Biotinidase deficiency

Summary

Biotinidase deficiency (MONDO:0009665) is a disease caused by BTD (GenCC Definitive), with 2 cohort genes and 7 clinical trials. Top therapeutic interventions include biotin.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: BTD (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 724
• Phenotypes (HPO): 38
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.6	Europe	Validated
Point prevalence	1-9 / 100 000		Italy	Validated
Point prevalence	<1 / 1 000 000	0.0069	China	Validated
Prevalence at birth	1-9 / 100 000	1.5	United States	Validated
Prevalence at birth	1-9 / 100 000	1.6	Brazil	Validated
Prevalence at birth	1-9 / 100 000	2	Sweden	Validated
Prevalence at birth	1-9 / 100 000	3.2	Italy	Validated
Prevalence at birth	1-9 / 100 000	1.4	Austria	Validated
Prevalence at birth	1-9 / 100 000	5	Hungary	Validated
Prevalence at birth	1-9 / 100 000	3	Turkey	Validated
Prevalence at birth	1-5 / 10 000	11.58	Czech Republic	Validated
Point prevalence	1-9 / 100 000		Worldwide	Not yet validated
Prevalence at birth	1-9 / 100 000	1.6	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0001992	Organic aciduria	Very frequent (80-99%)
HP:0005979	Metabolic ketoacidosis	Very frequent (80-99%)
HP:0410145	Decreased biotinidase activity	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0000988	Skin rash	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002715	Abnormality of the immune system	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000478	Abnormality of the eye	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000575	Scotoma	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001138	Optic neuropathy	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002196	Myelopathy	Occasional (5-29%)
HP:0002313	Spastic paraparesis	Occasional (5-29%)
HP:0002841	Recurrent fungal infections	Occasional (5-29%)
HP:0002883	Hyperventilation	Occasional (5-29%)
HP:0003690	Limb muscle weakness	Occasional (5-29%)
HP:0004429	Recurrent viral infections	Occasional (5-29%)
HP:0005401	Recurrent candida infections	Occasional (5-29%)
HP:0006511	Laryngeal stridor	Occasional (5-29%)
HP:0011153	Focal motor seizure	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0200068	Nonprogressive visual loss	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	biotinidase deficiency
Mondo ID	MONDO:0009665
MeSH	D028921
OMIM	253260
Orphanet	79241
DOID	DOID:856
ICD-10-CM	D81.810
NCIT	C84598
SNOMED CT	8808004
UMLS	C0220754
MedGen	66323
GARD	0000894
MedDRA	10071434
NORD	857
Is cancer (heuristic)	no

Also known as: biotin deficiency · biotinidase deficiency · BTD deficiency · juvenile-onset multiple carboxylase deficiency · late-onset biotin-responsive multiple carboxylase deficiency · late-onset multiple carboxylase deficiency

Data availability: 724 ClinVar variants · 7 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 › inborn carbohydrate metabolic disorder › multiple carboxylase deficiency › biotinidase deficiency

Related subtypes (1): holocarboxylase synthetase 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:

190 likely benign, 114 uncertain significance, 98 likely pathogenic, 75 pathogenic, 57 conflicting classifications of pathogenicity, 56 pathogenic/likely pathogenic, 6 benign/likely benign, 3 benign, 1 conflicting classifications of pathogenicity; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1904	NM_000060.2(BTD):c.[1207T>G;1330G>C]		Pathogenic	criteria provided, single submitter
25016	NM_000060.2(BTD):c.[511G>A;1330G>C]		Pathogenic	criteria provided, multiple submitters, no conflicts
4077513	NM_000060.4:c.98_104delinsTCC		Pathogenic	criteria provided, single submitter
4815964	NM_000060.4:c.1369G>A		Pathogenic	criteria provided, single submitter
1068552	NM_001370658.1(BTD):c.743dup (p.Tyr248Ter)	BTD	Pathogenic	criteria provided, single submitter
1069218	NM_001370658.1(BTD):c.359G>A (p.Trp120Ter)	BTD	Pathogenic	criteria provided, multiple submitters, no conflicts
1072526	NC_000003.11:g.(?15683405)(15687154_?)del	BTD	Pathogenic	criteria provided, single submitter
1075658	NM_001370658.1(BTD):c.56_59dup (p.Gly21fs)	BTD	Pathogenic	criteria provided, single submitter
1325380	NM_001370658.1(BTD):c.1103dup (p.Asn369fs)	BTD	Pathogenic	criteria provided, single submitter
1325381	NM_001370658.1(BTD):c.500del (p.Pro167fs)	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330018	NM_001370658.1(BTD):c.1036_1037dup (p.Gly347fs)	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343815	NM_001370658.1(BTD):c.424G>C (p.Ala142Pro)	BTD	Pathogenic	criteria provided, single submitter
1351678	NC_000003.11:g.(?15643358)(15683584_?)del	BTD	Pathogenic	criteria provided, single submitter
1408008	NC_000003.11:g.(?15643358)(15643421_?)del	BTD	Pathogenic	criteria provided, single submitter
1409898	NM_001370658.1(BTD):c.588C>G (p.Tyr196Ter)	BTD	Pathogenic	criteria provided, single submitter
1414441	NM_001370658.1(BTD):c.516C>A (p.Tyr172Ter)	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453530	NM_001370658.1(BTD):c.950del (p.Val317fs)	BTD	Pathogenic	criteria provided, single submitter
1453804	NM_001370658.1(BTD):c.477_478delinsAA (p.Cys159_His160delinsTer)	BTD	Pathogenic	criteria provided, single submitter
1456933	NM_001370658.1(BTD):c.1324del (p.Arg442fs)	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459410	NM_001370658.1(BTD):c.805G>C (p.Ala269Pro)	BTD	Pathogenic	criteria provided, single submitter
156003	NM_001370658.1(BTD):c.641C>T (p.Thr214Ile)	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156005	NM_001370658.1(BTD):c.1312dup (p.Cys438fs)	BTD	Pathogenic	no assertion criteria provided
156006	NM_001370658.1(BTD):c.250-15del	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675907	NM_001370658.1(BTD):c.1211G>C (p.Cys404Ser)	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704286	NM_001370658.1(BTD):c.550G>A (p.Gly184Arg)	BTD	Pathogenic	criteria provided, single submitter
1711566	NM_001370658.1(BTD):c.249+2C>G	BTD	Pathogenic	criteria provided, single submitter
188805	NM_001370658.1(BTD):c.1167_1181delinsTTCCAATGGCC (p.Trp389fs)	BTD	Pathogenic	criteria provided, multiple submitters, no conflicts
189072	NM_001370658.1(BTD):c.142_145dup (p.Leu49fs)	BTD	Pathogenic	criteria provided, multiple submitters, no conflicts
1895	NM_001370658.1(BTD):c.38_44delinsTCC (p.Cys13fs)	BTD	Pathogenic	criteria provided, multiple submitters, no conflicts
1897	NM_001370658.1(BTD):c.1535C>T (p.Thr512Met)	BTD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
BTD	Definitive	Autosomal recessive	biotinidase deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BTD	Orphanet:79241	Biotinidase 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
BTD	HGNC:1122	ENSG00000169814	P43251	Biotinidase	gencc,clinvar
MLKL	HGNC:26617	ENSG00000168404	Q8NB16	Mixed lineage kinase domain-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BTD	Biotinidase	Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation.
MLKL	Mixed lineage kinase domain-like protein	Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process.

