Efficacy Study of an Online Educational Module Before Carrier Genetic Screening in Persons of Ashkenazi Jewish Descent.
NCT04470713	Not specified	COMPLETED	Natural History Study for Pediatric Patients With Early Onset of Either GM1 Gangliosidosis, GM2 Gangliosidoses, or Gaucher Disease Type 2
NCT04624789	Not specified	UNKNOWN	Registry Gangliosidoses
NCT05109793	Not specified	COMPLETED	GM1 and GM2 Gangliosidosis PROspective Neurological Disease TrajectOry Study (PRONTO)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALEMTUZUMAB	4	1
BUSULFAN	4	1
CLOFARABINE	4	1
CYCLOPHOSPHAMIDE ANHYDROUS	4	1
HYDROXYUREA	4	1
LEVACETYLLEUCINE	4	1
MIGLUSTAT	4	1
PYRIMETHAMINE	4	1
TRENONACOG ALFA	3	1
VENGLUSTAT	3	1
GILAVEBEXAGENE ANVUPARVOVEC	1	1