Neuronal ceroid lipofuscinosis 2

Summary

Neuronal ceroid lipofuscinosis 2 (MONDO:0008769) is a disease caused by TPP1 (GenCC Definitive), with 2 cohort genes and 9 clinical trials. Top therapeutic interventions include cerliponase alfa.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TPP1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 405
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000	0.07	Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronal ceroid lipofuscinosis 2
Mondo ID	MONDO:0008769
OMIM	204500
Orphanet	228349
DOID	DOID:0110726
NCIT	C85864
UMLS	C1876161
MedGen	406281
GARD	0003045
Is cancer (heuristic)	no

Also known as: ceroid lipofuscinosis, neuronal, 2 · ceroid lipofuscinosis, neuronal, type 2 · CLN2 · CLN2 disease, juvenile (subtype) · CLN2 disease, late infantile (subtype) · late infantile neuronal ceroid lipofuscinosis · neuronal ceroid lipofuscinosis caused by mutation in TPP1 · neuronal ceroid lipofuscinosis type 2 · TPP1 neuronal ceroid lipofuscinosis

Data availability: 405 ClinVar variants · 6 GenCC gene-disease records · 31 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › lysosomal lipid storage disorder › neuronal ceroid lipofuscinosis › neuronal ceroid lipofuscinosis 2

Related subtypes (13): neuronal ceroid lipofuscinosis 3, ceroid lipofuscinosis, neuronal, 6B (Kufs type), neuronal ceroid lipofuscinosis 1, neuronal ceroid lipofuscinosis 5, neuronal ceroid lipofuscinosis 8, ceroid lipofuscinosis, neuronal, 6A, neuronal ceroid lipofuscinosis 10, neuronal ceroid lipofuscinosis 7, progressive myoclonic epilepsy type 3, adult neuronal ceroid lipofuscinosis, infantile neuronal ceroid lipofuscinosis, juvenile neuronal ceroid lipofuscinosis, congenital neuronal ceroid lipofuscinosis

Subtypes (3): infantile neuronal ceroid lipofuscinosis 2, late infantile neuronal ceroid lipofuscinosis 2, juvenile neuronal ceroid lipofuscinosis 2

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

405 retrieved; paginated sample, class counts are floors:

175 uncertain significance, 56 likely pathogenic, 44 pathogenic, 40 pathogenic/likely pathogenic, 40 conflicting classifications of pathogenicity, 18 likely benign, 16 benign, 12 benign/likely benign, 4 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065450	NM_000391.4(TPP1):c.987_989del (p.Glu329del)	TPP1	Pathogenic	criteria provided, single submitter
1073897	NM_000391.4(TPP1):c.1626G>A (p.Trp542Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1190419	NM_000391.4(TPP1):c.1496dup (p.Leu500fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380369	NM_000391.4(TPP1):c.1363_1425+9del	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449721	NM_000391.4(TPP1):c.1471del (p.His491fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686271	NM_000391.4(TPP1):c.899del (p.Gly300fs)	TPP1	Pathogenic	criteria provided, single submitter
1696130	NM_000391.4(TPP1):c.790C>T (p.Gln264Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1701805	NM_000391.4(TPP1):c.130G>T (p.Glu44Ter)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805012	NM_000391.4(TPP1):c.1012C>G (p.Gln338Glu)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188850	NM_000391.4(TPP1):c.972_979del (p.Ser324fs)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
188909	NM_000391.4(TPP1):c.1551+1G>A	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189179	NM_000391.4(TPP1):c.1379G>A (p.Trp460Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2052460	NM_000391.4(TPP1):c.146_155del (p.Leu49fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207561	NM_000391.4(TPP1):c.311T>A (p.Leu104Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207564	NM_000391.4(TPP1):c.196C>T (p.Gln66Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207567	NM_000391.4(TPP1):c.229G>C (p.Gly77Arg)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207569	NM_000391.4(TPP1):c.379C>T (p.Arg127Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207574	NM_000391.4(TPP1):c.509-1G>A	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207581	NM_000391.4(TPP1):c.827A>T (p.Asp276Val)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207582	NM_000391.4(TPP1):c.833A>G (p.Gln278Arg)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207586	NM_000391.4(TPP1):c.1015C>T (p.Arg339Trp)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207596	NM_000391.4(TPP1):c.1600C>T (p.Gln534Ter)	TPP1	Pathogenic	criteria provided, single submitter
2089504	NM_000391.3(TPP1):c.90del	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2098723	NM_000391.4(TPP1):c.1490del (p.Arg497fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2418966	NM_000391.4(TPP1):c.337dup (p.Ser113fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242356	NM_000391.4(TPP1):c.457_490del (p.Ser153fs)	TPP1	Pathogenic	criteria provided, single submitter
242357	NM_000391.4(TPP1):c.471C>A (p.Tyr157Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2627615	NM_000391.4(TPP1):c.1266_1266+1delinsTACAAACAAACA	TPP1	Pathogenic	criteria provided, single submitter
2627616	NM_000391.4(TPP1):c.182_184delinsC (p.Leu61fs)	TPP1	Pathogenic	criteria provided, single submitter
2627617	NM_000391.4(TPP1):c.1450dup (p.Ile484fs)	TPP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · 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
ACD	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	15
TPP1	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPP1	Orphanet:284324	Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia
TPP1	Orphanet:699751	Infantile CLN2 disease
TPP1	Orphanet:699761	Late infantile CLN2 disease
TPP1	Orphanet:699769	Juvenile CLN2 disease
ACD	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
ACD	Orphanet:397692	Hereditary isolated aplastic anemia
ACD	Orphanet:618	Familial melanoma

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
TPP1	HGNC:2073	ENSG00000166340	O14773	Tripeptidyl-peptidase 1	gencc,clinvar
ACD	HGNC:25070	ENSG00000102977	Q96AP0	Adrenocortical dysplasia protein homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPP1	Tripeptidyl-peptidase 1	Lysosomal serine protease with tripeptidyl-peptidase I activity.
ACD	Adrenocortical dysplasia protein homolog	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.

