Canavan disease

Summary

Canavan disease (MONDO:0010079) is a disease caused by ASPA (GenCC Definitive), with 4 cohort genes and 11 clinical trials. Top therapeutic interventions include levetiracetam.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: ASPA (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 487
• Phenotypes (HPO): 18
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1	Worldwide	Validated
Annual incidence	1-9 / 100 000	7	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0004372	Reduced consciousness/confusion	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000618	Blindness	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0007703	Abnormality of retinal pigmentation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Canavan disease
Mondo ID	MONDO:0010079
MeSH	D017825
OMIM	271900
Orphanet	141
DOID	DOID:3613
ICD-11	1576870846
NCIT	C84611
SNOMED CT	80544005
UMLS	C0206307
MedGen	61565
GARD	0005984
MedDRA	10067608
NORD	886
Is cancer (heuristic)	no

Also known as: ACY2 deficiency · aminoacylase 2 deficiency · aspartoacylase deficiency · Canavan disease · Canavan-VAN Bogaert-Bertrand disease · spongy degeneration of central nervous system · spongy degeneration of the brain · spongy degeneration of the central nervous system · Von Bogaert-Bertrand disease

Data availability: 487 ClinVar variants · 4 GenCC gene-disease records · 16 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn aminoacylase deficiency › Canavan disease

Related subtypes (1): aminoacylase 1 deficiency

Subtypes (2): severe Canavan disease, mild Canavan disease

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

487 retrieved; paginated sample, class counts are floors:

175 likely benign, 102 uncertain significance, 88 likely pathogenic, 56 pathogenic, 49 pathogenic/likely pathogenic, 13 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069303	NM_000049.4(ASPA):c.230dup (p.Asn77fs)	ASPA	Pathogenic	criteria provided, single submitter
1071154	NC_000017.10:g.(?3397634)(3397763_?)del	ASPA	Pathogenic	criteria provided, single submitter
1071503	NC_000017.10:g.(?3379444)(3402392_?)del	ASPA	Pathogenic	criteria provided, single submitter
1071504	NC_000017.10:g.(?3384887)(3386896_?)del	ASPA	Pathogenic	criteria provided, single submitter
1071506	NC_000017.10:g.(?3392519)(3397763_?)del	ASPA	Pathogenic	criteria provided, single submitter
1323943	NM_000049.4(ASPA):c.342C>A (p.Asp114Glu)	ASPA	Pathogenic	criteria provided, single submitter
1342193	NM_000049.4(ASPA):c.124C>T (p.Gln42Ter)	ASPA	Pathogenic	criteria provided, single submitter
1377669	NM_000049.4(ASPA):c.321_322del (p.Ser108fs)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1402186	NM_000049.4(ASPA):c.101G>A (p.Trp34Ter)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411157	NM_000049.4(ASPA):c.426C>A (p.Tyr142Ter)	ASPA	Pathogenic	criteria provided, single submitter
1449340	NC_000017.10:g.(?3392509)(3571820_?)del	ASPA	Pathogenic	criteria provided, single submitter
1454394	NC_000017.10:g.(?3402175)(3402392_?)del	ASPA	Pathogenic	criteria provided, single submitter
1454528	NM_000049.4(ASPA):c.27dup (p.His10fs)	ASPA	Pathogenic	criteria provided, single submitter
1700565	NM_000049.4(ASPA):c.526G>A (p.Gly176Ser)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1732890	NM_000049.4(ASPA):c.358_361del (p.Ser120fs)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188788	NM_000049.4(ASPA):c.820G>A (p.Gly274Arg)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188803	NM_000049.4(ASPA):c.859G>A (p.Ala287Thr)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188888	NM_000049.4(ASPA):c.79G>A (p.Gly27Arg)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189005	NM_000049.4(ASPA):c.244_245del (p.Met82fs)	ASPA	Pathogenic	criteria provided, multiple submitters, no conflicts
189114	NM_000049.4(ASPA):c.237-2A>T	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1965753	NM_000049.4(ASPA):c.283G>T (p.Glu95Ter)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1998122	NM_000049.4(ASPA):c.80del (p.Gly27fs)	ASPA	Pathogenic	criteria provided, single submitter
2000932	NM_000049.4(ASPA):c.291del (p.His98fs)	ASPA	Pathogenic	criteria provided, single submitter
2025519	NM_000049.4(ASPA):c.347_348insAA (p.His116fs)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2033374	NM_000049.4(ASPA):c.577del (p.Asp193fs)	ASPA	Pathogenic	criteria provided, single submitter
2089364	NM_000049.4(ASPA):c.325_328dup (p.Asp110delinsValTer)	ASPA	Pathogenic	criteria provided, single submitter
2107207	NM_000049.4(ASPA):c.102G>A (p.Trp34Ter)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2119193	NM_000049.4(ASPA):c.25G>T (p.Glu9Ter)	ASPA	Pathogenic	criteria provided, single submitter
2137874	NM_000049.4(ASPA):c.557T>A (p.Val186Asp)	ASPA	Pathogenic	criteria provided, single submitter
2137875	NM_000049.4(ASPA):c.610G>C (p.Asp204His)	ASPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
ASPA	Definitive	Autosomal recessive	Canavan disease	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASPA	Orphanet:314911	Severe Canavan disease
ASPA	Orphanet:314918	Mild Canavan disease

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ASPA	HGNC:756	ENSG00000108381	P45381	Aspartoacylase	gencc,clinvar
TRPV1	HGNC:12716	ENSG00000196689	Q8NER1	Transient receptor potential cation channel subfamily V member 1	clinvar
SPATA22	HGNC:30705	ENSG00000141255	Q8NHS9	Spermatogenesis-associated protein 22	clinvar
P2RX5	HGNC:8536	ENSG00000083454	Q93086	P2X purinoceptor 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASPA	Aspartoacylase	Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate.
TRPV1	Transient receptor potential cation channel subfamily V member 1	Non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli.
SPATA22	Spermatogenesis-associated protein 22	Meiosis-specific protein required for homologous recombination in meiosis I.
P2RX5	P2X purinoceptor 5	ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Ion channel	1	27.9×	0.106
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASPA	Enzyme (other)	yes	3.5.1.15	Aste_AspA_hybrid_dom, Aspartoacylase, AspA/AstE_fam
TRPV1	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
SPATA22	Other/Unknown	no		Spata22
P2RX5	Other/Unknown	no		P2X_purnocptor, P2X5_purnocptor, P2X_extracellular_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
medial globus pallidus	1
nephron tubule	1
right lobe of liver	1
sural nerve	1
tibial nerve	1
left testis	1
right testis	1
sperm	1
lymph node	1
spleen	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASPA	238	broad	marker	corpus callosum, nephron tubule, medial globus pallidus
TRPV1	189	tissue_specific	yes	right lobe of liver, sural nerve, tibial nerve
SPATA22	161	tissue_specific	marker	sperm, right testis, left testis
P2RX5	205	broad	marker	spleen, lymph node, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRPV1	2,258
SPATA22	912
P2RX5	821
ASPA	680

Intra-cohort edges

A	B	Sources
ASPA	TRPV1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPV1	Q8NER1	13
ASPA	P45381	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
P2RX5	Q93086	82.23
SPATA22	Q8NHS9	61.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Aspartate and asparagine metabolism	1	346.1×	0.013	ASPA
Elevation of cytosolic Ca2+ levels	1	237.9×	0.013	P2RX5
TRP channels	1	135.9×	0.015	TRPV1
Platelet homeostasis	1	92.8×	0.016	P2RX5
Metabolism of amino acids and derivatives	1	22.5×	0.052	ASPA
Metabolism	1	3.9×	0.237	ASPA

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
acetate metabolic process	1	4213.0×	0.003	ASPA
response to capsazepine	1	4213.0×	0.003	TRPV1
osteoclast maturation	1	2106.5×	0.003	P2RX5
regulation of skeletal muscle tissue regeneration	1	2106.5×	0.003	P2RX5
spermatocyte division	1	2106.5×	0.003	SPATA22
meiotic DNA repair synthesis	1	1404.3×	0.003	SPATA22
fever generation	1	1404.3×	0.003	TRPV1
detection of temperature stimulus involved in thermoception	1	1404.3×	0.003	TRPV1
peptide secretion	1	1053.2×	0.003	TRPV1
sensory perception of mechanical stimulus	1	1053.2×	0.003	TRPV1
thermoception	1	1053.2×	0.003	TRPV1
detection of chemical stimulus involved in sensory perception of pain	1	1053.2×	0.003	TRPV1
smooth muscle contraction involved in micturition	1	1053.2×	0.003	TRPV1
calcium ion transmembrane transport	2	105.3×	0.003	TRPV1, P2RX5
chemosensory behavior	1	842.6×	0.003	TRPV1
cellular response to alkaloid	1	842.6×	0.003	TRPV1
response to pH	1	702.2×	0.004	P2RX5
reproductive system development	1	601.9×	0.004	SPATA22
aspartate metabolic process	1	526.6×	0.004	ASPA
positive regulation of calcium ion import across plasma membrane	1	421.3×	0.005	P2RX5
diet induced thermogenesis	1	351.1×	0.006	TRPV1
positive regulation of calcium ion transport into cytosol	1	300.9×	0.006	P2RX5
sensory perception of taste	1	280.9×	0.007	TRPV1
response to ATP	1	247.8×	0.007	P2RX5
behavioral response to pain	1	221.7×	0.007	TRPV1
cellular response to ATP	1	221.7×	0.007	TRPV1
detection of temperature stimulus involved in sensory perception of pain	1	210.7×	0.008	TRPV1
regulation of meiotic cell cycle	1	191.5×	0.008	SPATA22
cellular response to acidic pH	1	183.2×	0.008	TRPV1
response to zinc ion	1	156.0×	0.009	P2RX5

