Progressive myoclonic epilepsy type 8

Summary

Progressive myoclonic epilepsy type 8 (MONDO:0014545) is a disease caused by CERS1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CERS1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 301

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive myoclonic epilepsy type 8
Mondo ID	MONDO:0014545
OMIM	616230
Orphanet	424027
DOID	DOID:0111451
UMLS	C5190825
MedGen	1680582
GARD	0017706
Is cancer (heuristic)	no

Also known as: CERS1 progressive myoclonic epilepsy · epilepsy, progressive myoclonic, 8 · epilepsy, progressive myoclonic, type 8 · EPM8 · PME type 8 · progressive myoclonic epilepsy caused by mutation in CERS1 · progressive myoclonic epilepsy due to CERS1 deficiency · progressive myoclonus epilepsy type 8

Data availability: 301 ClinVar variants · 3 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 › disorder of phospholipids, sphingolipids and fatty acids biosynthesis › progressive myoclonic epilepsy type 8

Related subtypes (16): Sengers syndrome, Sjogren-Larsson syndrome, Barth syndrome, megaconial type congenital muscular dystrophy, hereditary spastic paraplegia 39, PHARC syndrome, congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, spinocerebellar ataxia type 38, progressive encephalopathy with leukodystrophy due to DECR deficiency, neutral lipid storage disease, fatty acid hydroxylase-associated neurodegeneration, hereditary sensory and autonomic neuropathy type 1, GM3 synthase deficiency, nephrotic syndrome 14, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

301 retrieved; paginated sample, class counts are floors:

157 likely benign, 130 uncertain significance, 7 benign, 4 conflicting classifications of pathogenicity, 2 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3776097	NM_021267.5(CERS1):c.269del (p.Cys90fs)	CERS1	Pathogenic	criteria provided, single submitter
183023	NM_021267.5(CERS1):c.549C>G (p.His183Gln)	GDF1	Pathogenic	no assertion criteria provided
1430134	NM_021267.5(CERS1):c.571G>A (p.Val191Ile)	CERS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3143151	NM_021267.5(CERS1):c.214G>A (p.Ala72Thr)	CERS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542128	NM_021267.5(CERS1):c.16C>A (p.Pro6Thr)	CERS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801420	NM_021267.5(CERS1):c.763C>T (p.Arg255Cys)	CERS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1443735	NC_000019.9:g.(?18893725)(19312528_?)del	ARMC6	Uncertain significance	criteria provided, single submitter
1000785	NM_021267.5(CERS1):c.87C>G (p.Ser29Arg)	CERS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1009837	NM_021267.5(CERS1):c.701G>T (p.Arg234Leu)	CERS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1017566	NM_021267.5(CERS1):c.818G>A (p.Arg273His)	CERS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1017659	NM_021267.5(CERS1):c.550G>A (p.Val184Met)	CERS1	Uncertain significance	criteria provided, single submitter
1017910	NM_021267.5(CERS1):c.18_29dup (p.Pro10_Thr11insAlaAlaGlyPro)	CERS1	Uncertain significance	criteria provided, single submitter
1018476	NM_021267.5(CERS1):c.608T>C (p.Ile203Thr)	CERS1	Uncertain significance	criteria provided, single submitter
1020431	NM_021267.5(CERS1):c.689G>C (p.Gly230Ala)	CERS1	Uncertain significance	criteria provided, single submitter
1022761	NM_021267.5(CERS1):c.89C>T (p.Ala30Val)	CERS1	Uncertain significance	criteria provided, single submitter
1023831	NC_000019.9:g.(?19004205)(19006901_?)dup	CERS1	Uncertain significance	criteria provided, single submitter
1024152	NM_021267.5(CERS1):c.738C>G (p.Ser246Arg)	CERS1	Uncertain significance	criteria provided, single submitter
1025547	NM_021267.5(CERS1):c.173C>T (p.Pro58Leu)	CERS1	Uncertain significance	criteria provided, single submitter
1026558	NM_021267.5(CERS1):c.688G>A (p.Gly230Ser)	CERS1	Uncertain significance	criteria provided, single submitter
1027071	NM_021267.5(CERS1):c.835C>G (p.Pro279Ala)	CERS1	Uncertain significance	criteria provided, single submitter
1036000	NM_021267.5(CERS1):c.962G>A (p.Arg321Gln)	CERS1	Uncertain significance	criteria provided, single submitter
1036463	NM_021267.5(CERS1):c.821C>T (p.Thr274Met)	CERS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1038481	NM_021267.5(CERS1):c.610C>G (p.Leu204Val)	CERS1	Uncertain significance	criteria provided, single submitter
1040067	NM_021267.5(CERS1):c.74G>A (p.Arg25His)	CERS1	Uncertain significance	criteria provided, single submitter
1046336	NM_021267.5(CERS1):c.709G>A (p.Ala237Thr)	CERS1	Uncertain significance	criteria provided, single submitter
1051292	NM_021267.5(CERS1):c.102_103insTCG (p.Ala34_Arg35insSer)	CERS1	Uncertain significance	criteria provided, single submitter
1053870	NM_021267.5(CERS1):c.71_72delinsCC (p.Gln24Pro)	CERS1	Uncertain significance	criteria provided, single submitter
1061005	NM_021267.5(CERS1):c.511A>G (p.Thr171Ala)	CERS1	Uncertain significance	criteria provided, single submitter
1348675	NM_021267.5(CERS1):c.470G>A (p.Ser157Asn)	CERS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1353008	NM_021267.5(CERS1):c.46A>G (p.Met16Val)	CERS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 4 · 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
CERS1	Strong	Autosomal recessive	progressive myoclonic epilepsy type 8	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CERS1	Orphanet:424027	Progressive myoclonic epilepsy type 8
GDF1	Orphanet:216718	Isolated congenitally uncorrected transposition of the great arteries
GDF1	Orphanet:3303	Tetralogy of Fallot
GDF1	Orphanet:97548	Right isomerism

