Sandhoff disease, infantile form

Summary

Sandhoff disease, infantile form (MONDO:0017721) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 23

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0033978	Reduced beta-hexosaminidase activity	Obligate (100%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0008936	Axial hypotonia	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002267	Exaggerated startle response	Frequent (30-79%)
HP:0003429	CNS hypomyelination	Frequent (30-79%)
HP:0004481	Progressive macrocephaly	Frequent (30-79%)
HP:0007083	Hyperactive patellar reflex	Frequent (30-79%)
HP:0010729	Cherry red spot of the macula	Frequent (30-79%)
HP:0012696	Abnormal thalamic MRI signal intensity	Frequent (30-79%)
HP:0032794	Myoclonic seizure	Frequent (30-79%)
HP:0000280	Coarse facial features	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0010780	Hyperacusis	Occasional (5-29%)
HP:0100814	Blue nevus	Occasional (5-29%)
HP:0001634	Mitral valve prolapse	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Sandhoff disease, infantile form
Mondo ID	MONDO:0017721
Orphanet	309155
SNOMED CT	238018004
UMLS	C0751490
MedGen	199669
GARD	0007604
Is cancer (heuristic)	no

Also known as: Hexosaminidases A and B deficiency, infantile form · infantile GM2 gangliosidosis 0 variant

Data availability: 6 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Sandhoff disease › Sandhoff disease, infantile form

Related subtypes (2): Sandhoff disease, juvenile form, Sandhoff disease, adult form

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

6 retrieved; paginated sample, class counts are floors:

5 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3885	NM_000521.4(HEXB):c.1082+5G>C	HEXB	Pathogenic	no assertion criteria provided
3886	NM_000521.4(HEXB):c.76del (p.Met26fs)	HEXB	Pathogenic	criteria provided, single submitter
3887	NM_000521.4(HEXB):c.850C>T (p.Arg284Ter)	HEXB	Pathogenic	criteria provided, multiple submitters, no conflicts
557437	NM_000521.4(HEXB):c.965del (p.Ile322fs)	HEXB	Pathogenic	criteria provided, single submitter
3883	NC_000005.10:g.(?74640023)(74705321_74713505)del	LOC129994061	Pathogenic	no assertion criteria provided
3882	NM_000521.3(HEXB):c.185C>T (p.Ser62Leu)	HEXB	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HEXB	Orphanet:309155	Sandhoff disease, infantile form
HEXB	Orphanet:309162	Sandhoff disease, juvenile form
HEXB	Orphanet:309169	Sandhoff disease, adult form

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
HEXB	HGNC:4879	ENSG00000049860	P07686	Beta-hexosaminidase subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HEXB	Beta-hexosaminidase subunit beta	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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HEXB	Enzyme (other)	yes	3.2.1.52	GH20_cat, GH_hydrolase_sf, GH20

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
calcaneal tendon	1
placenta	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HEXB	289	ubiquitous	marker	placenta, stromal cell of endometrium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HEXB	2,557

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HEXB	P07686	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Defective HEXB causes GM2G2 (Hyaluronan metabolism)	1	11420.0×	5e-04	HEXB
Keratan sulfate degradation	1	713.8×	0.003	HEXB
Hyaluronan degradation	1	713.8×	0.003	HEXB
CS/DS degradation	1	543.8×	0.003	HEXB
Glycosphingolipid catabolism	1	292.8×	0.004	HEXB
Neutrophil degranulation	1	23.1×	0.043	HEXB

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
male courtship behavior	1	16852.0×	0.001	HEXB
dermatan sulfate proteoglycan catabolic process	1	4213.0×	0.002	HEXB
chondroitin sulfate proteoglycan catabolic process	1	2808.7×	0.002	HEXB
glycosaminoglycan metabolic process	1	2407.4×	0.002	HEXB
astrocyte cell migration	1	2407.4×	0.002	HEXB
ganglioside catabolic process	1	1872.4×	0.002	HEXB
penetration of zona pellucida	1	1532.0×	0.002	HEXB
oligosaccharide catabolic process	1	1532.0×	0.002	HEXB
N-acetylglucosamine metabolic process	1	1203.7×	0.002	HEXB
hyaluronan catabolic process	1	991.3×	0.003	HEXB
N-glycan processing	1	732.7×	0.003	HEXB
phospholipid biosynthetic process	1	674.1×	0.003	HEXB
lipid storage	1	543.6×	0.004	HEXB
neuron cellular homeostasis	1	455.5×	0.004	HEXB
oogenesis	1	383.0×	0.004	HEXB
neuromuscular process controlling balance	1	330.4×	0.005	HEXB
lysosome organization	1	306.4×	0.005	HEXB
myelination	1	251.5×	0.006	HEXB
single fertilization	1	183.2×	0.007	HEXB
locomotory behavior	1	179.3×	0.007	HEXB
intracellular calcium ion homeostasis	1	145.3×	0.008	HEXB
skeletal system development	1	125.8×	0.009	HEXB
regulation of cell shape	1	123.0×	0.009	HEXB
sensory perception of sound	1	100.9×	0.010	HEXB
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	HEXB

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
HEXB	PYRIMETHAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HEXB	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRIMETHAMINE	4	HEXB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HEXB	53	Binding:53

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HEXB	3.2.1.52	beta-N-acetylhexosaminidase

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)
PYRIMETHAMINE	4	HEXB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HEXB
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.