ceroid lipofuscinosis, neuronal, 6A

Summary

ceroid lipofuscinosis, neuronal, 6A (MONDO:0011144) is a disease caused by CLN6 (GenCC Definitive), with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CLN6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 126
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		125	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	ceroid lipofuscinosis, neuronal, 6A
Mondo ID	MONDO:0011144
MeSH	C566627
OMIM	601780
Orphanet	228363
DOID	DOID:0110729
UMLS	C5551375
MedGen	1790423
GARD	0001224
Is cancer (heuristic)	no

Also known as: ceroid lipofuscinosis, neuronal, 6 · ceroid lipofuscinosis, neuronal, type 6 · CLN6 · CLN6 disease, adult Kufs type A (subtype) · CLN6 disease, late infantile (subtype) · CLN6 late infantile neuronal ceroid lipofuscinosis · CLN6A · late infantile neuronal ceroid lipofuscinosis caused by mutation in CLN6 · neuronal ceroid lipofuscinosis type 6 · neuronal ceroid lipofuscinosis, Gypsy/Indian early juvenile variant · neuronal ceroid lipofuscinosis, late infantile, variant · vLINCL

Data availability: 126 ClinVar variants · 6 GenCC gene-disease records.

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 › lysosomal storage disease › late infantile neuronal ceroid lipofuscinosis › ceroid lipofuscinosis, neuronal, 6A

Related subtypes (2): neuronal ceroid lipofuscinosis 5, neuronal ceroid lipofuscinosis 7

Subtypes (2): late infantile neuronal ceroid lipofuscinosis 6, juvenile neuronal ceroid lipofuscinosis 6

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

126 retrieved; paginated sample, class counts are floors:

32 likely pathogenic, 27 conflicting classifications of pathogenicity, 26 uncertain significance, 19 pathogenic/likely pathogenic, 18 pathogenic, 2 benign/likely benign, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424727	NM_017882.2(CLN6):c.[460_462delATC];[829_837delGTCGCCTGG]		Pathogenic	no assertion criteria provided
1017289	NM_017882.3(CLN6):c.3G>A (p.Met1Ile)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072427	NM_017882.3(CLN6):c.768C>G (p.Asp256Glu)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072428	NM_017882.3(CLN6):c.712_713delinsAC (p.Phe238Thr)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1180629	NM_017882.3(CLN6):c.396dup (p.Val133fs)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
1184729	NM_017882.3(CLN6):c.218_220dup (p.Trp73dup)	CLN6	Pathogenic	no assertion criteria provided
1363826	NM_017882.3(CLN6):c.397_398del (p.Val133fs)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449558	NM_017882.3(CLN6):c.358_366del (p.Phe120_Met122del)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1990218	NM_017882.3(CLN6):c.827G>A (p.Trp276Ter)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205177	NM_017882.3(CLN6):c.767A>G (p.Asp256Gly)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2101649	NM_017882.3(CLN6):c.180_181del (p.Phe60fs)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2583179	NM_017882.3(CLN6):c.195dup (p.Met66fs)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627623	NM_017882.3(CLN6):c.278C>A (p.Thr93Lys)	CLN6	Pathogenic	criteria provided, single submitter
2911779	NM_017882.3(CLN6):c.168G>A (p.Trp56Ter)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30600	NM_017882.3(CLN6):c.308G>A (p.Arg103Gln)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233661	NM_017882.3(CLN6):c.829_836delinsCCT (p.Val277fs)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
3577615	NM_017882.3(CLN6):c.516T>A (p.Tyr172Ter)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4077	NM_017882.3(CLN6):c.214G>T (p.Glu72Ter)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
4078	NM_017882.3(CLN6):c.511TAT[1] (p.Tyr172del)	CLN6	Pathogenic	no assertion criteria provided
4080	NM_017882.3(CLN6):c.7del (p.Ala3fs)	CLN6	Pathogenic	no assertion criteria provided
4081	NM_017882.3(CLN6):c.316dup (p.Arg106fs)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
4082	NM_017882.3(CLN6):c.395_396del (p.Ser132fs)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
4083	NC_000015.9:g.68504037_68504039delGAT	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4084	NM_017882.3(CLN6):c.663C>G (p.Tyr221Ter)	CLN6	Pathogenic	no assertion criteria provided
4086	NM_017882.3(CLN6):c.268_271dup (p.Val91fs)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
424086	NM_017882.3(CLN6):c.84-1G>A	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431958	NM_017882.3(CLN6):c.722T>C (p.Met241Thr)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522639	NM_017882.3(CLN6):c.476C>T (p.Pro159Leu)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550973	NM_017882.3(CLN6):c.896C>T (p.Pro299Leu)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
551500	NM_017882.3(CLN6):c.543G>A (p.Trp181Ter)	CLN6	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
CLN6	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLN6	Orphanet:700467	Late infantile CLN6 disease
CLN6	Orphanet:700472	Juvenile CLN6 disease
CLN6	Orphanet:700477	Adult CLN6 disease
SMPD1	Orphanet:77292	Infantile neurovisceral acid sphingomyelinase deficiency
SMPD1	Orphanet:77293	Chronic visceral acid sphingomyelinase deficiency

