Pyridoxal phosphate-responsive seizures

Summary

Pyridoxal phosphate-responsive seizures (MONDO:0012407) is a disease caused by PNPO (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: PNPO (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 351
• Phenotypes (HPO): 29
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0002133	Status epilepticus	Very frequent (80-99%)
HP:0200134	Epileptic encephalopathy	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001560	Abnormality of the amniotic fluid	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0001942	Metabolic acidosis	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002283	Global brain atrophy	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0003785	Decreased CSF homovanillic acid concentration	Frequent (30-79%)
HP:0005961	Hypoargininemia	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0010851	EEG with burst suppression	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0025430	High-pitched cry	Frequent (30-79%)
HP:0030917	Low APGAR score	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0005522	Pyridoxine-responsive sideroblastic anemia	Occasional (5-29%)
HP:0010895	Abnormality of glycine metabolism	Occasional (5-29%)
HP:0010900	Abnormality of threonine metabolism	Occasional (5-29%)
HP:0010904	Abnormal circulating histidine concentration	Occasional (5-29%)
HP:0010909	Abnormality of arginine metabolism	Occasional (5-29%)
HP:0010917	Abnormality of tyrosine metabolism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyridoxal phosphate-responsive seizures
Mondo ID	MONDO:0012407
MeSH	C566449
OMIM	610090
Orphanet	79096
DOID	DOID:0111329
ICD-11	1632334328, 604024463
SNOMED CT	724576005
UMLS	C1864723
MedGen	350498
GARD	0010730
Is cancer (heuristic)	no

Also known as: PNPO deficiency · PNPO-related neonatal epileptic encephalopathy · PNPOD · pyridox(am)ine 5’-phosphate oxidase deficiency · pyridoxal 5’-phosphate-dependent epilepsy · pyridoxal phosphate-dependent seizures · pyridoxamine 5’-phosphate oxidase deficiency · pyridoxine 5’ phosphate oxidase deficiency · pyridoxine-5’-phosphate oxidase deficiency

Data availability: 351 ClinVar variants · 5 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 › pyridoxal phosphate-responsive seizures

Related subtypes (1): pyridoxine-dependent epilepsy

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

351 retrieved; paginated sample, class counts are floors:

137 likely benign, 135 uncertain significance, 21 pathogenic, 18 benign, 13 conflicting classifications of pathogenicity, 11 likely pathogenic, 10 pathogenic/likely pathogenic, 5 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1297019	NM_018129.4(PNPO):c.283C>T (p.Arg95Cys)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323480	NM_018129.4(PNPO):c.178A>T (p.Lys60Ter)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
1412292	NM_018129.4(PNPO):c.263+1G>C	PNPO	Pathogenic	criteria provided, single submitter
1452659	NM_018129.4(PNPO):c.346C>T (p.Arg116Ter)	PNPO	Pathogenic	criteria provided, single submitter
1704283	NM_018129.4(PNPO):c.546+1G>A	PNPO	Pathogenic	no assertion criteria provided
1704285	NM_018129.3(PNPO):c.620delG	PNPO	Pathogenic	no assertion criteria provided
206442	NM_018129.4(PNPO):c.471C>A (p.Tyr157Ter)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206446	NM_018129.4(PNPO):c.481C>T (p.Arg161Cys)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206450	NM_018129.4(PNPO):c.673C>T (p.Arg225Cys)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206451	NM_018129.4(PNPO):c.674G>T (p.Arg225Leu)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
206452	NM_018129.4(PNPO):c.686G>A (p.Arg229Gln)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206458	NM_018129.4(PNPO):c.98A>T (p.Asp33Val)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
206460	NM_018129.4(PNPO):c.448_451del (p.Pro150fs)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
2128382	NM_018129.4(PNPO):c.422_433del (p.Arg141_Gly144del)	PNPO	Pathogenic	criteria provided, single submitter
2138063	NM_018129.4(PNPO):c.421C>T (p.Arg141Cys)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223153	NM_018129.4(PNPO):c.674G>A (p.Arg225His)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
2426449	NC_000017.10:g.(?46019042)(46024148_?)del	PNPO	Pathogenic	criteria provided, single submitter
2736611	NM_018129.4(PNPO):c.246del (p.Leu83fs)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
2882403	NM_018129.4(PNPO):c.69dup (p.His24fs)	PNPO	Pathogenic	criteria provided, single submitter
2892339	NM_018129.4(PNPO):c.412C>T (p.Arg138Cys)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3613711	NM_018129.4(PNPO):c.123C>A (p.Tyr41Ter)	PNPO	Pathogenic	criteria provided, single submitter
3702113	NM_018129.4(PNPO):c.364-1G>C	PNPO	Pathogenic	criteria provided, single submitter
391570	NM_018129.4(PNPO):c.399G>A (p.Trp133Ter)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4769621	NM_018129.4(PNPO):c.118_119del (p.Ser40fs)	PNPO	Pathogenic	criteria provided, single submitter
6523	NM_018129.4(PNPO):c.685C>T (p.Arg229Trp)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6524	NM_018129.4(PNPO):c.364-1G>A	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
6525	NM_018129.4(PNPO):c.784T>C (p.Ter262Gln)	PNPO	Pathogenic	criteria provided, single submitter
6526	NM_018129.4(PNPO):c.520C>T (p.Gln174Ter)	PNPO	Pathogenic	no assertion criteria provided
658245	NM_018129.4(PNPO):c.657G>A (p.Trp219Ter)	PNPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
849386	NM_018129.4(PNPO):c.284G>A (p.Arg95His)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PNPO	Definitive	Autosomal recessive	pyridoxal phosphate-responsive seizures	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNPO	Orphanet:79096	Pyridoxamine-5-phosphate deficiency-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
PNPO	HGNC:30260	ENSG00000108439	Q9NVS9	Pyridoxine-5’-phosphate oxidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPO	Pyridoxine-5’-phosphate oxidase	Catalyzes the oxidation of either pyridoxine 5’-phosphate (PNP) or pyridoxamine 5’-phosphate (PMP) into pyridoxal 5’-phosphate (PLP).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPO	Enzyme (other)	yes	1.4.3.5	Pyridox_Oxase, Pyridox_Oxase_N, Split_barrel_FMN-bd

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
kidney epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPO	230	ubiquitous	marker	right lobe of liver, liver, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNPO	1,710

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PNPO	Q9NVS9	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin B6 activation to pyridoxal phosphate	1	3806.7×	3e-04	PNPO

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
pyridoxal 5’-phosphate biosynthetic process	1	16852.0×	1e-04	PNPO
pyridoxine biosynthetic process	1	8426.0×	1e-04	PNPO
pyridoxamine metabolic process	1	8426.0×	1e-04	PNPO

Therapeutics

Drug target analysis

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

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
PNPO	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
PNPO	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNPO	1.4.3.5	pyridoxal 5’-phosphate synthase

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

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	1	PNPO
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PNPO	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

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