epilepsy, early-onset, vitamin B6-dependent

Summary

epilepsy, early-onset, vitamin B6-dependent (MONDO:0015005) is a disease caused by PLPBP (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: PLPBP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 36
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy, early-onset, vitamin B6-dependent
Mondo ID	MONDO:0015005
OMIM	617290
DOID	DOID:0080769
UMLS	C4310632
MedGen	934599
GARD	0025048
Is cancer (heuristic)	no

Also known as: epilepsy, early-onset, vitamin B6-dependent · epilepsy, early-onset, vitamin B6-dependent; EPVB6D · EPVB6D

Data availability: 36 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 › inborn disorder of biogenic amine metabolism and transport › inborn disorder of pyridoxine metabolism › pyridoxine-dependent epilepsy › epilepsy, early-onset, vitamin B6-dependent

Related subtypes (1): 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

36 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 7 pathogenic, 5 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 2 likely benign, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323499	NM_007198.4(PLPBP):c.211C>T (p.Gln71Ter)	PLPBP	Pathogenic	criteria provided, single submitter
1805767	NM_007198.4(PLPBP):c.207+1G>T	PLPBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1806055	NM_007198.4(PLPBP):c.387del (p.Trp130fs)	PLPBP	Pathogenic	criteria provided, single submitter
374852	NM_007198.4(PLPBP):c.233C>G (p.Ser78Ter)	PLPBP	Pathogenic	criteria provided, single submitter
374853	NM_007198.4(PLPBP):c.524T>C (p.Leu175Pro)	PLPBP	Pathogenic	no assertion criteria provided
374854	NM_007198.4(PLPBP):c.207+1G>A	PLPBP	Pathogenic	criteria provided, single submitter
374855	NM_007198.4(PLPBP):c.320-2A>G	PLPBP	Pathogenic	criteria provided, multiple submitters, no conflicts
374856	NM_007198.4(PLPBP):c.260C>T (p.Pro87Leu)	PLPBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374857	NM_007198.4(PLPBP):c.722G>A (p.Arg241Gln)	PLPBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
503895	NM_007198.4(PLPBP):c.370_373del (p.Asp124fs)	PLPBP	Pathogenic	criteria provided, multiple submitters, no conflicts
2444519	NM_007198.4(PLPBP):c.389G>A (p.Trp130Ter)	PLPBP	Likely pathogenic	criteria provided, single submitter
1956005	NM_007198.4(PLPBP):c.695C>T (p.Ala232Val)	PLPBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1965429	NM_007198.4(PLPBP):c.676T>C (p.Ser226Pro)	PLPBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2159457	NM_007198.4(PLPBP):c.199G>A (p.Glu67Lys)	PLPBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2186044	NM_007198.4(PLPBP):c.721C>T (p.Arg241Ter)	PLPBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802398	NM_007198.4(PLPBP):c.704T>G (p.Val235Gly)	PLPBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032529	NM_007198.4(PLPBP):c.40G>C (p.Gly14Arg)	LOC113788277	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032530	NM_007198.4(PLPBP):c.52C>T (p.Arg18Trp)	LOC113788277	Uncertain significance	criteria provided, single submitter
1213761	NM_007198.4(PLPBP):c.86C>T (p.Ala29Val)	LOC113788277	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805772	NM_007198.4(PLPBP):c.88C>G (p.Arg30Gly)	LOC113788277	Uncertain significance	criteria provided, single submitter
1878666	NM_007198.4(PLPBP):c.19A>C (p.Met7Leu)	LOC113788277	Uncertain significance	criteria provided, multiple submitters, no conflicts
1918828	NM_007198.4(PLPBP):c.19A>T (p.Met7Leu)	LOC113788277	Uncertain significance	criteria provided, multiple submitters, no conflicts
3234881	NM_007198.4(PLPBP):c.19A>G (p.Met7Val)	LOC113788277	Uncertain significance	criteria provided, multiple submitters, no conflicts
1027730	NM_007198.4(PLPBP):c.137G>A (p.Ser46Asn)	PLPBP	Uncertain significance	criteria provided, single submitter
1027731	NM_007198.4(PLPBP):c.347C>T (p.Thr116Ile)	PLPBP	Uncertain significance	criteria provided, single submitter
1027732	NM_007198.4(PLPBP):c.823C>G (p.His275Asp)	PLPBP	Uncertain significance	criteria provided, single submitter
1696739	NM_007198.4(PLPBP):c.793G>A (p.Val265Met)	PLPBP	Uncertain significance	criteria provided, single submitter
2170415	NM_007198.4(PLPBP):c.281T>C (p.Ile94Thr)	PLPBP	Uncertain significance	criteria provided, multiple submitters, no conflicts
3383355	NM_007198.4(PLPBP):c.727G>A (p.Gly243Arg)	PLPBP	Uncertain significance	criteria provided, single submitter
3384686	NM_007198.4(PLPBP):c.204C>A (p.Asn68Lys)	PLPBP	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
PLPBP	Strong	Autosomal recessive	epilepsy, early-onset, vitamin B6-dependent	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLPBP	Orphanet:3006	Pyridoxine-dependent-developmental and epileptic encephalopathy

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
PLPBP	HGNC:9457	ENSG00000147471	O94903	Pyridoxal phosphate homeostasis protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

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)
PLPBP	Other/Unknown	no		Ala_racemase_N, PyrdxlP_homeostasis, PLP-binding_barrel

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
cardia of stomach	1
pericardium	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLPBP	292	ubiquitous	marker	cardia of stomach, pericardium, renal medulla

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLPBP	1,577

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLPBP	O94903	89.49

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
vitamin B6 metabolic process	1	16852.0×	6e-05	PLPBP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLPBP	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	PLPBP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PLPBP	6	Binding:6

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

1 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)
MOLIBRESIB	2	PLPBP

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	1	PLPBP
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns