Pyridoxine-dependent epilepsy

Summary

Pyridoxine-dependent epilepsy (MONDO:0009945) is a disease caused by ALDH7A1 (GenCC Definitive), with 8 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: ALDH7A1 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 1,012
• Phenotypes (HPO): 35
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.2	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.13	United Kingdom	Validated
Prevalence at birth	1-9 / 1 000 000	0.25	Netherlands	Validated
Prevalence at birth	1-9 / 100 000	5	Germany	Not yet validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Obligate (100%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0001557	Prenatal movement abnormality	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)
HP:0002643	Neonatal respiratory distress	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0010845	EEG with generalized slow activity	Frequent (30-79%)
HP:0010851	EEG with burst suppression	Frequent (30-79%)
HP:0011152	Early onset absence seizures	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0020217	Focal aware motor seizure	Frequent (30-79%)
HP:0025116	Fetal distress	Frequent (30-79%)
HP:0030917	Low APGAR score	Frequent (30-79%)
HP:0000273	Facial grimacing	Occasional (5-29%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000711	Restlessness	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002188	Delayed CNS myelination	Occasional (5-29%)
HP:0002280	Enlarged cisterna magna	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0010841	Multifocal epileptiform discharges	Occasional (5-29%)
HP:0011097	Epileptic spasm	Occasional (5-29%)
HP:0011166	Focal myoclonic seizure	Occasional (5-29%)
HP:0011198	EEG with generalized epileptiform discharges	Occasional (5-29%)
HP:0011199	EEG with generalized sharp slow waves	Occasional (5-29%)
HP:0012420	Meconium stained amniotic fluid	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0012704	Widened subarachnoid space	Occasional (5-29%)
HP:0012768	Neonatal asphyxia	Occasional (5-29%)
HP:0003128	Lactic acidosis	Very rare (<1-4%)
HP:0001943	Hypoglycemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyridoxine-dependent epilepsy
Mondo ID	MONDO:0009945
MeSH	C536254
Orphanet	3006
DOID	DOID:0080768
SNOMED CT	734434007
UMLS	C1849508
MedGen	340341
GARD	0009298
NORD	1639
Is cancer (heuristic)	no

Also known as: antiquitin deficiency · EPD · epilepsy, pyridoxine-dependent · pyridoxine dependency · pyridoxine-dependent epilepsy · vitamin B6-dependent seizures

Data availability: 1,012 ClinVar variants · 5 GenCC gene-disease records · 4 cell lines.

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 › inborn disorder of biogenic amine metabolism and transport › inborn disorder of pyridoxine metabolism › pyridoxine-dependent epilepsy

Related subtypes (1): pyridoxal phosphate-responsive seizures

Subtypes (2): epilepsy, early-onset, vitamin B6-dependent, pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

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

600 retrieved; paginated sample, class counts are floors:

