Juvenile neuronal ceroid lipofuscinosis

Summary

Juvenile neuronal ceroid lipofuscinosis (MONDO:0019262) is a disease (an umbrella term covering 8 Mondo subtypes) with 3 cohort genes and 28 clinical trials. Top therapeutic interventions include cerliponase alfa, busulfan, and cyclophosphamide anhydrous.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 84
• Clinical trials: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	juvenile neuronal ceroid lipofuscinosis
Mondo ID	MONDO:0019262
Orphanet	79264
DOID	DOID:0050756
ICD-11	1716107919
SNOMED CT	61663001
GARD	0004938
MedDRA	10052073
Is cancer (heuristic)	no

Also known as: batten disease · JNCL · juvenile NCL · juvenile neuronal ceroid lipofuscinosis · Spielmeyer-Vogt disease

Data availability: 84 ClinVar variants.

Disease family

An umbrella term covering 8 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 › juvenile neuronal ceroid lipofuscinosis

Related subtypes (13): neuronal ceroid lipofuscinosis 3, ceroid lipofuscinosis, neuronal, 6B (Kufs type), neuronal ceroid lipofuscinosis 2, 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, congenital neuronal ceroid lipofuscinosis

Subtypes (8): neuronal ceroid lipofuscinosis 9, parkinsonism due to ATP13A2 deficiency, juvenile neuronal ceroid lipofuscinosis 1, juvenile neuronal ceroid lipofuscinosis 2, juvenile neuronal ceroid lipofuscinosis 3, juvenile neuronal ceroid lipofuscinosis 5, juvenile neuronal ceroid lipofuscinosis 6, juvenile neuronal ceroid lipofuscinosis 10

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

84 retrieved; paginated sample, class counts are floors:

23 pathogenic/likely pathogenic, 23 uncertain significance, 22 likely pathogenic, 10 pathogenic, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012398	NM_001042432.2(CLN3):c.678-2A>G	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075948	NM_001042432.2(CLN3):c.992_993del (p.Phe331fs)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1378760	NM_001042432.2(CLN3):c.639del (p.Leu214fs)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1908122	NM_001042432.2(CLN3):c.1197+1G>A	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2032700	NM_001042432.2(CLN3):c.552G>A (p.Trp184Ter)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205095	NM_001042432.2(CLN3):c.988G>A (p.Val330Ile)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2417180	NM_001042432.2(CLN3):c.551G>A (p.Trp184Ter)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680813	NM_001042432.2(CLN3):c.379dup (p.Arg127fs)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2782846	NM_001042432.2(CLN3):c.3G>A (p.Met1Ile)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2850686	NM_001042432.2(CLN3):c.461-2A>G	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3556	NM_001042432.2(CLN3):c.883G>A (p.Glu295Lys)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
3557	NM_001042432.2(CLN3):c.597C>A (p.Tyr199Ter)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
418137	NM_001042432.2(CLN3):c.1213C>T (p.Arg405Trp)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420007	NM_001042432.2(CLN3):c.784A>T (p.Lys262Ter)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56243	NM_001042432.2(CLN3):c.1000C>T (p.Arg334Cys)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56244	NM_001042432.2(CLN3):c.1001G>A (p.Arg334His)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56246	NM_001042432.2(CLN3):c.1054C>T (p.Gln352Ter)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56253	NM_001042432.2(CLN3):c.125+5G>A	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56258	NM_001042432.2(CLN3):c.214C>T (p.Gln72Ter)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56262	NM_001042432.2(CLN3):c.265C>T (p.Arg89Ter)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56264	NM_001042432.2(CLN3):c.370dup (p.Tyr124fs)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56267	NM_001042432.2(CLN3):c.379del (p.Arg127fs)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56269	NM_001042432.2(CLN3):c.424del (p.Val142fs)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56279	NM_001042432.2(CLN3):c.533+1G>C	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56280	NM_001042432.2(CLN3):c.558_559del (p.Gly187fs)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56287	NM_001042432.2(CLN3):c.622dup (p.Ser208fs)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56290	NM_001042432.2(CLN3):c.883G>T (p.Glu295Ter)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56292	NM_001042432.2(CLN3):c.944dup (p.His315fs)	CLN3	Pathogenic	criteria provided, multiple submitters, no conflicts
56293	NM_001042432.2(CLN3):c.954_962+18del	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56296	NM_001042432.2(CLN3):c.988G>T (p.Val330Phe)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
CLN3	Orphanet:699780	Juvenile CLN3 disease
CLN3	Orphanet:699796	Protracted juvenile CLN3 disease
ACD	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
ACD	Orphanet:397692	Hereditary isolated aplastic anemia
ACD	Orphanet:618	Familial melanoma