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
CERS1	HGNC:14253	ENSG00000223802	P27544	Ceramide synthase 1	gencc,clinvar
ARMC6	HGNC:25049	ENSG00000105676	Q6NXE6	Armadillo repeat-containing protein 6	clinvar
GDF1	HGNC:4214	ENSG00000130283	P27539	Embryonic growth/differentiation factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CERS1	Ceramide synthase 1	Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA).
GDF1	Embryonic growth/differentiation factor 1	May mediate cell differentiation events during embryonic development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CERS1	Enzyme (other)	yes	2.3.1.299	TLC-dom, Lag1/Lac1-like
ARMC6	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
GDF1	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_CS

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
right frontal lobe	1
spinal cord	1
cortical plate	1
primordial germ cell in gonad	1
right lobe of liver	1
primary visual cortex	1
superior frontal gyrus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CERS1	177	broad	yes	C1 segment of cervical spinal cord, right frontal lobe, spinal cord
ARMC6	259	ubiquitous	marker	right lobe of liver, cortical plate, primordial germ cell in gonad
GDF1	34	ubiquitous	yes	primary visual cortex, sural nerve, superior frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDF1	1,066
ARMC6	1,001
CERS1	76

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARMC6	Q6NXE6	91.10
CERS1	P27544	88.95
GDF1	P27539	74.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Signaling by NODAL	1	248.3×	0.007	GDF1
Sphingolipid de novo biosynthesis	1	142.8×	0.007	CERS1

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
cellular response to dithiothreitol	1	5617.3×	0.001	CERS1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1	5617.3×	0.001	GDF1
cellular response to mycotoxin	1	2808.7×	0.002	CERS1
cellular response to UV-A	1	468.1×	0.006	CERS1
negative regulation of D-glucose import across plasma membrane	1	401.2×	0.006	CERS1
negative regulation of cardiac muscle hypertrophy	1	374.5×	0.006	CERS1
positive regulation of mitophagy	1	374.5×	0.006	CERS1
endoderm development	1	208.1×	0.010	GDF1
mesoderm development	1	175.5×	0.010	GDF1
ceramide biosynthetic process	1	140.4×	0.011	CERS1
sphingolipid biosynthetic process	1	119.5×	0.012	CERS1
cellular response to xenobiotic stimulus	1	80.2×	0.015	CERS1
hematopoietic progenitor cell differentiation	1	79.1×	0.015	ARMC6
BMP signaling pathway	1	66.9×	0.017	GDF1
brain development	1	26.5×	0.040	CERS1
in utero embryonic development	1	24.0×	0.041	GDF1

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
CERS1	0	0
ARMC6	0	0
GDF1	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
CERS1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CERS1	2.3.1.299	sphingoid base N-stearoyltransferase

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	0
D	Druggable family + AlphaFold only, no drug	1	CERS1
E	Difficult family or no structure, no drug	2	ARMC6, GDF1

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)
CERS1	2	—
ARMC6	0	—
GDF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.