peroxisomal acyl-CoA oxidase deficiency

Summary

peroxisomal acyl-CoA oxidase deficiency (MONDO:0009919) is a disease caused by ACOX1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ACOX1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 837
• Phenotypes (HPO): 29
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Very frequent (80-99%)
HP:0000649	Abnormality of visual evoked potentials	Very frequent (80-99%)
HP:0000668	Hypodontia	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0012639	Abnormal nervous system morphology	Very frequent (80-99%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001522	Death in infancy	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0001161	Hand polydactyly	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisomal acyl-CoA oxidase deficiency
Mondo ID	MONDO:0009919
MeSH	C536662
OMIM	264470
Orphanet	2971
DOID	DOID:0050797
ICD-11	927825451
NCIT	C170437
SNOMED CT	238069004
UMLS	C1849678
MedGen	376636
GARD	0004543
Is cancer (heuristic)	no

Also known as: ACOX1 deficiency · peroxisomal acyl-CoA oxidase deficiency · pseudo-NALD · pseudo-neonatal adrenoleukodystrophy · Pseudoadrenoleukodystrophy

Data availability: 837 ClinVar variants · 5 GenCC gene-disease records · 5 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 › peroxisomal disease › peroxisomal single enzyme/protein defect › disorder of peroxisomal beta oxidation › peroxisomal acyl-CoA oxidase deficiency

Related subtypes (4): d-bifunctional protein deficiency, sterol carrier protein 2 deficiency, alpha-methylacyl-CoA racemase deficiency, acyl-CoA binding domain containing protein 5 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:

343 likely benign, 167 uncertain significance, 35 pathogenic, 24 benign, 13 likely pathogenic, 8 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030736	NM_004035.7(ACOX1):c.270-1_277delinsA	ACOX1	Pathogenic	criteria provided, single submitter
1075695	NM_004035.7(ACOX1):c.1312del (p.Ser438fs)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252014	NM_004035.7(ACOX1):c.431-1G>A	ACOX1	Pathogenic	criteria provided, single submitter
1396619	NM_004035.7(ACOX1):c.879_882del (p.Ser294fs)	ACOX1	Pathogenic	criteria provided, single submitter
1415947	NC_000017.10:g.(?73951637)(73956466_?)del	ACOX1	Pathogenic	criteria provided, single submitter
1458434	NM_004035.7(ACOX1):c.1119del (p.Thr374fs)	ACOX1	Pathogenic	criteria provided, single submitter
1459059	NM_004035.7(ACOX1):c.468T>A (p.Tyr156Ter)	ACOX1	Pathogenic	criteria provided, single submitter
1459402	NM_004035.7(ACOX1):c.1704_1707del (p.Ser568fs)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1498	NG_008190.1:g.(?18821)(36526_?)del	ACOX1	Pathogenic	no assertion criteria provided
1499	NM_004035.7(ACOX1):c.832A>G (p.Met278Val)	ACOX1	Pathogenic	no assertion criteria provided
1500	NM_004035.7(ACOX1):c.532G>T (p.Gly178Cys)	ACOX1	Pathogenic	no assertion criteria provided
1501	NM_004035.7(ACOX1):c.926A>G (p.Gln309Arg)	ACOX1	Pathogenic	no assertion criteria provided
1502	NM_004035.7(ACOX1):c.442C>T (p.Arg148Ter)	ACOX1	Pathogenic	criteria provided, multiple submitters, no conflicts
1503	NM_004035.7(ACOX1):c.372_389del (p.Phe124_Asn129del)	ACOX1	Pathogenic	no assertion criteria provided
1504	NG_008190.1:g.(22608_?)_(?_41151)del	ACOX1	Pathogenic	no assertion criteria provided
1685498	NM_004035.7(ACOX1):c.280C>T (p.Arg94Ter)	ACOX1	Pathogenic	criteria provided, multiple submitters, no conflicts
1691302	NM_004035.7(ACOX1):c.904C>T (p.Arg302Ter)	ACOX1	Pathogenic	criteria provided, multiple submitters, no conflicts
1960019	NM_004035.7(ACOX1):c.250G>T (p.Glu84Ter)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2013180	NM_004035.7(ACOX1):c.1599del (p.His532_Tyr533insTer)	ACOX1	Pathogenic	criteria provided, single submitter
2040363	NM_004035.7(ACOX1):c.193del (p.Arg65fs)	ACOX1	Pathogenic	criteria provided, single submitter
2066414	NM_004035.7(ACOX1):c.33del (p.Ala12fs)	ACOX1	Pathogenic	criteria provided, single submitter
2104874	NM_004035.7(ACOX1):c.260G>A (p.Trp87Ter)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2110077	NM_004035.7(ACOX1):c.1406del (p.Ala469fs)	ACOX1	Pathogenic	criteria provided, single submitter
2138110	NM_004035.7(ACOX1):c.1789_1792del (p.Leu596_Thr597insTer)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2425011	NC_000017.10:g.(?73956286)(73956466_?)del	ACOX1	Pathogenic	criteria provided, single submitter
2501787	NM_004035.7(ACOX1):c.1728+1G>A	ACOX1	Pathogenic	criteria provided, single submitter
2680344	NM_004035.7(ACOX1):c.1276_1277del (p.Val426fs)	ACOX1	Pathogenic	criteria provided, multiple submitters, no conflicts
2696493	NM_004035.7(ACOX1):c.909C>G (p.Tyr303Ter)	ACOX1	Pathogenic	criteria provided, single submitter
2702029	NM_004035.7(ACOX1):c.684del (p.Lys229fs)	ACOX1	Pathogenic	criteria provided, single submitter
2708348	NM_004035.7(ACOX1):c.979C>T (p.Gln327Ter)	ACOX1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
ACOX1	Definitive	Autosomal recessive	peroxisomal acyl-CoA oxidase deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACOX1	Orphanet:2971	Peroxisomal acyl-CoA oxidase deficiency
ACOX1	Orphanet:631248	Mitchell Syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACOX1	HGNC:119	ENSG00000161533	Q15067	Peroxisomal acyl-coenzyme A oxidase 1	gencc,clinvar
FBF1	HGNC:24674	ENSG00000188878	Q8TES7	Fas-binding factor 1	clinvar
TEN1	HGNC:37242	ENSG00000257949	Q86WV5	CST complex subunit TEN1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACOX1	Peroxisomal acyl-coenzyme A oxidase 1	Involved in the initial and rate-limiting step of peroxisomal beta-oxidation of straight-chain saturated and unsaturated very-long-chain fatty acids.
FBF1	Fas-binding factor 1	Keratin-binding protein required for epithelial cell polarization.
TEN1	CST complex subunit TEN1	Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACOX1	Enzyme (other)	yes	1.3.3.6	Acyl-CoA_oxidase_C, AcylCoA_DH/ox_M, AcylCoA_DH/oxidase_NM_dom_sf
FBF1	Other/Unknown	no		FBF1, FBF1_C
TEN1	Other/Unknown	no		NA-bd_OB-fold, Ten1_animal_plant