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)
TPP1	Protease	yes	3.4.14.9	Peptidase_S8/S53_dom, S53_propep, Sedolisin_dom
ACD	Other/Unknown	no		TPP1/Est3, ACD

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
dorsal motor nucleus of vagus nerve	1
pigmented layer of retina	1
retina	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPP1	298	ubiquitous	marker	pigmented layer of retina, retina, dorsal motor nucleus of vagus nerve
ACD	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPP1	1,739
ACD	1,044

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACD	Q96AP0	19
TPP1	O14773	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
Depurination	1	815.7×	0.011	ACD
Depyrimidination	1	475.8×	0.011	ACD
Base-Excision Repair, AP Site Formation	1	439.2×	0.011	ACD
Telomere C-strand synthesis initiation	1	407.9×	0.011	ACD
Processive synthesis on the C-strand of the telomere	1	380.7×	0.011	ACD
Telomere C-strand (Lagging Strand) Synthesis	1	380.7×	0.011	ACD
Base Excision Repair	1	356.9×	0.011	ACD
Removal of the Flap Intermediate from the C-strand	1	317.2×	0.011	ACD
Extension of Telomeres	1	300.5×	0.011	ACD
Telomere Extension By Telomerase	1	228.4×	0.012	ACD
Polymerase switching on the C-strand of the telomere	1	211.5×	0.012	ACD
Telomere Maintenance	1	184.2×	0.013	ACD
Meiosis	1	142.8×	0.015	ACD
Packaging Of Telomere Ends	1	109.8×	0.015	ACD
XBP1(S) activates chaperone genes	1	107.7×	0.015	TPP1
Chromosome Maintenance	1	105.7×	0.015	ACD
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.015	ACD
Cleavage of the damaged purine	1	102.0×	0.015	ACD
Reproduction	1	95.2×	0.015	ACD
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.015	ACD
Cleavage of the damaged pyrimidine	1	92.1×	0.015	ACD
Inhibition of DNA recombination at telomere	1	84.0×	0.015	ACD
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.015	ACD
Meiotic synapsis	1	70.5×	0.017	ACD
Cellular Senescence	1	68.8×	0.017	ACD
DNA Repair	1	49.2×	0.023	ACD
Cellular responses to stress	1	18.4×	0.057	ACD
Cell Cycle	1	18.0×	0.057	ACD
Cellular responses to stimuli	1	15.7×	0.063	ACD

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
protein localization to chromosome, telomeric region	2	1532.0×	1e-05	TPP1, ACD
segmentation	1	4213.0×	0.003	ACD
regulation of establishment of protein localization to telomere	1	2808.7×	0.003	ACD
telomere assembly	1	2106.5×	0.003	ACD
protection from non-homologous end joining at telomere	1	1203.7×	0.004	ACD
establishment of protein localization to telomere	1	1053.2×	0.004	ACD
telomere capping	1	648.1×	0.005	ACD
peptide catabolic process	1	526.6×	0.005	TPP1
lysosomal protein catabolic process	1	526.6×	0.005	TPP1
urogenital system development	1	495.6×	0.005	ACD
telomere maintenance via telomerase	1	366.4×	0.006	ACD
negative regulation of telomere maintenance via telomerase	1	366.4×	0.006	ACD
bone resorption	1	290.6×	0.007	TPP1
positive regulation of telomere maintenance	1	255.3×	0.007	ACD
embryonic limb morphogenesis	1	200.6×	0.009	ACD
neuromuscular process controlling balance	1	165.2×	0.010	TPP1
lysosome organization	1	153.2×	0.010	TPP1
telomere maintenance	1	133.8×	0.011	ACD
protein catabolic process	1	118.7×	0.012	TPP1
epithelial cell differentiation	1	87.8×	0.015	TPP1
skeletal system development	1	62.9×	0.020	ACD
central nervous system development	1	57.7×	0.020	TPP1
lipid metabolic process	1	45.8×	0.025	TPP1
intracellular protein transport	1	32.4×	0.033	ACD
nervous system development	1	23.0×	0.045	TPP1
proteolysis	1	17.1×	0.058	TPP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPP1	0	0
ACD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TPP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPP1	3.4.14.9	tripeptidyl-peptidase I

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

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)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TPP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACD

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)
TPP1	1	—
ACD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE1/PHASE2	3
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05152914	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Intravitreal ERT to Prevent Retinal Disease Progression in Children With CLN2
NCT05791864	PHASE1/PHASE2	RECRUITING	A First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Tolerability of Gene Therapy With TTX-381 for the Ocular Manifestations Associated With Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease
NCT01414985	PHASE1/PHASE2	COMPLETED	AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis
NCT00151216	PHASE1	COMPLETED	Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis
NCT03862274	Not specified	ENROLLING_BY_INVITATION	Examining Developmental Outcomes of Children Diagnosed With CLN2 Disease
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT01035424	Not specified	COMPLETED	Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis
NCT01698229	Not specified	TERMINATED	Collection of Cerebrospinal Fluid in Healthy Children
NCT04462692	Not specified	WITHDRAWN	An Observational Study in Children With CLN2 Batten Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CERLIPONASE ALFA	4	1