Progressive demyelinating neuropathy with bilateral striatal necrosis
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Also known as thiamine metabolism dysfunction syndrome 4 (bilateral striatal degeneration and progressive polyneuropathy type)thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type)THMD4
Summary
Progressive demyelinating neuropathy with bilateral striatal necrosis (MONDO:0013382) is a disease caused by SLC25A19 (GenCC Strong), with 2 cohort genes and 1 clinical trial.
At a glance
- Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
- Causal gene: SLC25A19 (GenCC Strong)
- Cohort genes: 2
- ClinVar variants: 21
- Clinical trials: 1
Clinical features
Epidemiology
Prevalence records
2 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Cases/families | 4 | Worldwide | Validated | |
| Point prevalence | <1 / 1 000 000 | Worldwide | Validated |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | progressive demyelinating neuropathy with bilateral striatal necrosis |
| Mondo ID | MONDO:0013382 |
| OMIM | 613710 |
| Orphanet | 217396 |
| UMLS | C3150973 |
| MedGen | 462323 |
| GARD | 0017123 |
| Is cancer (heuristic) | no |
Also known as: thiamine metabolism dysfunction syndrome 4 (bilateral striatal degeneration and progressive polyneuropathy type) · thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type) · THMD4
Data availability: 21 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 › progressive demyelinating neuropathy with bilateral striatal necrosis
Related subtypes (4): thiamine-responsive megaloblastic anemia syndrome, Amish lethal microcephaly, biotin-responsive basal ganglia disease, childhood encephalopathy due to thiamine pyrophosphokinase deficiency
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
21 retrieved; paginated sample, class counts are floors:
9 pathogenic, 5 uncertain significance, 4 benign, 2 conflicting classifications of pathogenicity, 1 likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1695339 | NM_001126121.2(SLC25A19):c.869T>A (p.Leu290Gln) | MIF4GD-DT | Pathogenic | no assertion criteria provided |
| 1695342 | NM_001126121.2(SLC25A19):c.910G>A (p.Glu304Lys) | MIF4GD-DT | Pathogenic | no assertion criteria provided |
| 1695338 | NM_001126121.2(SLC25A19):c.576G>C (p.Gln192His) | SLC25A19 | Pathogenic | no assertion criteria provided |
| 1695340 | NM_001126121.2(SLC25A19):c.745T>A (p.Phe249Ile) | SLC25A19 | Pathogenic | no assertion criteria provided |
| 1695341 | NM_001126121.2(SLC25A19):c.76G>A (p.Gly26Arg) | SLC25A19 | Pathogenic | no assertion criteria provided |
| 30590 | NM_001126121.2(SLC25A19):c.373G>A (p.Gly125Ser) | SLC25A19 | Pathogenic | no assertion criteria provided |
| 438730 | NM_001126121.2(SLC25A19):c.194C>T (p.Ala65Val) | SLC25A19 | Pathogenic | no assertion criteria provided |
| 438731 | NM_001126121.2(SLC25A19):c.454C>A (p.Pro152Thr) | SLC25A19 | Pathogenic | no assertion criteria provided |
| 438733 | NM_001126121.2(SLC25A19):c.550G>C (p.Ala184Pro) | SLC25A19 | Pathogenic | no assertion criteria provided |
| 488598 | NM_001126121.2(SLC25A19):c.240A>C (p.Lys80Asn) | SLC25A19 | Likely pathogenic | criteria provided, single submitter |
| 198247 | NM_001126121.2(SLC25A19):c.590G>T (p.Ser197Ile) | SLC25A19 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 198249 | NM_001126121.2(SLC25A19):c.565G>A (p.Ala189Thr) | SLC25A19 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1480823 | NM_001126121.2(SLC25A19):c.635A>G (p.Lys212Arg) | SLC25A19 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2585316 | NM_001126121.2(SLC25A19):c.748G>A (p.Glu250Lys) | SLC25A19 | Uncertain significance | criteria provided, single submitter |
| 4292975 | NM_001126121.2(SLC25A19):c.220G>A (p.Gly74Ser) | SLC25A19 | Uncertain significance | criteria provided, single submitter |
| 436748 | NM_001126121.2(SLC25A19):c.73T>G (p.Ser25Ala) | SLC25A19 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 438732 | NM_001126121.2(SLC25A19):c.481G>A (p.Ala161Thr) | SLC25A19 | Uncertain significance | criteria provided, single submitter |
| 130327 | NM_001126121.2(SLC25A19):c.*2T>C | MIF4GD-DT | Benign | criteria provided, multiple submitters, no conflicts |
| 130333 | NM_001126121.2(SLC25A19):c.819G>A (p.Leu273=) | MIF4GD-DT | Benign | criteria provided, multiple submitters, no conflicts |
| 1290939 | NM_001126121.2(SLC25A19):c.289-26G>A | SLC25A19 | Benign | criteria provided, multiple submitters, no conflicts |
| 130330 | NM_001126121.2(SLC25A19):c.339T>C (p.Tyr113=) | SLC25A19 | Benign | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 9 · Orphanet: 2 · 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 |
|---|---|---|---|---|
| SLC25A19 | Strong | Autosomal recessive | progressive demyelinating neuropathy with bilateral striatal necrosis | 9 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| SLC25A19 | Orphanet:217396 | Progressive polyneuropathy with bilateral striatal necrosis |
| SLC25A19 | Orphanet:99742 | Amish lethal microcephaly |
Cohort genes → proteins
2 cohort genes, 1 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 2 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| SLC25A19 | HGNC:14409 | ENSG00000125454 | Q9HC21 | Mitochondrial thiamine pyrophosphate carrier | gencc,clinvar |
| MIF4GD-DT | HGNC:55335 | ENSG00000263843 | MIF4GD divergent transcript | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| SLC25A19 | Mitochondrial thiamine pyrophosphate carrier | Mitochondrial transporter mediating uptake of thiamine diphosphate into mitochondria. |
Protein-family classification
Druggable: 0 · Difficult: 0 · Unknown: 2 · 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 | 2 | 1.8× | 0.312 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| SLC25A19 | Other/Unknown | no | MCP, MCP_transmembrane, MCP_dom_sf | |
| MIF4GD-DT | Other/Unknown | no |
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) | 2 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| left testis | 1 |
| right testis | 1 |
| testis | 1 |
| bone marrow cell | 1 |
| cortical plate | 1 |
| male germ line stem cell (sensu Vertebrata) in testis | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| SLC25A19 | 232 | ubiquitous | marker | left testis, right testis, testis |
| MIF4GD-DT | 130 | broad | yes | male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, cortical plate |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| SLC25A19 | 1,492 |
| MIF4GD-DT | 0 |
Structural data
PDB: 0 · AlphaFold-only: 1 · No structure: 1
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| SLC25A19 | Q9HC21 | 85.23 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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 B1 (thiamin) metabolism | 1 | 2284.0× | 4e-04 | SLC25A19 |
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 |
|---|---|---|---|---|
| deoxynucleotide transport | 1 | 16852.0× | 2e-04 | SLC25A19 |
| thiamine pyrophosphate transmembrane transport | 1 | 8426.0× | 2e-04 | SLC25A19 |
| thiamine-containing compound metabolic process | 1 | 5617.3× | 2e-04 | SLC25A19 |
| thiamine diphosphate biosynthetic process | 1 | 3370.4× | 3e-04 | SLC25A19 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2
Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| SLC25A19 | 0 | 0 |
| MIF4GD-DT | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 0.
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 | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 2 | SLC25A19, MIF4GD-DT |
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) |
|---|---|---|
| SLC25A19 | 0 | — |
| MIF4GD-DT | 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 |