Childhood encephalopathy due to thiamine pyrophosphokinase deficiency

Summary

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (MONDO:0013761) is a disease caused by TPK1 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TPK1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 260
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	childhood encephalopathy due to thiamine pyrophosphokinase deficiency
Mondo ID	MONDO:0013761
OMIM	614458
Orphanet	293955
UMLS	C3280866
MedGen	482496
GARD	0013571
Is cancer (heuristic)	no

Also known as: childhood encephalopathy due to thiamine pyrophosphokinase deficiency · thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) · THMD5

Data availability: 260 ClinVar variants · 4 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 › disorder of metabolite absorption and transport › disorder of vitamin and non-protein cofactor absorption and transport › disorder of thiamine metabolism and transport › thiamine-responsive dysfunction syndrome › childhood encephalopathy due to thiamine pyrophosphokinase deficiency

Related subtypes (4): thiamine-responsive megaloblastic anemia syndrome, Amish lethal microcephaly, biotin-responsive basal ganglia disease, progressive demyelinating neuropathy with bilateral striatal necrosis

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

260 retrieved; paginated sample, class counts are floors:

107 uncertain significance, 101 likely benign, 26 pathogenic, 10 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 benign/likely benign, 4 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2426756	NC_000007.13:g.(?144094333)(144532695_?)del	NOBOX	Pathogenic	criteria provided, single submitter
1073305	NC_000007.13:g.(?144150618)(144532715_?)del	TPK1	Pathogenic	criteria provided, single submitter
1073306	NC_000007.13:g.(?144245564)(144532715_?)del	TPK1	Pathogenic	criteria provided, single submitter
1075880	NM_022445.4(TPK1):c.243del (p.Glu81fs)	TPK1	Pathogenic	criteria provided, single submitter
215274	NM_022445.4(TPK1):c.185+1G>A	TPK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215275	NM_022445.4(TPK1):c.501+4A>T	TPK1	Pathogenic	criteria provided, multiple submitters, no conflicts
215276	NM_022445.4(TPK1):c.44-2A>G	TPK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2426747	NC_000007.13:g.(?144532633)(144532695_?)del	TPK1	Pathogenic	criteria provided, single submitter
2426749	NC_000007.13:g.(?144245564)(144463064_?)del	TPK1	Pathogenic	criteria provided, single submitter
2426750	NC_000007.13:g.(?144288496)(144345992_?)del	TPK1	Pathogenic	criteria provided, single submitter
2426751	NC_000007.13:g.(?144288496)(144320374_?)del	TPK1	Pathogenic	criteria provided, single submitter
265278	NM_022445.4(TPK1):c.426G>C (p.Leu142Phe)	TPK1	Pathogenic	criteria provided, multiple submitters, no conflicts
2819348	NM_022445.4(TPK1):c.191dup (p.Leu64fs)	TPK1	Pathogenic	criteria provided, single submitter
2857481	NM_022445.4(TPK1):c.565G>T (p.Gly189Ter)	TPK1	Pathogenic	criteria provided, single submitter
30568	NM_022445.4(TPK1):c.148A>C (p.Asn50His)	TPK1	Pathogenic	no assertion criteria provided
3245796	NC_000007.13:g.(?144462953)(144532695_?)del	TPK1	Pathogenic	criteria provided, single submitter
3363129	NM_022445.4(TPK1):c.355-2A>G	TPK1	Pathogenic	criteria provided, single submitter
3643694	NM_022445.4(TPK1):c.108G>A (p.Trp36Ter)	TPK1	Pathogenic	criteria provided, single submitter
3675841	NM_022445.4(TPK1):c.181_182del (p.Glu61fs)	TPK1	Pathogenic	criteria provided, single submitter
419232	NM_022445.4(TPK1):c.664G>C (p.Asp222His)	TPK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438734	NM_022445.4(TPK1):c.395T>C (p.Phe132Ser)	TPK1	Pathogenic	no assertion criteria provided
438735	NM_022445.4(TPK1):c.614-1G>A	TPK1	Pathogenic	no assertion criteria provided
4719345	NM_022445.4(TPK1):c.1A>G (p.Met1Val)	TPK1	Pathogenic	criteria provided, single submitter
583968	NC_000007.14:g.(?144623146)(144682998_?)del	TPK1	Pathogenic	criteria provided, single submitter
640613	NM_022445.4(TPK1):c.613+1G>C	TPK1	Pathogenic	criteria provided, single submitter
665627	NC_000007.14:g.(?144682889)(144682998_?)del	TPK1	Pathogenic	criteria provided, single submitter
832084	NC_000007.14:g.(?144682889)(144765971_?)del	TPK1	Pathogenic	criteria provided, single submitter
833116	NC_000007.14:g.(?144591403)(144835622_?)del	TPK1	Pathogenic	criteria provided, single submitter
944675	NM_022445.4(TPK1):c.405del (p.Met136fs)	TPK1	Pathogenic	criteria provided, single submitter
962978	NM_022445.4(TPK1):c.246C>A (p.Tyr82Ter)	TPK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TPK1	Strong	Autosomal recessive	childhood encephalopathy due to thiamine pyrophosphokinase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPK1	Orphanet:293955	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPK1	HGNC:17358	ENSG00000196511	Q9H3S4	Thiamine pyrophosphokinase 1	gencc,clinvar
NOBOX	HGNC:22448	ENSG00000106410	O60393	Homeobox protein NOBOX	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPK1	Thiamine pyrophosphokinase 1	Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate (TPP) utilizing UTP and therefore links the biosynthesis of TPP to pyrimidines metabolism.
NOBOX	Homeobox protein NOBOX	Transcription factor which may play a role in oogenesis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPK1	Kinase	yes	2.7.6.2	Thi_PPkinase, TPK_catalytic, Thiamin_PyroPKinase_B1-bd
NOBOX	Transcription factor	no		HD, Homeodomain-like_sf, NOBOX

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
monocyte	1
secondary oocyte	1
colonic epithelium	1
granulocyte	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPK1	229	ubiquitous	yes	secondary oocyte, jejunal mucosa, monocyte
NOBOX	8		yes	primordial germ cell in gonad, colonic epithelium, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPK1	1,009
NOBOX	855

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TPK1	Q9H3S4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NOBOX	O60393	48.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin B1 (thiamin) metabolism	1	1142.0×	0.002	TPK1
M-decay: degradation of maternal mRNAs by maternally stored factors	1	163.1×	0.006	NOBOX

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thiamine metabolic process	1	2106.5×	0.001	TPK1
thiamine diphosphate biosynthetic process	1	1685.2×	0.001	TPK1
regulation of pyruvate decarboxylation to acetyl-CoA	1	1404.3×	0.001	TPK1
oogenesis	1	191.5×	0.007	NOBOX
regulation of transcription by RNA polymerase II	1	5.8×	0.164	NOBOX

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPK1	0	0
NOBOX	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
TPK1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPK1	2.7.6.2	thiamine diphosphokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	TPK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NOBOX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TPK1	1	—
NOBOX	0	—

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
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening