Neuronal ceroid lipofuscinosis 1

Summary

Neuronal ceroid lipofuscinosis 1 (MONDO:0009744) is a disease caused by PPT1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PPT1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 711
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronal ceroid lipofuscinosis 1
Mondo ID	MONDO:0009744
OMIM	214200, 256730
Orphanet	228329
DOID	DOID:0110721
NCIT	C85861
SNOMED CT	720830009
UMLS	C1850451
MedGen	340540
GARD	0001219
Is cancer (heuristic)	no

Also known as: adult CLN (type of CLN1) · ceroid lipofuscinosis neuronal 1 · ceroid lipofuscinosis, neuronal, 1 · ceroid lipofuscinosis, neuronal, 1, variable Age at onset · ceroid lipofuscinosis, neuronal, type 1 · ceroid storage disease · classic late infantile CLN (type of CLN1) · CLN1 · CLN1 disease · CLN1 variable age at onset · congenital neuronal ceroid lipofuscinosis · infantile CLN (type of CLN1) · infantile neuronal ceroid lipofuscinosis · juvenile CLN (type of CLN1) · neuronal ceroid lipofuscinosis 1 · neuronal ceroid lipofuscinosis caused by mutation in PPT1 · neuronal ceroid lipofuscinosis type 1 · neuronal ceroid lipofuscinosis, infantile · PPT1 neuronal ceroid lipofuscinosis · Santavuori disease (+1 more)

Data availability: 711 ClinVar variants · 6 GenCC gene-disease records · 16 cell lines.

Disease family

An umbrella term covering 4 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 1

Related subtypes (13): neuronal ceroid lipofuscinosis 3, ceroid lipofuscinosis, neuronal, 6B (Kufs type), neuronal ceroid lipofuscinosis 2, 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 (4): infantile neuronal ceroid lipofuscinosis 1, late infantile neuronal ceroid lipofuscinosis 1, juvenile neuronal ceroid lipofuscinosis 1, adult neuronal ceroid lipofuscinosis 1

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:

242 likely benign, 160 uncertain significance, 70 likely pathogenic, 57 pathogenic, 24 conflicting classifications of pathogenicity, 20 benign, 18 pathogenic/likely pathogenic, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3707169	NM_000310.4(PPT1):c.124+1G>T	LOC129930245	Pathogenic	criteria provided, single submitter
1067368	NM_000310.4(PPT1):c.628-2A>G	PPT1	Pathogenic	criteria provided, single submitter
1069555	NM_000310.4(PPT1):c.712_713del (p.Pro238fs)	PPT1	Pathogenic	criteria provided, single submitter
1070722	NC_000001.10:g.(?_40557947)_40561572del	PPT1	Pathogenic	criteria provided, single submitter
1071260	NM_000310.4(PPT1):c.614_620del (p.Ile205fs)	PPT1	Pathogenic	criteria provided, single submitter
1072746	NM_000310.4(PPT1):c.541G>C (p.Val181Leu)	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073044	NM_000310.4(PPT1):c.263del (p.Val88fs)	PPT1	Pathogenic	criteria provided, single submitter
1074230	NM_000310.4(PPT1):c.51G>A (p.Trp17Ter)	PPT1	Pathogenic	criteria provided, single submitter
1076529	NM_000310.4(PPT1):c.343_344dup (p.Gln116fs)	PPT1	Pathogenic	criteria provided, single submitter
1385000	NM_000310.4(PPT1):c.728G>A (p.Trp243Ter)	PPT1	Pathogenic	criteria provided, single submitter
1388947	NM_000310.4(PPT1):c.741C>A (p.Tyr247Ter)	PPT1	Pathogenic	criteria provided, single submitter
1389507	NM_000310.4(PPT1):c.2T>A (p.Met1Lys)	PPT1	Pathogenic	criteria provided, single submitter
1454858	NC_000001.10:g.(?40558060)(40561460_?)del	PPT1	Pathogenic	criteria provided, single submitter
1455107	NM_000310.4(PPT1):c.29_41del (p.Leu10fs)	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188857	NM_000310.4(PPT1):c.541G>A (p.Val181Met)	PPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
199010	NM_000310.4(PPT1):c.810del (p.Gly270_Leu271insTer)	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2011017	NM_000310.4(PPT1):c.722C>A (p.Ser241Ter)	PPT1	Pathogenic	criteria provided, single submitter
2022496	NM_000310.4(PPT1):c.775C>T (p.Gln259Ter)	PPT1	Pathogenic	criteria provided, single submitter
2027871	NM_000310.4(PPT1):c.112del (p.Trp38fs)	PPT1	Pathogenic	criteria provided, single submitter
2035352	NM_000310.4(PPT1):c.1A>C (p.Met1Leu)	PPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2035598	NM_000310.4(PPT1):c.21_25dup (p.Leu9fs)	PPT1	Pathogenic	criteria provided, single submitter
206642	NM_000310.4(PPT1):c.234+1G>A	PPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
206645	NM_000310.4(PPT1):c.424C>T (p.Gln142Ter)	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206651	NM_000310.4(PPT1):c.2T>C (p.Met1Thr)	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2110798	NM_000310.4(PPT1):c.440_441del (p.Phe147fs)	PPT1	Pathogenic	criteria provided, single submitter
2132906	NM_000310.4(PPT1):c.72_73delinsTT (p.Gln25Ter)	PPT1	Pathogenic	criteria provided, single submitter
236407	NM_000310.4(PPT1):c.713C>T (p.Pro238Leu)	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236410	NM_000310.4(PPT1):c.532del (p.Glu178fs)	PPT1	Pathogenic	criteria provided, single submitter
237631	NM_000310.4(PPT1):c.798+1G>T	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422850	NC_000001.10:g.(?40542494)(40562910_?)del	PPT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
PPT1	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PPT1	Orphanet:699718	Infantile CLN1 disease
PPT1	Orphanet:699734	Late infantile CLN1 disease
PPT1	Orphanet:699739	Juvenile CLN1 disease
PPT1	Orphanet:699745	Adult CLN1 disease
CLN8	Orphanet:1947	Northern epilepsy
CLN8	Orphanet:700484	Late infantile CLN8 disease

