Neurodegeneration, infantile-onset, biotin-responsive

Summary

Neurodegeneration, infantile-onset, biotin-responsive (MONDO:0033546) is a disease caused by SLC5A6 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SLC5A6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration, infantile-onset, biotin-responsive
Mondo ID	MONDO:0033546
OMIM	618973
Orphanet	521268
UMLS	C5436520
MedGen	1771692
GARD	0027272
Is cancer (heuristic)	no

Also known as: NERIB · SMVT deficiency · sodium-dependent multivitamin transporter deficiency

Data availability: 18 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › neurodegeneration, infantile-onset, biotin-responsive

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

18 retrieved; paginated sample, class counts are floors:

5 likely pathogenic, 4 conflicting classifications of pathogenicity, 4 pathogenic, 3 pathogenic/likely pathogenic, 1 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1341352	NM_021095.4(SLC5A6):c.1285A>G (p.Ser429Gly)	SLC5A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341576	NM_021095.4(SLC5A6):c.1005+1G>A	SLC5A6	Pathogenic	criteria provided, single submitter
1802141	NM_021095.4(SLC5A6):c.393+2T>C	SLC5A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
975021	NM_021095.4(SLC5A6):c.422_423del (p.Val141fs)	SLC5A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
975022	NM_021095.4(SLC5A6):c.1199G>C (p.Arg400Thr)	SLC5A6	Pathogenic	no assertion criteria provided
975023	NM_021095.4(SLC5A6):c.280C>T (p.Arg94Ter)	SLC5A6	Pathogenic	criteria provided, multiple submitters, no conflicts
975024	NM_021095.4(SLC5A6):c.368G>T (p.Arg123Leu)	SLC5A6	Pathogenic	no assertion criteria provided
1341577	NM_021095.4(SLC5A6):c.1865_1866del (p.Gln622fs)	SLC5A6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2507024	NM_021095.4(SLC5A6):c.460-19T>G	SLC5A6	Likely pathogenic	criteria provided, single submitter
2627917	NM_021095.4(SLC5A6):c.1403del (p.Phe468fs)	SLC5A6	Likely pathogenic	criteria provided, single submitter
4291821	NM_021095.4(SLC5A6):c.1648+2T>G	SLC5A6	Likely pathogenic	criteria provided, single submitter
4845873	NM_021095.4(SLC5A6):c.957C>G (p.Tyr319Ter)	SLC5A6	Likely pathogenic	criteria provided, single submitter
1316087	NM_021095.4(SLC5A6):c.1310C>T (p.Pro437Leu)	SLC5A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1317298	NM_021095.4(SLC5A6):c.182T>A (p.Met61Lys)	SLC5A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1704719	NM_021095.4(SLC5A6):c.1282A>G (p.Ile428Val)	SLC5A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3600297	NM_021095.4(SLC5A6):c.814G>A (p.Gly272Arg)	SLC5A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4292403	NM_021095.4(SLC5A6):c.317A>G (p.Tyr106Cys)	SLC5A6	Uncertain significance	criteria provided, single submitter
713562	NM_021095.4(SLC5A6):c.1658G>A (p.Arg553Gln)	SLC5A6	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 0 · 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
SLC5A6	Strong	Autosomal recessive	neurodegeneration, infantile-onset, biotin-responsive	6

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
SLC5A6	HGNC:11041	ENSG00000138074	Q9Y289	Sodium-dependent multivitamin transporter	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC5A6	Sodium-dependent multivitamin transporter	Sodium-dependent multivitamin transporter that mediates the electrogenic transport of pantothenate, biotin, lipoate and iodide.

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)
SLC5A6	Other/Unknown	no		Na/solute_symporter, Na/solute_symporter_CS, Na/Glc_symporter_sf

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
left testis	1
right lobe of liver	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC5A6	222	ubiquitous	marker	right lobe of liver, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC5A6	1,281

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC5A6	Q9Y289	79.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Biotin transport and metabolism	1	1038.2×	0.005	SLC5A6
Vitamin B5 (pantothenate) metabolism	1	761.3×	0.005	SLC5A6
Transport of vitamins, nucleosides, and related molecules	1	271.9×	0.010	SLC5A6
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.011	SLC5A6
Metabolism of vitamins and cofactors	1	116.5×	0.014	SLC5A6
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC5A6
Transport of small molecules	1	25.1×	0.045	SLC5A6
Metabolism	1	11.6×	0.086	SLC5A6

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
pantothenate transmembrane transport	1	16852.0×	3e-04	SLC5A6
iodide transmembrane transport	1	8426.0×	3e-04	SLC5A6
biotin import across plasma membrane	1	8426.0×	3e-04	SLC5A6
biotin transport	1	5617.3×	3e-04	SLC5A6
biotin metabolic process	1	4213.0×	3e-04	SLC5A6
sodium ion transport	1	271.8×	0.004	SLC5A6
transport across blood-brain barrier	1	179.3×	0.006	SLC5A6

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
SLC5A6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC5A6	1	Binding:1

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	1	SLC5A6

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)
SLC5A6	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.