Familial infantile myoclonic epilepsy

Summary

Familial infantile myoclonic epilepsy (MONDO:0011506) is a disease caused by TBC1D24 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TBC1D24 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 211
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002123	Generalized myoclonic seizure	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0006891	Thick cerebral cortex	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0011171	Simple febrile seizures	Frequent (30-79%)
HP:0011197	EEG with focal spike waves	Frequent (30-79%)
HP:0025190	Bilateral tonic-clonic seizure with generalized onset	Frequent (30-79%)
HP:0025373	Interictal EEG abnormality	Frequent (30-79%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0006889	Intellectual disability, borderline	Occasional (5-29%)
HP:0025100	Abnormal hippocampus morphology	Occasional (5-29%)
HP:0032388	Periventricular nodular heterotopia	Occasional (5-29%)
HP:0045084	Limb myoclonus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial infantile myoclonic epilepsy
Mondo ID	MONDO:0011506
OMIM	605021
Orphanet	352582
UMLS	C0917800
MedGen	181488
GARD	0017521
Is cancer (heuristic)	no

Also known as: familial infantile myoclonus epilepsy · FIME · myoclonic epilepsy, familial infantile · myoclonic epilepsy, infantile, familial

Data availability: 211 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › familial infantile myoclonic epilepsy

Related subtypes (17): Mowat-Wilson syndrome, developmental and epileptic encephalopathy, 2, severe neonatal-onset encephalopathy with microcephaly, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, polyhydramnios, megalencephaly, and symptomatic epilepsy, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 23, spastic paraplegia-severe developmental delay-epilepsy syndrome, X-linked intellectual disability-epilepsy syndrome, focal epilepsy-intellectual disability-cerebro-cerebellar malformation, infantile-onset mesial temporal lobe epilepsy with severe cognitive regression, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, developmental and epileptic encephalopathy, 73, neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

211 retrieved; paginated sample, class counts are floors:

123 uncertain significance, 27 conflicting classifications of pathogenicity, 25 benign, 13 benign/likely benign, 12 likely benign, 7 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
424742	NM_020705.2(TBC1D24):c.[338C>A];[476T>C]		Pathogenic	no assertion criteria provided
1071941	NM_001199107.2(TBC1D24):c.642_793del (p.Trp215fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
1456664	NM_001199107.2(TBC1D24):c.752del (p.Phe251fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
207499	NM_001199107.2(TBC1D24):c.457G>A (p.Glu153Lys)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
421795	NM_001199107.2(TBC1D24):c.1360_1363dup (p.Pro455fs)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
474302	NM_001199107.2(TBC1D24):c.116C>T (p.Ala39Val)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
48	NM_001199107.2(TBC1D24):c.439G>C (p.Asp147His)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
50	NM_001199107.2(TBC1D24):c.751T>C (p.Phe251Leu)	TBC1D24	Pathogenic	no assertion criteria provided
523796	NM_001199107.2(TBC1D24):c.619C>T (p.Gln207Ter)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
424803	NM_020705.2(TBC1D24):c.[1218G>C];[1270T>C]		Likely pathogenic	criteria provided, single submitter
436948	NM_001199107.2(TBC1D24):c.866C>T (p.Ala289Val)	TBC1D24	Likely pathogenic	criteria provided, multiple submitters, no conflicts
130540	NM_001199107.2(TBC1D24):c.641G>A (p.Arg214His)	CCNF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884387	NM_001199107.2(TBC1D24):c.-135G>A	LOC130058245	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130541	NM_001199107.2(TBC1D24):c.1015A>G (p.Asn339Asp)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139392	NM_001199107.2(TBC1D24):c.-7C>T	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139399	NM_001199107.2(TBC1D24):c.1143-15G>A	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195364	NM_001199107.2(TBC1D24):c.169C>T (p.Arg57Cys)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197189	NM_001199107.2(TBC1D24):c.1125C>T (p.His375=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
207487	NM_001199107.2(TBC1D24):c.702G>A (p.Val234=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
207488	NM_001199107.2(TBC1D24):c.951C>T (p.Thr317=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
207518	NM_001199107.2(TBC1D24):c.179G>A (p.Arg60Gln)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208413	NM_001199107.2(TBC1D24):c.1327G>A (p.Glu443Lys)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212371	NM_001199107.2(TBC1D24):c.1026G>A (p.Ser342=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
227980	NM_001199107.2(TBC1D24):c.1570C>T (p.Arg524Trp)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
227985	NM_001199107.2(TBC1D24):c.90T>C (p.Thr30=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318607	NM_001199107.2(TBC1D24):c.-99C>G	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318616	NM_001199107.2(TBC1D24):c.1038C>T (p.Ser346=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318618	NM_001199107.2(TBC1D24):c.1341C>T (p.Ile447=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318619	NM_001199107.2(TBC1D24):c.1425C>T (p.Pro475=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
378702	NM_001199107.2(TBC1D24):c.408C>T (p.Ala136=)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 11 · 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
TBC1D24	Definitive	Autosomal recessive	familial infantile myoclonic epilepsy	21
CPLX1	Supportive	Autosomal recessive	familial infantile myoclonic epilepsy	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBC1D24	Orphanet:163727	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
TBC1D24	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
TBC1D24	Orphanet:352582	Familial infantile myoclonic epilepsy
TBC1D24	Orphanet:352587	Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
TBC1D24	Orphanet:352596	Progressive myoclonic epilepsy with dystonia
TBC1D24	Orphanet:79500	DOORS syndrome
TBC1D24	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TBC1D24	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CPLX1	Orphanet:280	Wolf-Hirschhorn syndrome
CPLX1	Orphanet:352582	Familial infantile myoclonic epilepsy
CCNF	Orphanet:803	Amyotrophic lateral sclerosis

