Neuronal ceroid lipofuscinosis 8 northern epilepsy variant

Summary

Neuronal ceroid lipofuscinosis 8 northern epilepsy variant (MONDO:0012391) is a disease caused by CLN8 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: CLN8 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 33
• Phenotypes (HPO): 40

Clinical features

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001272	Cerebellar atrophy	Very frequent (80-99%)
HP:0002540	Inability to walk	Very frequent (80-99%)
HP:0003204	Intracellular accumulation of autofluorescent lipopigment storage material	Very frequent (80-99%)
HP:0003657	Granular osmiophilic deposits (GROD) in cells	Very frequent (80-99%)
HP:0000529	Progressive visual loss	Frequent (30-79%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000550	Undetectable electroretinogram	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002333	Motor deterioration	Frequent (30-79%)
HP:0002371	Loss of speech	Frequent (30-79%)
HP:0002510	Spastic tetraplegia	Frequent (30-79%)
HP:0003205	Curvilinear intracellular accumulation of autofluorescent lipopigment storage material	Frequent (30-79%)
HP:0003208	Fingerprint intracellular accumulation of autofluorescent lipopigment storage material	Frequent (30-79%)
HP:0003698	Difficulty standing	Frequent (30-79%)
HP:0005268	Spontaneous abortion	Frequent (30-79%)
HP:0011198	EEG with generalized epileptiform discharges	Frequent (30-79%)
HP:0011203	EEG with abnormally slow frequencies	Frequent (30-79%)
HP:0030455	Abnormality of pattern visual evoked potentials	Frequent (30-79%)
HP:0033044	Motor regression	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0012690	T2 hypointense thalamus	Occasional (5-29%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronal ceroid lipofuscinosis 8 northern epilepsy variant
Mondo ID	MONDO:0012391
OMIM	610003
Orphanet	1947, 530298
DOID	DOID:0110724
ICD-10-CM	G40.3
UMLS	C1864923
MedGen	355328
GARD	0004010
Is cancer (heuristic)	no

Also known as: ceroid lipofuscinosis neuronal 8 · CLN8 · CLN8 disease, EPMR (subtype) · CLN8 disease, late infantile (subtype) · CLN8 disease, Northern epilepsy variant · early onset familial encephalopathy with neuroserpin inclusion bodies · epilepsy mental deterioration Finnish type · epilepsy, progressive, with mental retardation · EPMR · NCL, Northern epilepsy variant · neuronal ceroid lipofuscinosis 8 · neuronal ceroid lipofuscinosis, Northern epilepsy variant · Northern epilepsy · progressive epilepsy - intellectual disability, Finnish type · progressive epilepsy with intellectual disability, northern epilepsy · progressive epilepsy-intellectual disability syndrome, Finnish type · progressive myoclonic epilepsy with neuroserpin inclusion bodies

Data availability: 33 ClinVar variants · 2 GenCC gene-disease records.

Disease family

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 8 › neuronal ceroid lipofuscinosis 8 northern epilepsy variant

Related subtypes (1): late infantile neuronal ceroid lipofuscinosis 8

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

33 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 7 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 benign, 2 benign/likely benign, 2 pathogenic, 2 likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
205194	NM_018941.4(CLN8):c.499G>T (p.Glu167Ter)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2802	NM_018941.4(CLN8):c.70C>G (p.Arg24Gly)	CLN8	Pathogenic	criteria provided, multiple submitters, no conflicts
2804	NM_018941.4(CLN8):c.610C>T (p.Arg204Cys)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595450	NM_018941.4(CLN8):c.1del (p.Met1*)	CLN8	Pathogenic	criteria provided, single submitter
56710	NM_018941.4(CLN8):c.473A>G (p.Tyr158Cys)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
654163	NM_018941.4(CLN8):c.295C>T (p.Gln99Ter)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595452	NM_018941.4(CLN8):c.353dup (p.Asn118fs)	CLN8	Likely pathogenic	criteria provided, single submitter
3595453	NM_018941.4(CLN8):c.609C>A (p.Cys203Ter)	CLN8	Likely pathogenic	criteria provided, single submitter
100736	NM_018941.4(CLN8):c.792C>G (p.Asn264Lys)	CLN8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195345	NM_018941.4(CLN8):c.200C>T (p.Ala67Val)	CLN8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195348	NM_018941.4(CLN8):c.11C>T (p.Ala4Val)	CLN8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196493	NM_018941.4(CLN8):c.806A>T (p.Glu269Val)	CLN8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205196	NM_018941.4(CLN8):c.779C>T (p.Pro260Leu)	CLN8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205207	NM_018941.4(CLN8):c.374A>G (p.Asn125Ser)	CLN8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2161147	NM_018941.4(CLN8):c.782T>C (p.Val261Ala)	CLN8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333622	NM_018941.4(CLN8):c.570G>T (p.Trp190Cys)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1354506	NM_018941.4(CLN8):c.374A>T (p.Asn125Ile)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1436830	NM_018941.4(CLN8):c.844C>T (p.Arg282Trp)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
195346	NM_018941.4(CLN8):c.94T>G (p.Phe32Val)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
205191	NM_018941.4(CLN8):c.556G>A (p.Glu186Lys)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
205200	NM_018941.4(CLN8):c.17A>G (p.Asp6Gly)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
205202	NM_018941.4(CLN8):c.53A>T (p.Tyr18Phe)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
205203	NM_018941.4(CLN8):c.59C>G (p.Ser20Cys)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
451285	NM_018941.4(CLN8):c.619C>G (p.Leu207Val)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
527744	NM_018941.4(CLN8):c.697C>G (p.Leu233Val)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
56709	NM_018941.4(CLN8):c.46C>A (p.Leu16Met)	CLN8	Uncertain significance	criteria provided, multiple submitters, no conflicts
626088	NM_018941.4(CLN8):c.98T>C (p.Val33Ala)	CLN8	Uncertain significance	criteria provided, single submitter
1185277	NM_018941.4(CLN8):c.544-227A>G	CLN8	Benign	criteria provided, multiple submitters, no conflicts
136803	NM_018941.4(CLN8):c.777T>C (p.Asn259=)	CLN8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
136805	NM_018941.4(CLN8):c.-123-4T>C	CLN8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
CLN8	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis 8	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLN8	Orphanet:1947	Northern epilepsy
CLN8	Orphanet:700484	Late infantile CLN8 disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CLN8	HGNC:2079	ENSG00000182372	Q9UBY8	Protein CLN8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLN8	Protein CLN8	Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLN8	Other/Unknown	no		TLC-dom, TLCD

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
CLN8	134	ubiquitous	marker	corpus callosum, C1 segment of cervical spinal cord, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLN8	1,122

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLN8	Q9UBY8	90.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glutamate reuptake	1	8426.0×	0.002	CLN8
retinal rod cell apoptotic process	1	8426.0×	0.002	CLN8
somatic motor neuron differentiation	1	5617.3×	0.002	CLN8
musculoskeletal movement	1	2808.7×	0.002	CLN8
mitochondrial membrane organization	1	2407.4×	0.002	CLN8
neurofilament cytoskeleton organization	1	1685.2×	0.003	CLN8
neuromuscular process controlling posture	1	1053.2×	0.003	CLN8
lipid biosynthetic process	1	991.3×	0.003	CLN8
ceramide metabolic process	1	802.5×	0.004	CLN8
regulation of cell size	1	766.0×	0.004	CLN8
negative regulation of proteolysis	1	674.1×	0.004	CLN8
adult walking behavior	1	495.6×	0.004	CLN8
associative learning	1	481.5×	0.004	CLN8
ceramide biosynthetic process	1	421.3×	0.005	CLN8
photoreceptor cell maintenance	1	358.6×	0.005	CLN8
phospholipid metabolic process	1	343.9×	0.005	CLN8
lipid homeostasis	1	337.0×	0.005	CLN8
neuromuscular process controlling balance	1	330.4×	0.005	CLN8
lysosome organization	1	306.4×	0.005	CLN8
social behavior	1	271.8×	0.005	CLN8
lipid transport	1	263.3×	0.005	CLN8
retina development in camera-type eye	1	255.3×	0.005	CLN8
protein catabolic process	1	237.3×	0.005	CLN8
cholesterol metabolic process	1	195.9×	0.006	CLN8
negative regulation of neuron apoptotic process	1	110.9×	0.010	CLN8
visual perception	1	79.5×	0.013	CLN8
nervous system development	1	45.9×	0.022	CLN8

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLN8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLN8

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)
CLN8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.