287 likely benign, 137 uncertain significance, 64 pathogenic, 35 conflicting classifications of pathogenicity, 30 likely pathogenic, 20 pathogenic/likely pathogenic, 15 benign/likely benign, 11 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033773	NM_001182.5(ALDH7A1):c.1412_1415+9delinsGTTGGG	ALDH7A1	Pathogenic	criteria provided, single submitter
1067854	NM_001182.5(ALDH7A1):c.1192G>A (p.Gly398Arg)	ALDH7A1	Pathogenic	criteria provided, single submitter
1071019	NC_000005.9:g.(?125880657)(125930890_?)del	ALDH7A1	Pathogenic	criteria provided, single submitter
1072992	NM_001182.5(ALDH7A1):c.241C>T (p.Arg81Ter)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073579	NM_001182.5(ALDH7A1):c.859C>T (p.Gln287Ter)	ALDH7A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074016	NM_001182.5(ALDH7A1):c.834G>C (p.Val278=)	ALDH7A1	Pathogenic	criteria provided, single submitter
1074455	NM_001182.5(ALDH7A1):c.1061A>G (p.Tyr354Cys)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075197	NM_001182.5(ALDH7A1):c.538dup (p.Glu180fs)	ALDH7A1	Pathogenic	criteria provided, single submitter
1076094	NM_001182.5(ALDH7A1):c.130G>T (p.Glu44Ter)	ALDH7A1	Pathogenic	criteria provided, single submitter
1303050	NM_001182.5(ALDH7A1):c.950C>T (p.Ser317Leu)	ALDH7A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328029	NM_001182.5(ALDH7A1):c.1483G>A (p.Ala495Thr)	ALDH7A1	Pathogenic	criteria provided, single submitter
1341558	NM_001182.5(ALDH7A1):c.187G>T (p.Gly63Ter)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1341559	NM_001182.5(ALDH7A1):c.1411_1412insG (p.Leu471fs)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1355701	NM_001182.5(ALDH7A1):c.1088G>A (p.Trp363Ter)	ALDH7A1	Pathogenic	criteria provided, single submitter
1409272	NC_000005.9:g.(?125929344)(125930707_?)del	ALDH7A1	Pathogenic	criteria provided, single submitter
1451488	NM_001182.5(ALDH7A1):c.841C>T (p.Gln281Ter)	ALDH7A1	Pathogenic	criteria provided, single submitter
1456756	NM_001182.5(ALDH7A1):c.1477G>T (p.Gly493Ter)	ALDH7A1	Pathogenic	criteria provided, single submitter
1457545	NM_001182.5(ALDH7A1):c.1072C>T (p.Arg358Ter)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1499726	NM_001182.5(ALDH7A1):c.1318-1G>C	ALDH7A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685518	NM_001182.5(ALDH7A1):c.509C>T (p.Pro170Leu)	ALDH7A1	Pathogenic	criteria provided, single submitter
1696912	NM_001182.5(ALDH7A1):c.984del (p.Arg329fs)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1704270	NM_001182.5(ALDH7A1):c.1327G>T (p.Glu443Ter)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1705018	NM_001182.5(ALDH7A1):c.388_518-1428del	ALDH7A1	Pathogenic	no assertion criteria provided
1705019	Single allele	ALDH7A1	Pathogenic	no assertion criteria provided
1709791	NM_001182.5(ALDH7A1):c.500del (p.Pro167fs)	ALDH7A1	Pathogenic	criteria provided, single submitter
17994	NM_001182.5(ALDH7A1):c.1279G>C (p.Glu427Gln)	ALDH7A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17995	NM_001182.5(ALDH7A1):c.328C>T (p.Arg110Ter)	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17996	NM_001182.5(ALDH7A1):c.518-1G>C	ALDH7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17997	NM_001182.5(ALDH7A1):c.312+2T>A	ALDH7A1	Pathogenic	no assertion criteria provided
17998	NM_001182.5(ALDH7A1):c.596C>T (p.Ala199Val)	ALDH7A1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 27 · 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
ALDH7A1	Definitive	Autosomal dominant	pyridoxine-dependent epilepsy caused by ALDH7A1 mutant	7
PLPBP	Strong	Autosomal recessive	epilepsy, early-onset, vitamin B6-dependent	3
SLC13A5	Supportive	Autosomal recessive	pyridoxine-dependent epilepsy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH7A1	Orphanet:3006	Pyridoxine-dependent-developmental and epileptic encephalopathy
SLC13A5	Orphanet:1946	Amelocerebrohypohidrotic syndrome
SLC13A5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
PLPBP	Orphanet:3006	Pyridoxine-dependent-developmental and epileptic encephalopathy
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
GAD1	Orphanet:210141	Inherited congenital spastic tetraplegia
GRIN2A	Orphanet:163721	Rolandic epilepsy-speech dyspraxia syndrome
GRIN2A	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GRIN2A	Orphanet:289266	Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
GRIN2A	Orphanet:725	Developmental and epileptic encephalopathy with spike-wave activation in sleep
GRIN2A	Orphanet:98818	Landau-Kleffner syndrome
PNKP	Orphanet:101101	Charcot-Marie-Tooth disease type 2B2
PNKP	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
PNKP	Orphanet:459033	Ataxia-oculomotor apraxia type 4
POMT1	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMT1	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
POMT1	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
POMT1	Orphanet:588	Muscle-eye-brain disease
POMT1	Orphanet:86812	POMT1-related limb-girdle muscular dystrophy R11
POMT1	Orphanet:899	Walker-Warburg syndrome

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH7A1	HGNC:877	ENSG00000164904	P49419	Alpha-aminoadipic semialdehyde dehydrogenase	gencc,clinvar
SLC13A5	HGNC:23089	ENSG00000141485	Q86YT5	Na(+)/citrate cotransporter	gencc
PLPBP	HGNC:9457	ENSG00000147471	O94903	Pyridoxal phosphate homeostasis protein	gencc
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
GAD1	HGNC:4092	ENSG00000128683	Q99259	Glutamate decarboxylase 1	clinvar
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	clinvar
PNKP	HGNC:9154	ENSG00000039650	Q96T60	Bifunctional polynucleotide phosphatase/kinase	clinvar
POMT1	HGNC:9202	ENSG00000130714	Q9Y6A1	Protein O-mannosyl-transferase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH7A1	Alpha-aminoadipic semialdehyde dehydrogenase	Aldehyde dehydrogenase enzyme that mediates important protective effects.
SLC13A5	Na(+)/citrate cotransporter	High-affinity sodium/citrate cotransporter that mediates the entry of citrate into cells, which is a critical participant of biochemical pathways.
PLPBP	Pyridoxal phosphate homeostasis protein	Pyridoxal 5’-phosphate (PLP)-binding protein, which may be involved in intracellular homeostatic regulation of pyridoxal 5’-phosphate (PLP), the active form of vitamin B6.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
GAD1	Glutamate decarboxylase 1	Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5’-phosphate as cofactor.
GRIN2A	Glutamate receptor ionotropic, NMDA 2A	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
PNKP	Bifunctional polynucleotide phosphatase/kinase	Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways.
POMT1	Protein O-mannosyl-transferase 1	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.