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
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	gencc,clinvar
CPLX1	HGNC:2309	ENSG00000168993	O14810	Complexin-1	gencc
CCNF	HGNC:1591	ENSG00000162063	P41002	Cyclin-F	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
CPLX1	Complexin-1	Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles.
CCNF	Cyclin-F	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
CPLX1	Other/Unknown	no		Synaphin
CCNF	Other/Unknown	no		F-box_dom, Cyclin_C-dom, Cyclin_N

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
Brodmann (1909) area 23	1
middle temporal gyrus	1
parotid gland	1
lateral globus pallidus	1
lateral nuclear group of thalamus	1
postcentral gyrus	1
hair follicle	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus
CPLX1	187	broad	marker	lateral nuclear group of thalamus, lateral globus pallidus, postcentral gyrus
CCNF	213	ubiquitous	marker	type B pancreatic cell, olfactory bulb, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCNF	6,626
CPLX1	1,894
TBC1D24	1,016

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CPLX1	O14810	2
CCNF	P41002	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBC1D24	Q9ULP9	84.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Acetylcholine Neurotransmitter Release Cycle	1	223.9×	0.019	CPLX1
Serotonin Neurotransmitter Release Cycle	1	211.5×	0.019	CPLX1
Norepinephrine Neurotransmitter Release Cycle	1	211.5×	0.019	CPLX1
GABA synthesis, release, reuptake and degradation	1	211.5×	0.019	CPLX1
Dopamine Neurotransmitter Release Cycle	1	165.5×	0.019	CPLX1
Glutamate Neurotransmitter Release Cycle	1	152.3×	0.019	CPLX1
Rab regulation of trafficking	1	122.8×	0.020	TBC1D24
TBC/RABGAPs	1	86.5×	0.024	TBC1D24
Class I MHC mediated antigen processing & presentation	1	23.4×	0.080	CCNF
Neddylation	1	15.8×	0.105	CCNF
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.109	CCNF
Membrane Trafficking	1	12.4×	0.109	TBC1D24
Vesicle-mediated transport	1	11.6×	0.109	TBC1D24
Adaptive Immune System	1	9.9×	0.118	CCNF
Post-translational protein modification	1	6.4×	0.168	CCNF
Immune System	1	4.3×	0.223	CCNF
Metabolism of proteins	1	4.1×	0.223	CCNF

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
regulation of exocytic insertion of neurotransmitter receptor to postsynaptic membrane	1	5617.3×	0.004	CPLX1
re-entry into mitotic cell cycle	1	1872.4×	0.006	CCNF
negative regulation of cellular response to oxidative stress	1	1404.3×	0.006	TBC1D24
negative regulation of centrosome duplication	1	1123.5×	0.006	CCNF
regulation of synaptic vesicle fusion to presynaptic active zone membrane	1	702.2×	0.007	CPLX1
positive regulation of neuron migration	1	330.4×	0.012	TBC1D24
positive regulation of dendrite morphogenesis	1	295.6×	0.012	TBC1D24
synaptic vesicle exocytosis	1	255.3×	0.012	CPLX1
regulation of exocytosis	1	234.1×	0.012	CPLX1
positive regulation of excitatory postsynaptic potential	1	175.5×	0.012	TBC1D24
axon development	1	151.8×	0.012	TBC1D24
placenta development	1	147.8×	0.012	CCNF
insulin secretion	1	144.0×	0.012	CPLX1
synaptic vesicle endocytosis	1	144.0×	0.012	TBC1D24
dendrite development	1	130.6×	0.012	TBC1D24
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	124.8×	0.012	CCNF
G1/S transition of mitotic cell cycle	1	66.9×	0.022	CCNF
modulation of chemical synaptic transmission	1	61.1×	0.023	CPLX1
cellular response to oxidative stress	1	51.5×	0.025	TBC1D24
exocytosis	1	50.6×	0.025	CPLX1
neuron projection development	1	40.7×	0.029	TBC1D24
chemical synaptic transmission	1	25.8×	0.043	CPLX1
regulation of cell cycle	1	24.9×	0.043	CCNF
cell division	1	15.4×	0.066	CCNF
protein ubiquitination	1	13.8×	0.071	CCNF

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
TBC1D24	0	0
CPLX1	0	0
CCNF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	3	TBC1D24, CPLX1, CCNF

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)
TBC1D24	0	—
CPLX1	0	—
CCNF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.