Infantile epileptic-dyskinetic encephalopathy

Summary

Infantile epileptic-dyskinetic encephalopathy (MONDO:0018226) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile epileptic-dyskinetic encephalopathy
Mondo ID	MONDO:0018226
MeSH	C567924
Orphanet	364063
UMLS	C4552072
MedGen	1637882
GARD	0017582
Is cancer (heuristic)	no

Data availability: 13 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › combined dystonia › infantile epileptic-dyskinetic encephalopathy

Related subtypes (9): myoclonus-dystonia syndrome, dystonia 12, X-linked dystonia-parkinsonism, dystonia 16, parkinsonism-dystonia, infantile, paroxysmal dystonia, ataxia - telangiectasia variant, combined cervical dystonia, dystonia-aphonia syndrome

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

13 retrieved; paginated sample, class counts are floors:

6 conflicting classifications of pathogenicity, 3 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
422220	NM_004341.5(CAD):c.5429G>A (p.Arg1810Gln)	CAD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4848445	NM_004341.5(CAD):c.3596del (p.Phe1199fs)	CAD	Pathogenic	criteria provided, single submitter
1359934	NM_033453.4(ITPA):c.270G>A (p.Trp90Ter)	ITPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2045104	NM_033453.4(ITPA):c.519del (p.Asn173fs)	ITPA	Pathogenic	criteria provided, multiple submitters, no conflicts
537000	NM_006772.3(SYNGAP1):c.3583-9G>A	SYNGAP1-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1722399	NM_004341.5(CAD):c.2378_2379del (p.Thr793fs)	CAD	Likely pathogenic	criteria provided, single submitter
4689095	NM_004341.5(CAD):c.5164C>T (p.Arg1722Trp)	CAD	Likely pathogenic	criteria provided, single submitter
1411932	NM_004341.5(CAD):c.5060A>G (p.His1687Arg)	CAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1489256	NM_004341.5(CAD):c.1576G>A (p.Gly526Arg)	CAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1515573	NM_004341.5(CAD):c.4424G>A (p.Arg1475Gln)	CAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2151926	NM_004341.5(CAD):c.5366G>A (p.Arg1789Gln)	CAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218090	NM_033453.4(ITPA):c.532C>T (p.Arg178Cys)	ITPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193225	NM_001161352.2(KCNMA1):c.36CGG[8] (p.Gly20dup)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 12 · 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
ARX	Strong	X-linked	developmental and epileptic encephalopathy, 1	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARX	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
ARX	Orphanet:2508	Corpus callosum agenesis-abnormal genitalia syndrome
ARX	Orphanet:3175	X-linked spasticity-intellectual disability-epilepsy syndrome
ARX	Orphanet:364063	Infantile epileptic-dyskinetic encephalopathy
ARX	Orphanet:452	X-linked lissencephaly with abnormal genitalia
ARX	Orphanet:697160	Infantile epileptic spasms syndrome
ARX	Orphanet:777	X-linked non-syndromic intellectual disability
ARX	Orphanet:94083	Partington syndrome
CAD	Orphanet:448010	CAD-CDG
ITPA	Orphanet:457375	ITPA-related lethal infantile neurological disorder with cataract and cardiac involvement
KCNMA1	Orphanet:664438	Gingival fibromatosis-aortic root dilatation-facial dysmorphism-intellectual disability syndrome
KCNMA1	Orphanet:79137	Generalized epilepsy-paroxysmal dyskinesia syndrome

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	gencc
CAD	HGNC:1424	ENSG00000084774	P27708	Multifunctional protein CAD	clinvar
SYNGAP1-AS1	HGNC:53831	ENSG00000274259		SYNGAP1 antisense RNA 1	clinvar
ITPA	HGNC:6176	ENSG00000125877	Q9BY32	Inosine triphosphate pyrophosphatase	clinvar
KCNMA1	HGNC:6284	ENSG00000156113	Q12791	Calcium-activated potassium channel subunit alpha-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARX	Homeobox protein ARX	Transcription factor.
CAD	Multifunctional protein CAD	Multifunctional protein that encodes the first 3 enzymatic activities of the de novo pyrimidine pathway: carbamoylphosphate synthetase (CPSase; EC 6.3.5.5), aspartate transcarbamylase (ATCase; EC 2.1.3.2) and dihydroorotase (DHOase; EC 3.5…
ITPA	Inosine triphosphate pyrophosphatase	Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2’-deoxy-N-6-hydroxylaminopurine triphosphate (dHAPTP) and xanthosine 5’-triphosphate (XTP) to the…
KCNMA1	Calcium-activated potassium channel subunit alpha-1	Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+).

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.6

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
Ion channel	1	22.3×	0.117
Enzyme (other)	2	4.8×	0.117
Transcription factor	1	1.6×	0.634
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
CAD	Enzyme (other)	yes	2.1.3.2	Asp_carbamoyltransf, Dihydroorotase_CS, CarbamoylP_synth_ssu_N
SYNGAP1-AS1	Other/Unknown	no
ITPA	Enzyme (other)	yes	3.6.1.66	RdgB/HAM1, ITPase, ITPase-like_fam
KCNMA1	Ion channel	yes		RCK_N, K_chnl_BK_asu, Ion_trans_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ovary	1
ovary	1
right ovary	1
body of uterus	1
right lobe of liver	1
stromal cell of endometrium	1
primordial germ cell in gonad	1
sural nerve	1
thymus	1
left lobe of thyroid gland	1
metanephros cortex	1
right lobe of thyroid gland	1
parotid gland	1
saphenous vein	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARX	162	broad	marker	left ovary, ovary, right ovary
CAD	223	ubiquitous	marker	body of uterus, stromal cell of endometrium, right lobe of liver
SYNGAP1-AS1	133	broad	yes	thymus, sural nerve, primordial germ cell in gonad
ITPA	274	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, metanephros cortex
KCNMA1	275	ubiquitous	marker	parotid gland, saphenous vein, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAD	3,613
ITPA	2,856
KCNMA1	2,606
ARX	758
SYNGAP1-AS1	0

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAD	P27708	55
KCNMA1	Q12791	36
ITPA	Q9BY32	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARX	Q96QS3	56.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 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
Pyrimidine biosynthesis	1	1268.9×	0.009	CAD
Acetylcholine inhibits contraction of outer hair cells	1	761.3×	0.009	KCNMA1
Nucleotide catabolism	1	423.0×	0.009	ITPA
Ca2+ activated K+ channels	1	380.7×	0.009	KCNMA1
Purine catabolism	1	346.1×	0.009	ITPA
Ribavirin ADME	1	346.1×	0.009	ITPA
Nitric oxide stimulates guanylate cyclase	1	271.9×	0.010	KCNMA1
cGMP effects	1	237.9×	0.010	KCNMA1
Sensory processing of sound	1	102.9×	0.019	KCNMA1
Metabolism of nucleotides	1	100.2×	0.019	ITPA
Platelet homeostasis	1	92.8×	0.019	KCNMA1
Drug ADME	1	76.1×	0.021	ITPA
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.021	KCNMA1
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.025	KCNMA1
Potassium Channels	1	44.8×	0.028	KCNMA1
Sensory Perception	1	31.7×	0.037	KCNMA1
Neuronal System	1	14.8×	0.074	KCNMA1
Hemostasis	1	12.0×	0.085	KCNMA1
Metabolism	1	3.9×	0.237	ITPA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ITP catabolic process	1	4213.0×	0.004	ITPA
deoxyribonucleoside triphosphate catabolic process	1	4213.0×	0.004	ITPA
embryonic olfactory bulb interneuron precursor migration	1	2106.5×	0.004	ARX
response to carbon monoxide	1	1404.3×	0.004	KCNMA1
‘de novo’ UMP biosynthetic process	1	1404.3×	0.004	CAD
micturition	1	1404.3×	0.004	KCNMA1
L-citrulline biosynthetic process	1	1053.2×	0.004	CAD
cerebral cortex tangential migration	1	1053.2×	0.004	ARX
smooth muscle contraction involved in micturition	1	1053.2×	0.004	KCNMA1
epithelial cell fate commitment	1	1053.2×	0.004	ARX
UDP biosynthetic process	1	842.6×	0.004	CAD
nucleoside triphosphate catabolic process	1	842.6×	0.004	ITPA
globus pallidus development	1	842.6×	0.004	ARX
lipid digestion	1	842.6×	0.004	ARX
negative regulation of cell volume	1	842.6×	0.004	KCNMA1
‘de novo’ pyrimidine nucleobase biosynthetic process	1	702.2×	0.004	CAD
cerebral cortex GABAergic interneuron migration	1	702.2×	0.004	ARX
response to caffeine	1	601.9×	0.005	CAD
UTP biosynthetic process	1	468.1×	0.006	CAD
response to amine	1	468.1×	0.006	CAD
response to cortisol	1	421.3×	0.006	CAD
response to osmotic stress	1	383.0×	0.006	KCNMA1
positive regulation of organ growth	1	351.1×	0.007	ARX
L-glutamine metabolic process	1	324.1×	0.007	CAD
cell proliferation in forebrain	1	324.1×	0.007	ARX
intracellular potassium ion homeostasis	1	247.8×	0.008	KCNMA1
regulation of epithelial cell proliferation	1	234.1×	0.008	ARX
neuron fate commitment	1	200.6×	0.009	ARX
organ growth	1	183.2×	0.010	ARX
animal organ regeneration	1	150.5×	0.012	CAD

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
KCNMA1	CANNABIDIOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNMA1	2	4
ARX	0	0
CAD	0	0
SYNGAP1-AS1	0	0
ITPA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABIDIOL	4	KCNMA1
FLINDOKALNER	3	KCNMA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KCNMA1	94	Binding:91, Functional:2, Toxicity:1
CAD	17	Binding:16, ADMET:1
ITPA	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAD	2.1.3.2, 3.5.2.3, 6.3.5.5	aspartate carbamoyltransferase, dihydroorotase, carbamoyl-phosphate synthase (glutamine-hydrolysing)
ITPA	3.6.1.66, 3.6.1.9	XTP/dITP diphosphatase, nucleotide diphosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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)
CANNABIDIOL	4	KCNMA1
FLINDOKALNER	3	KCNMA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNMA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CAD, ITPA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ARX, SYNGAP1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARX	0	—
CAD	17	—
SYNGAP1-AS1	0	—
ITPA	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.