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
TRPV1	CANNABIDIOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPV1	19	4
P2RX5	1	3
ASPA	0	0
SPATA22	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABIDIOL	4	TRPV1
CAPSAICIN	4	TRPV1
PROPOFOL	4	TRPV1
RESINIFERATOXIN	3	TRPV1
FRAMYCETIN	3	TRPV1
ZUCAPSAICIN	3	TRPV1
CANNABINOL	3	TRPV1
SURAMIN	3	P2RX5
ILEPCIMIDE	2	TRPV1
SB-705498	2	TRPV1
NGD-8243	2	TRPV1
MAVATREP	2	TRPV1
TETRAHYDROCANNABIVARIN	2	TRPV1
CANNABIDIVARIN	2	TRPV1
PIPERINE	2	TRPV1
CANNABIGEROL	2	TRPV1
JTS-653	2	TRPV1
OLVANIL	2	TRPV1
AMG-517	1	TRPV1
ABT-102	1	TRPV1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TRPV1	674	Binding:506, Functional:166, ADMET:2
P2RX5	13	Binding:10, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASPA	3.5.1.15	aspartoacylase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TRPV1	674

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

20 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)
CANNABIDIOL	4	TRPV1
CAPSAICIN	4	TRPV1
PROPOFOL	4	TRPV1
RESINIFERATOXIN	3	TRPV1
FRAMYCETIN	3	TRPV1
ZUCAPSAICIN	3	TRPV1
CANNABINOL	3	TRPV1
SURAMIN	3	P2RX5
ILEPCIMIDE	2	TRPV1
SB-705498	2	TRPV1
NGD-8243	2	TRPV1
MAVATREP	2	TRPV1
TETRAHYDROCANNABIVARIN	2	TRPV1
CANNABIDIVARIN	2	TRPV1
PIPERINE	2	TRPV1
CANNABIGEROL	2	TRPV1
JTS-653	2	TRPV1
OLVANIL	2	TRPV1
AMG-517	1	TRPV1
ABT-102	1	TRPV1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TRPV1
B	Phased (≥1) drug, not yet approved	1	P2RX5
C	Druggable family + PDB, no drug	1	ASPA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SPATA22

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ASPA	0	—
SPATA22	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE1/PHASE2	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04833907	PHASE1/PHASE2	ENROLLING_BY_INVITATION	rAAV-Olig001-ASPA Gene Therapy for Treatment of Children With Typical Canavan Disease
NCT04998396	PHASE1/PHASE2	RECRUITING	A Study of AAV9 Gene Therapy in Participants With Canavan Disease (CANaspire Clinical Trial)
NCT00657748	PHASE2	WITHDRAWN	Lithium and Acetate for Canavan Disease
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT00724802	Not specified	UNKNOWN	Oral Glyceryl Triacetate (GTA) in Newborns With Canavan
NCT01999257	Not specified	COMPLETED	Efficacy Study of an Online Educational Module Before Carrier Genetic Screening in Persons of Ashkenazi Jewish Descent.
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02851563	Not specified	COMPLETED	A Natural History Study of Canavan Disease
NCT04126005	Not specified	COMPLETED	Natural History Study of Patients With Canavan Disease (CANinform Study)
NCT05317780	Not specified	NO_LONGER_AVAILABLE	Canavan-Single Patient IND

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEVETIRACETAM	4	1