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
duodenum	1
jejunal mucosa	1
left testis	1
right lobe of thyroid gland	1
right testis	1
lower esophagus mucosa	1
primordial germ cell in gonad	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACOX1	290	ubiquitous	marker	jejunal mucosa, buccal mucosa cell, duodenum
FBF1	163	ubiquitous	yes	right testis, left testis, right lobe of thyroid gland
TEN1	132	broad	yes	lower esophagus mucosa, primordial germ cell in gonad, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACOX1	3,503
FBF1	1,413
TEN1	391

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TEN1	Q86WV5	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACOX1	Q15067	93.95
FBF1	Q8TES7	64.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TYSND1 cleaves peroxisomal proteins	1	475.8×	0.012	ACOX1
Beta-oxidation of very long chain fatty acids	1	292.8×	0.012	ACOX1
Telomere C-strand synthesis initiation	1	271.9×	0.012	TEN1
Telomere C-strand (Lagging Strand) Synthesis	1	253.8×	0.012	TEN1
alpha-linolenic acid (ALA) metabolism	1	237.9×	0.012	ACOX1
Extension of Telomeres	1	200.3×	0.012	TEN1
Polymerase switching on the C-strand of the telomere	1	141.0×	0.014	TEN1
Telomere Maintenance	1	122.8×	0.014	TEN1
Chromosome Maintenance	1	70.5×	0.022	TEN1
Protein localization	1	63.4×	0.022	ACOX1
Peroxisomal protein import	1	57.7×	0.022	ACOX1
Anchoring of the basal body to the plasma membrane	1	37.7×	0.031	FBF1
PPARA activates gene expression	1	31.5×	0.034	ACOX1
Cell Cycle	1	12.0×	0.081	TEN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
very long-chain fatty acid beta-oxidation	1	5617.3×	0.004	ACOX1
apical junction assembly	1	702.2×	0.006	FBF1
peroxisome fission	1	510.7×	0.006	ACOX1
fatty acid derivative biosynthetic process	1	510.7×	0.006	ACOX1
hydrogen peroxide biosynthetic process	1	468.1×	0.006	ACOX1
fatty acid catabolic process	1	432.1×	0.006	ACOX1
telomere capping	1	432.1×	0.006	TEN1
establishment of epithelial cell polarity	1	401.2×	0.006	FBF1
fatty acid beta-oxidation using acyl-CoA oxidase	1	374.5×	0.006	ACOX1
fatty acid oxidation	1	351.1×	0.006	ACOX1
alpha-linolenic acid metabolic process	1	295.6×	0.006	ACOX1
prostaglandin metabolic process	1	280.9×	0.006	ACOX1
very long-chain fatty acid metabolic process	1	255.3×	0.006	ACOX1
negative regulation of telomere maintenance via telomerase	1	244.2×	0.006	TEN1
unsaturated fatty acid biosynthetic process	1	216.1×	0.007	ACOX1
long-chain fatty acid biosynthetic process	1	147.8×	0.009	ACOX1
generation of precursor metabolites and energy	1	114.6×	0.011	ACOX1
lipid homeostasis	1	112.3×	0.011	ACOX1
cholesterol homeostasis	1	52.0×	0.022	ACOX1
lipid metabolic process	1	30.5×	0.036	ACOX1
cilium assembly	1	24.5×	0.042	FBF1
spermatogenesis	1	11.7×	0.083	ACOX1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
ACOX1	ALECTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACOX1	3	4
FBF1	0	0
TEN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALECTINIB	4	ACOX1
HYDRALAZINE	4	ACOX1
MASITINIB	3	ACOX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ACOX1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACOX1	1.3.3.6	acyl-CoA oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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)
ALECTINIB	4	ACOX1
HYDRALAZINE	4	ACOX1
MASITINIB	3	ACOX1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACOX1
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	FBF1, TEN1

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)
FBF1	0	—
TEN1	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
NCT01668186	Not specified	RECRUITING	Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)