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
PPT1	HGNC:9325	ENSG00000131238	P50897	Palmitoyl-protein thioesterase 1	gencc,clinvar
CLN8	HGNC:2079	ENSG00000182372	Q9UBY8	Protein CLN8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPT1	Palmitoyl-protein thioesterase 1	Has thioesterase activity against fatty acid thioesters with 14 -18 carbons, including palmitoyl-CoA, S-palmitoyl-N-acetylcysteamine, and palmitoylated proteins.
CLN8	Protein CLN8	Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPT1	Enzyme (other)	yes	3.1.2.2	Palm_thioest, AB_hydrolase_fold
CLN8	Other/Unknown	no		TLC-dom, TLCD

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
leukocyte	1
monocyte	1
mononuclear cell	1
C1 segment of cervical spinal cord	1
corpus callosum	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPT1	294	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
CLN8	134	ubiquitous	marker	corpus callosum, C1 segment of cervical spinal cord, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPT1	2,444
CLN8	1,122

Intra-cohort edges

A	B	Sources
CLN8	PPT1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPT1	P50897	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLN8	Q9UBY8	90.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Fatty acyl-CoA biosynthesis	1	439.2×	0.002	PPT1

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
associative learning	2	481.5×	2e-04	PPT1, CLN8
protein catabolic process	2	237.3×	4e-04	PPT1, CLN8
negative regulation of neuron apoptotic process	2	110.9×	0.001	PPT1, CLN8
visual perception	2	79.5×	0.002	PPT1, CLN8
glutamate reuptake	1	4213.0×	0.002	CLN8
retinal rod cell apoptotic process	1	4213.0×	0.002	CLN8
somatic motor neuron differentiation	1	2808.7×	0.002	CLN8
pinocytosis	1	2106.5×	0.002	PPT1
membrane raft organization	1	1685.2×	0.002	PPT1
negative regulation of toll-like receptor 9 signaling pathway	1	1685.2×	0.002	PPT1
positive regulation of pinocytosis	1	1685.2×	0.002	PPT1
protein depalmitoylation	1	1404.3×	0.002	PPT1
regulation of synapse structure or activity	1	1404.3×	0.002	PPT1
musculoskeletal movement	1	1404.3×	0.002	CLN8
nervous system development	2	45.9×	0.002	PPT1, CLN8
mitochondrial membrane organization	1	1203.7×	0.002	CLN8
fatty-acyl-CoA biosynthetic process	1	936.2×	0.003	PPT1
neurofilament cytoskeleton organization	1	842.6×	0.003	CLN8
grooming behavior	1	561.7×	0.004	PPT1
sphingolipid catabolic process	1	561.7×	0.004	PPT1
neuromuscular process controlling posture	1	526.6×	0.004	CLN8
lipid biosynthetic process	1	495.6×	0.004	CLN8
ceramide metabolic process	1	401.2×	0.005	CLN8
positive regulation of receptor-mediated endocytosis	1	401.2×	0.005	PPT1
regulation of cell size	1	383.0×	0.005	CLN8
neurotransmitter secretion	1	351.1×	0.005	PPT1
lysosomal lumen acidification	1	337.0×	0.005	PPT1
negative regulation of proteolysis	1	337.0×	0.005	CLN8
adult walking behavior	1	247.8×	0.007	CLN8
ceramide biosynthetic process	1	210.7×	0.008	CLN8

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
PPT1	0	0
CLN8	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
PPT1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPT1	3.1.2.2, 3.1.2.22	palmitoyl-CoA hydrolase, palmitoyl[protein] hydrolase

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	PPT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLN8

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)
PPT1	5	—
CLN8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database