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPP1	HGNC:2073	ENSG00000166340	O14773	Tripeptidyl-peptidase 1	clinvar
CLN3	HGNC:2074	ENSG00000188603	Q13286	Battenin	clinvar
ACD	HGNC:25070	ENSG00000102977	Q96AP0	Adrenocortical dysplasia protein homolog	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.
CLN3	Battenin	Mediates microtubule-dependent, anterograde transport connecting the Golgi network, endosomes, autophagosomes, lysosomes and plasma membrane, and participates in several cellular processes such as regulation of lysosomal pH, lysosome prote…
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: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Transporter	1	25.9×	0.114
Protease	1	12.2×	0.120
Other/Unknown	1	0.6×	0.914

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
CLN3	Transporter	yes		Battenin_disease_Cln3, Battenin_disease_Cln3_subgr, MFS_trans_sf
ACD	Other/Unknown	no		TPP1/Est3, ACD

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
pigmented layer of retina	1
retina	1
granulocyte	1
mucosa of transverse colon	1
placenta	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
CLN3	134	ubiquitous	marker	mucosa of transverse colon, placenta, granulocyte
ACD	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPP1	1,739
CLN3	1,613
ACD	1,044

Intra-cohort edges

A	B	Sources
CLN3	TPP1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACD	Q96AP0	19
TPP1	O14773	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLN3	Q13286	81.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 3 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
Depurination	1	543.8×	0.015	ACD
Glycosphingolipid transport	1	475.8×	0.015	CLN3
Depyrimidination	1	317.2×	0.015	ACD
Base-Excision Repair, AP Site Formation	1	292.8×	0.015	ACD
Telomere C-strand synthesis initiation	1	271.9×	0.015	ACD
Processive synthesis on the C-strand of the telomere	1	253.8×	0.015	ACD
Telomere C-strand (Lagging Strand) Synthesis	1	253.8×	0.015	ACD
Base Excision Repair	1	237.9×	0.015	ACD
Removal of the Flap Intermediate from the C-strand	1	211.5×	0.015	ACD
Extension of Telomeres	1	200.3×	0.015	ACD
Telomere Extension By Telomerase	1	152.3×	0.018	ACD
Polymerase switching on the C-strand of the telomere	1	141.0×	0.018	ACD
Telomere Maintenance	1	122.8×	0.019	ACD
Meiosis	1	95.2×	0.022	ACD
Packaging Of Telomere Ends	1	73.2×	0.022	ACD
XBP1(S) activates chaperone genes	1	71.8×	0.022	TPP1
Chromosome Maintenance	1	70.5×	0.022	ACD
Recognition and association of DNA glycosylase with site containing an affected purine	1	68.0×	0.022	ACD
Cleavage of the damaged purine	1	68.0×	0.022	ACD
Reproduction	1	63.4×	0.022	ACD
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	61.4×	0.022	ACD
Cleavage of the damaged pyrimidine	1	61.4×	0.022	ACD
Inhibition of DNA recombination at telomere	1	56.0×	0.023	ACD
DNA Damage/Telomere Stress Induced Senescence	1	54.4×	0.023	ACD
Meiotic synapsis	1	47.0×	0.025	ACD
Cellular Senescence	1	45.9×	0.025	ACD
DNA Repair	1	32.8×	0.034	ACD
Cellular responses to stress	1	12.3×	0.084	ACD
Cell Cycle	1	12.0×	0.084	ACD
Cellular responses to stimuli	1	10.5×	0.092	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 3 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	1021.3×	8e-05	TPP1, ACD
lysosomal protein catabolic process	2	702.2×	9e-05	TPP1, CLN3
neuromuscular process controlling balance	2	220.3×	6e-04	TPP1, CLN3
lysosome organization	2	204.3×	6e-04	TPP1, CLN3
obsolete phagosome-lysosome docking	1	5617.3×	0.002	CLN3
regulation of cellular response to osmotic stress	1	5617.3×	0.002	CLN3
regulation of arginine biosynthetic process	1	5617.3×	0.002	CLN3
segmentation	1	2808.7×	0.003	ACD
renal potassium excretion	1	2808.7×	0.003	CLN3
regulation of phagosome maturation	1	2808.7×	0.003	CLN3
regulation of autophagosome size	1	1872.4×	0.003	CLN3
glycolipid transport	1	1872.4×	0.003	CLN3
regulation of establishment of protein localization to telomere	1	1872.4×	0.003	ACD
regulation of modification of synaptic structure	1	1872.4×	0.003	CLN3
telomere assembly	1	1404.3×	0.003	ACD
positive regulation of caveolin-mediated endocytosis	1	1404.3×	0.003	CLN3
lysosomal lumen pH elevation	1	1123.5×	0.004	CLN3
positive regulation of pinocytosis	1	1123.5×	0.004	CLN3
positive regulation of Golgi to plasma membrane protein transport	1	936.2×	0.004	CLN3
plasma membrane raft organization	1	936.2×	0.004	CLN3
regulation of autophagosome maturation	1	936.2×	0.004	CLN3
intracellular water homeostasis	1	802.5×	0.004	CLN3
protection from non-homologous end joining at telomere	1	802.5×	0.004	ACD
establishment of protein localization to telomere	1	702.2×	0.004	ACD
glycerophospholipid biosynthetic process	1	624.1×	0.005	CLN3
ceramide transport	1	510.7×	0.005	CLN3
regulation of protein processing	1	510.7×	0.005	CLN3
Golgi to lysosome transport	1	510.7×	0.005	CLN3
blood vessel endothelial cell migration	1	468.1×	0.005	CLN3
L-arginine transmembrane transport	1	468.1×	0.005	CLN3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
CLN3	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: 3; 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	1	CLN3
E	Difficult family or no structure, no drug	1	ACD

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TPP1	1	—
CLN3	0	—
ACD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE1/PHASE2	6
PHASE1	4
PHASE2	2
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04637282	PHASE3	NOT_YET_RECRUITING	Safety, Tolerability, and Efficacy of PLX-200 in Patients With CLN3
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT03770572	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Gene Therapy for Children With CLN3 Batten Disease
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT01399047	PHASE2	COMPLETED	Cellcept for Treatment of Juvenile Neuronal Ceroid Lipofuscinosis
NCT01414985	PHASE1/PHASE2	COMPLETED	AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis
NCT01907087	PHASE1/PHASE2	COMPLETED	A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients With Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN2) Disease
NCT02485899	PHASE1/PHASE2	COMPLETED	An Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients With CLN2 Disease
NCT02678689	PHASE2	COMPLETED	A Safety, Tolerability, and Efficacy Study of BMN 190 in Pediatric Patients < 18 Years of Age With CLN2 Disease
NCT05174039	PHASE1/PHASE2	COMPLETED	An Open-label Safety, Pharmacokinetic, and Efficacy Study of Miglustat for the Treatment of Subjects With Batten Ceroid Lipofuscinosis, Neuronal 3 (CLN3) Disease
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT00151216	PHASE1	COMPLETED	Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis
NCT01161576	PHASE1	COMPLETED	Safety Study of a Gene Transfer Vector (Rh.10) for Children With Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT03285425	Not specified	ACTIVE_NOT_RECRUITING	Natural History of Neuronal Ceroid Lipofuscinosis, Batten’s CLN6 Diseae
NCT03307304	Not specified	RECRUITING	Investigations of Juvenile Neuronal Ceroid Lipofuscinosis
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03862274	Not specified	ENROLLING_BY_INVITATION	Examining Developmental Outcomes of Children Diagnosed With CLN2 Disease
NCT04273243	Not specified	ACTIVE_NOT_RECRUITING	Long-Term Follow Up of CLN6 Batten Disease Subjects Following Gene Transfer
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database
NCT06203106	Not specified	RECRUITING	NYSCF Scientific Discovery Biobank
NCT00151268	Not specified	COMPLETED	Genotype - Phenotype Correlations of LINCL
NCT01035424	Not specified	COMPLETED	Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis
NCT01698229	Not specified	TERMINATED	Collection of Cerebrospinal Fluid in Healthy Children
NCT04644549	Not specified	TERMINATED	Natural History Study of Batten Disease
NCT05642221	Not specified	COMPLETED	Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CERLIPONASE ALFA	4	2
BUSULFAN	4	1
CYCLOPHOSPHAMIDE ANHYDROUS	4	1
MIGLUSTAT	4	1