Protein-family classification

Druggable: 5 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.62

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)	3	4.5×	0.094
Ion channel	1	13.9×	0.122
Phosphatase	1	10.5×	0.122
Other/Unknown	3	0.7×	0.919

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH7A1	Enzyme (other)	yes	1.2.1.3	Aldehyde_DH_dom, Ald_DH/histidinol_DH, Ald_DH_N
SLC13A5	Other/Unknown	no		SLC13A/DASS, Na/sul_symport_CS
PLPBP	Other/Unknown	no		Ala_racemase_N, PyrdxlP_homeostasis, PLP-binding_barrel
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
GAD1	Enzyme (other)	yes	4.1.1.15	PyrdxlP-dep_de-COase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
PNKP	Phosphatase	yes	2.7.1.78	HAD-SF_hydro_IIIA, PNKP, Polynucleotide_phosphatase
POMT1	Enzyme (other)	yes	2.4.1.109	ArnT-like_N, MIR_motif, PMT-like

Expression context

Cohort genes with no expression data: 0.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	3
middle temporal gyrus	3
right lobe of liver	2
endothelial cell	2
left ovary	1
ventricular zone	1
liver	1
parotid gland	1
cardia of stomach	1
pericardium	1
renal medulla	1
cerebellar vermis	1
granulocyte	1
right adrenal gland cortex	1
right uterine tube	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH7A1	255	ubiquitous	marker	right lobe of liver, ventricular zone, left ovary
SLC13A5	148	broad	yes	right lobe of liver, liver, parotid gland
PLPBP	292	ubiquitous	marker	cardia of stomach, pericardium, renal medulla
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
GAD1	199	broad	marker	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
PNKP	259	ubiquitous	marker	right uterine tube, granulocyte, right adrenal gland cortex
POMT1	264	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH7A1	4,544
GAD1	4,362
GRIN2A	3,146
SCN2A	2,810
PNKP	2,445
PLPBP	1,577
SLC13A5	1,574
POMT1	1,475

Intra-cohort edges

A	B	Sources
ALDH7A1	PLPBP	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIN2A	Q12879	37
ALDH7A1	P49419	20
SCN2A	Q99250	5
SLC13A5	Q86YT5	4
GAD1	Q99259	2
PNKP	Q96T60	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLPBP	O94903	89.49
POMT1	Q9Y6A1	88.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GABA synthesis	1	815.7×	0.014	GAD1
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	1	543.8×	0.014	POMT1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	1	543.8×	0.014	POMT1
MECP2 regulates transcription of genes involved in GABA signaling	1	543.8×	0.014	GAD1
SLC-mediated transport of organic anions	1	543.8×	0.014	SLC13A5
DAG1 core M1 glycosylations	1	407.9×	0.014	POMT1
Sodium-coupled sulphate, di- and tri-carboxylate transporters	1	326.3×	0.014	SLC13A5
DAG1 core M2 glycosylations	1	326.3×	0.014	POMT1
DAG1 core M3 glycosylations	1	271.9×	0.015	POMT1
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	233.1×	0.016	PNKP
Choline catabolism	1	203.9×	0.016	ALDH7A1
Lysine catabolism	1	163.1×	0.019	ALDH7A1
GABA synthesis, release, reuptake and degradation	1	90.6×	0.028	GAD1
MECP2 regulates neuronal receptors and channels	1	85.9×	0.028	GRIN2A
Unblocking of NMDA receptors, glutamate binding and activation	1	77.7×	0.028	GRIN2A
Synaptic adhesion-like molecules	1	77.7×	0.028	GRIN2A
Negative regulation of NMDA receptor-mediated neuronal transmission	1	77.7×	0.028	GRIN2A
Long-term potentiation	1	68.0×	0.030	GRIN2A
Interaction between L1 and Ankyrins	1	52.6×	0.035	SCN2A
Phase 0 - rapid depolarisation	1	49.4×	0.035	SCN2A
Sensory perception of taste	1	48.0×	0.035	SCN2A
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	48.0×	0.035	POMT1
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	39.8×	0.040	SCN2A
Assembly and cell surface presentation of NMDA receptors	1	36.2×	0.042	GRIN2A
Neurexins and neuroligins	1	28.1×	0.052	GRIN2A
R-HSA-425366	1	25.9×	0.054	SLC13A5
L1CAM interactions	1	17.2×	0.078	SCN2A
Cardiac conduction	1	15.5×	0.083	SCN2A
Sensory Perception	1	13.6×	0.091	SCN2A
Muscle contraction	1	11.0×	0.108	SCN2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
succinate transport	1	2106.5×	0.007	SLC13A5
L-lysine catabolic process	1	2106.5×	0.007	ALDH7A1
vitamin B6 metabolic process	1	2106.5×	0.007	PLPBP
negative regulation of endosome to plasma membrane protein transport	1	2106.5×	0.007	ALDH7A1
GABA shunt	1	1053.2×	0.007	GAD1
intrinsic apoptotic signaling pathway in response to osmotic stress	1	1053.2×	0.007	SCN2A
oxaloacetate transport	1	1053.2×	0.007	SLC13A5
fumarate transport	1	1053.2×	0.007	SLC13A5
obsolete glycine betaine biosynthetic process from choline	1	1053.2×	0.007	ALDH7A1
sodium ion transmembrane transport	2	50.8×	0.007	SCN2A, GRIN2A
memory	2	45.8×	0.007	SCN2A, GRIN2A
citrate transport	1	702.2×	0.008	SLC13A5
directional locomotion	1	702.2×	0.008	GRIN2A
protein localization to postsynaptic membrane	1	702.2×	0.008	GRIN2A
L-glutamate catabolic process	1	526.6×	0.009	GAD1
alpha-ketoglutarate transport	1	526.6×	0.009	SLC13A5
choline catabolic process	1	526.6×	0.009	ALDH7A1
negative regulation of Golgi to plasma membrane protein transport	1	351.1×	0.013	ALDH7A1
obsolete lysine catabolic process	1	300.9×	0.013	ALDH7A1
sleep	1	300.9×	0.013	GRIN2A
GABA biosynthetic process	1	263.3×	0.014	GAD1
regulation of monoatomic cation transmembrane transport	1	263.3×	0.014	GRIN2A
chemical synaptic transmission	2	19.3×	0.016	GAD1, GRIN2A
serotonin metabolic process	1	210.7×	0.016	GRIN2A
plasma membrane to endosome transport	1	191.5×	0.016	ALDH7A1
calcium ion transmembrane import into cytosol	1	191.5×	0.016	GRIN2A
aldehyde metabolic process	1	162.0×	0.017	ALDH7A1
ionotropic glutamate receptor signaling pathway	1	162.0×	0.017	GRIN2A
excitatory chemical synaptic transmission	1	162.0×	0.017	GRIN2A
response to radiation	1	150.5×	0.017	PNKP

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 7 of 8 evidence-associated genes (88%) 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
SCN2A	BEPRIDIL
GRIN2A	MEMANTINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
GRIN2A	37	4
PLPBP	1	2
ALDH7A1	0	0
SLC13A5	0	0
GAD1	0	0
PNKP	0	0
POMT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SLC13A5	14	Binding:11, Functional:3
PNKP	8	Binding:8
PLPBP	6	Binding:6
ALDH7A1	1	Binding:1
GAD1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH7A1	1.2.1.3, 1.2.1.31	aldehyde dehydrogenase (NAD+), L-aminoadipate-semialdehyde dehydrogenase
GAD1	4.1.1.15	glutamate decarboxylase
PNKP	2.7.1.78, 3.1.3.32	polynucleotide 5’-hydroxyl-kinase, polynucleotide 3’-phosphatase
POMT1	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN2A	203
GRIN2A	324

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN2A, GRIN2A
B	Phased (≥1) drug, not yet approved	1	PLPBP
C	Druggable family + PDB, no drug	3	ALDH7A1, GAD1, PNKP
D	Druggable family + AlphaFold only, no drug	1	POMT1
E	Difficult family or no structure, no drug	1	SLC13A5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDH7A1	1	—
SLC13A5	14	—
GAD1	1	—
PNKP	8	—
POMT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06054347	Not specified	COMPLETED	Evaluation by a Vineland II Scale of Long-term Development of Children With Pyridoxine Dependent Epilepsy