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
CLN6	HGNC:2077	ENSG00000128973	Q9NWW5	Ceroid-lipofuscinosis neuronal protein 6	gencc,clinvar
SMPD1	HGNC:11120	ENSG00000166311	P17405	Sphingomyelin phosphodiesterase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMPD1	Sphingomyelin phosphodiesterase	Converts sphingomyelin to ceramide.

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)
CLN6	Other/Unknown	no		CLN6
SMPD1	Enzyme (other)	yes	3.1.4.12	Calcineurin-like_PHP, SaposinB_dom, Saposin-like

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
bone marrow	1
leukocyte	1
monocyte	1
islet of Langerhans	1
stromal cell of endometrium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLN6	139	ubiquitous	marker	monocyte, leukocyte, bone marrow
SMPD1	262	ubiquitous	marker	type B pancreatic cell, stromal cell of endometrium, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMPD1	1,729
CLN6	1,107

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMPD1	P17405	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLN6	Q9NWW5	85.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Glycosphingolipid metabolism	1	300.5×	0.009	SMPD1
Glycosphingolipid catabolism	1	292.8×	0.009	SMPD1
Regulation of clotting cascade	1	233.1×	0.009	SMPD1
Sphingolipid metabolism	1	167.9×	0.009	SMPD1
Metabolism of lipids	1	31.6×	0.038	SMPD1
Metabolism	1	11.6×	0.086	SMPD1

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
cholesterol metabolic process	2	195.9×	8e-04	CLN6, SMPD1
termination of signal transduction	1	2808.7×	0.004	SMPD1
ganglioside metabolic process	1	2106.5×	0.004	CLN6
sphingomyelin metabolic process	1	1685.2×	0.004	SMPD1
sphingomyelin catabolic process	1	1685.2×	0.004	SMPD1
glycosaminoglycan metabolic process	1	1203.7×	0.004	CLN6
locomotion involved in locomotory behavior	1	1203.7×	0.004	CLN6
response to type I interferon	1	936.2×	0.004	SMPD1
glycosphingolipid catabolic process	1	766.0×	0.005	SMPD1
positive regulation of viral entry into host cell	1	601.9×	0.005	SMPD1
positive regulation of endocytosis	1	401.2×	0.007	SMPD1
positive regulation of proteolysis	1	401.2×	0.007	CLN6
lysosomal lumen acidification	1	337.0×	0.007	CLN6
response to tumor necrosis factor	1	312.1×	0.007	SMPD1
plasma membrane repair	1	290.6×	0.007	SMPD1
response to cocaine	1	290.6×	0.007	SMPD1
response to interleukin-1	1	255.3×	0.007	SMPD1
ceramide biosynthetic process	1	210.7×	0.008	SMPD1
response to ionizing radiation	1	205.5×	0.008	SMPD1
symbiont entry into host cell	1	200.6×	0.008	SMPD1
lysosome organization	1	153.2×	0.009	CLN6
negative regulation of MAPK cascade	1	150.5×	0.009	SMPD1
cellular response to UV	1	147.8×	0.009	SMPD1
protein catabolic process	1	118.7×	0.011	CLN6
wound healing	1	113.9×	0.011	SMPD1
cellular response to calcium ion	1	100.3×	0.012	SMPD1
response to virus	1	72.0×	0.016	SMPD1
visual perception	1	39.8×	0.029	CLN6
response to xenobiotic stimulus	1	34.5×	0.032	SMPD1
positive regulation of apoptotic process	1	28.4×	0.037	SMPD1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
SMPD1	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMPD1	3	4
CLN6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
FENDILINE	2	SMPD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SMPD1	42	Binding:40, Functional:2
CLN6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMPD1	3.1.4.12	sphingomyelin phosphodiesterase

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

3 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)
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
FENDILINE	2	SMPD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SMPD1
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	1	CLN6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLN6	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT03285425	Not specified	ACTIVE_NOT_RECRUITING	Natural History of Neuronal Ceroid Lipofuscinosis, Batten’s CLN6 Diseae
NCT04273243	Not specified	ACTIVE_NOT_RECRUITING	Long-Term Follow Up of CLN6 Batten Disease Subjects Following Gene Transfer