Protein-family classification

Druggable: 2 · 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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BTD	Enzyme (other)	yes	3.5.1.12	C-N_Hydrolase, Biotinidase-like_euk, C-N_Hydrolase_sf
MLKL	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Kinase-like_dom_sf

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
islet of Langerhans	1
liver	1
right lobe of liver	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BTD	261	ubiquitous	marker	islet of Langerhans, right lobe of liver, liver
MLKL	234	ubiquitous	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MLKL	2,090
BTD	1,311

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MLKL	Q8NB16	22

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BTD	P43251	86.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Defective BTD causes biotidinase deficiency	1	5710.0×	0.004	BTD
Microbial modulation of RIPK1-mediated regulated necrosis	1	1427.5×	0.006	MLKL
Defects in biotin (Btn) metabolism	1	1142.0×	0.006	BTD
Defective RIPK1-mediated regulated necrosis	1	951.7×	0.006	MLKL
Biotin transport and metabolism	1	519.1×	0.008	BTD
Regulated Necrosis	1	356.9×	0.009	MLKL
Diseases of programmed cell death	1	317.2×	0.009	MLKL
Defects in vitamin and cofactor metabolism	1	300.5×	0.009	BTD
RIPK1-mediated regulated necrosis	1	228.4×	0.009	MLKL
Regulation of necroptotic cell death	1	219.6×	0.009	MLKL
TRP channels	1	203.9×	0.009	MLKL
Disease	2	13.1×	0.010	BTD, MLKL
NS1 Mediated Effects on Host Pathways	1	142.8×	0.011	MLKL
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.017	BTD
Programmed Cell Death	1	73.2×	0.019	MLKL
Stimuli-sensing channels	1	68.0×	0.019	MLKL
Metabolism of vitamins and cofactors	1	58.3×	0.021	BTD
Ion channel transport	1	48.0×	0.024	MLKL
Diseases of metabolism	1	40.2×	0.027	BTD
Transport of small molecules	1	12.6×	0.082	MLKL
Metabolism	1	5.8×	0.165	BTD

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
execution phase of necroptosis	1	4213.0×	0.002	MLKL
biotin metabolic process	1	2106.5×	0.002	BTD
necroptotic signaling pathway	1	1053.2×	0.003	MLKL
necroptotic process	1	526.6×	0.003	MLKL
protein homotrimerization	1	495.6×	0.003	MLKL
central nervous system development	1	57.7×	0.023	BTD
defense response to virus	1	34.7×	0.031	MLKL
cell surface receptor signaling pathway	1	32.0×	0.031	MLKL

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MLKL	CRIZOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MLKL	1	4
BTD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRIZOTINIB	4	MLKL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MLKL	112	Binding:112
BTD	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BTD	3.5.1.12	biotinidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MLKL	112

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
CRIZOTINIB	4	MLKL

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MLKL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	BTD
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)
BTD	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03269045	PHASE1/PHASE2	COMPLETED	Study of ORL-1B in Patients With Biotinidase Deficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06723925	Not specified	RECRUITING	Neonatal Screening of Biotinidase Deficiency: Genotype-phenotype Correlation and Clinical Follow-up
NCT00894920	Not specified	COMPLETED	Biotin Status in Pregnancy
NCT03268681	Not specified	COMPLETED	BIOtinidase Test In Optic-Neuropathy
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BIOTIN	4	1
CHEMBL4782949	0	1