Biotin-responsive basal ganglia disease

Summary

Biotin-responsive basal ganglia disease (MONDO:0011841) is a disease caused by SLC19A3 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC19A3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 628
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	biotin-responsive basal ganglia disease
Mondo ID	MONDO:0011841
MeSH	C537658
OMIM	607483
Orphanet	199348, 65284
DOID	DOID:0050659
ICD-11	1776831202
SNOMED CT	703522009, 723557004
UMLS	C1843807
MedGen	375289
GARD	0010237
Is cancer (heuristic)	no

Also known as: BBGD · biotin-responsive basal ganglia disease · biotin-thiamine-responsive basal ganglia disease · BTBGD · encephalopathy, thiamine-responsive · thiamine metabolism dysfunction syndrome 2 (biotin- and thiamine-responsive type) · thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive type) · thiamine-responsive encephalopathy · THMD2

Data availability: 628 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

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 › biotin-responsive basal ganglia disease

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

600 retrieved; paginated sample, class counts are floors:

224 uncertain significance, 216 likely benign, 48 pathogenic, 41 conflicting classifications of pathogenicity, 35 benign, 15 likely pathogenic, 13 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
805846	NC_000002.12:g.(?227616600)(227744395_?)del	C2orf83	Pathogenic	no assertion criteria provided
1071924	NM_025243.4(SLC19A3):c.776_777del (p.Val259fs)	SLC19A3	Pathogenic	criteria provided, single submitter
1073682	NM_025243.4(SLC19A3):c.1257del (p.Ile420fs)	SLC19A3	Pathogenic	criteria provided, single submitter
1074726	NM_025243.4(SLC19A3):c.1164del (p.Thr388_Ile389insTer)	SLC19A3	Pathogenic	criteria provided, single submitter
1216993	NM_025243.4(SLC19A3):c.171del (p.Val58fs)	SLC19A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1332819	NM_025243.4(SLC19A3):c.307dup (p.Val103fs)	SLC19A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1453971	NM_025243.4(SLC19A3):c.855G>A (p.Trp285Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
1454463	NM_025243.4(SLC19A3):c.36G>A (p.Trp12Ter)	SLC19A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459929	NM_025243.4(SLC19A3):c.426del (p.Cys143fs)	SLC19A3	Pathogenic	criteria provided, single submitter
1460288	NC_000002.11:g.(?228552113)(228567034_?)del	SLC19A3	Pathogenic	criteria provided, single submitter
1505253	NM_025243.4(SLC19A3):c.1172+2T>G	SLC19A3	Pathogenic	criteria provided, multiple submitters, no conflicts
162137	NM_025243.4(SLC19A3):c.20C>A (p.Ser7Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
1899857	NM_025243.4(SLC19A3):c.623_626del (p.Lys208fs)	SLC19A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190224	NM_025243.4(SLC19A3):c.74dup (p.Ser26fs)	SLC19A3	Pathogenic	criteria provided, multiple submitters, no conflicts
2022485	NM_025243.4(SLC19A3):c.160G>T (p.Glu54Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2697815	NM_025243.4(SLC19A3):c.885_888dup (p.Asn297fs)	SLC19A3	Pathogenic	criteria provided, single submitter
2700091	NM_025243.4(SLC19A3):c.795G>A (p.Trp265Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2734426	NM_025243.4(SLC19A3):c.507C>G (p.Tyr169Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2759263	NM_025243.4(SLC19A3):c.12C>G (p.Tyr4Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2762268	NM_025243.4(SLC19A3):c.125dup (p.Asp43fs)	SLC19A3	Pathogenic	criteria provided, single submitter
2768019	NM_025243.4(SLC19A3):c.513C>A (p.Tyr171Ter)	SLC19A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2780017	NM_025243.4(SLC19A3):c.816C>A (p.Cys272Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2824259	NM_025243.4(SLC19A3):c.129dup (p.Lys44Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2832768	NM_025243.4(SLC19A3):c.856del (p.Ala286fs)	SLC19A3	Pathogenic	criteria provided, single submitter
2836128	NM_025243.4(SLC19A3):c.1212dup (p.Val406fs)	SLC19A3	Pathogenic	criteria provided, single submitter
2840050	NM_025243.4(SLC19A3):c.177G>A (p.Trp59Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2840270	NM_025243.4(SLC19A3):c.475C>T (p.Gln159Ter)	SLC19A3	Pathogenic	criteria provided, single submitter
2859471	NM_025243.4(SLC19A3):c.701del (p.Thr234fs)	SLC19A3	Pathogenic	criteria provided, single submitter
2917962	NM_025243.4(SLC19A3):c.597del (p.His200fs)	SLC19A3	Pathogenic	criteria provided, multiple submitters, no conflicts
3069169	NM_025243.4(SLC19A3):c.696del (p.Lys232fs)	SLC19A3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
SLC19A3	Definitive	Autosomal recessive	biotin-responsive basal ganglia disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC19A3	Orphanet:199348	Thiamine-responsive encephalopathy
SLC19A3	Orphanet:263410	Infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome
SLC19A3	Orphanet:65284	Biotin-thiamine-responsive basal ganglia disease

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
SLC19A3	HGNC:16266	ENSG00000135917	Q9BZV2	Thiamine transporter 2	gencc,clinvar
SLC19A4P	HGNC:25344	ENSG00000042304	Q53S99	Putative solute carrier family 19 member 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC19A3	Thiamine transporter 2	Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC19A3	Transporter	yes		Folate_carrier, ThTr-2, MFS_trans_sf
SLC19A4P	Other/Unknown	no		Folate_carrier

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adipose tissue	1
adipose tissue of abdominal region	1
subcutaneous adipose tissue	1
buccal mucosa cell	1
cervix squamous epithelium	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
SLC19A3	185	broad	marker	subcutaneous adipose tissue, adipose tissue, adipose tissue of abdominal region
SLC19A4P	83	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC19A3	1,101
SLC19A4P	212

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC19A3	Q9BZV2	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC19A4P	Q53S99	54.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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×	0.002	SLC19A3
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.011	SLC19A3
Metabolism of vitamins and cofactors	1	116.5×	0.011	SLC19A3
Metabolism	1	11.6×	0.086	SLC19A3

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
pyridoxine transport	1	5617.3×	3e-04	SLC19A3
thiamine-containing compound metabolic process	1	5617.3×	3e-04	SLC19A3
thiamine transport	1	4213.0×	3e-04	SLC19A3
thiamine transmembrane transport	1	4213.0×	3e-04	SLC19A3
thiamine diphosphate biosynthetic process	1	3370.4×	3e-04	SLC19A3

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
SLC19A3	0	0
SLC19A4P	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	SLC19A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC19A4P

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)
SLC19A3	0	—
SLC19A4P	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
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns