Mitchell syndrome

Summary

Mitchell syndrome (MONDO:0030073) is a disease caused by ACOX1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ACOX1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 42

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Mitchell syndrome
Mondo ID	MONDO:0030073
OMIM	618960
Orphanet	631248
DOID	DOID:0070516
UMLS	C5394554
MedGen	1714342
GARD	0025523
Is cancer (heuristic)	no

Also known as: ACOX1 upregulation · MITCH · Mitchell syndrome

Data availability: 42 ClinVar variants · 2 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 › peroxisomal disease › peroxisomal single enzyme/protein defect › disorder of defective peroxisome oxidative status › Mitchell syndrome

Related subtypes (2): mulibrey nanism, acatalasia

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

42 retrieved; paginated sample, class counts are floors:

15 likely pathogenic, 10 pathogenic/likely pathogenic, 6 uncertain significance, 5 benign, 3 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075695	NM_004035.7(ACOX1):c.1312del (p.Ser438fs)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459402	NM_004035.7(ACOX1):c.1704_1707del (p.Ser568fs)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1502	NM_004035.7(ACOX1):c.442C>T (p.Arg148Ter)	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
2104874	NM_004035.7(ACOX1):c.260G>A (p.Trp87Ter)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138110	NM_004035.7(ACOX1):c.1789_1792del (p.Leu596_Thr597insTer)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680344	NM_004035.7(ACOX1):c.1276_1277del (p.Val426fs)	ACOX1	Pathogenic	criteria provided, multiple submitters, no conflicts
3240957	NM_004035.7(ACOX1):c.908dup (p.Tyr303Ter)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
578920	NM_004035.7(ACOX1):c.139del (p.Gln47fs)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
584427	NM_004035.7(ACOX1):c.710A>G (p.Asn237Ser)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
656515	NM_004035.7(ACOX1):c.1717del (p.Asp573fs)	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
852761	NM_004035.7(ACOX1):c.538+1G>A	ACOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1511590	NM_004035.7(ACOX1):c.945-1G>C	ACOX1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680338	NM_004035.7(ACOX1):c.846_856dup (p.Val286fs)	ACOX1	Likely pathogenic	criteria provided, single submitter
2680342	NM_004035.7(ACOX1):c.420_421del (p.Glu140fs)	ACOX1	Likely pathogenic	criteria provided, single submitter
2680345	NM_004035.7(ACOX1):c.795C>A (p.Tyr265Ter)	ACOX1	Likely pathogenic	criteria provided, single submitter
2680348	NM_004035.7(ACOX1):c.539-2A>G	ACOX1	Likely pathogenic	criteria provided, single submitter
2680351	NM_004035.7(ACOX1):c.1453G>T (p.Glu485Ter)	ACOX1	Likely pathogenic	criteria provided, single submitter
2680353	NM_004035.7(ACOX1):c.1729-2del	ACOX1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680356	NM_004035.7(ACOX1):c.498_499del (p.Asn166fs)	ACOX1	Likely pathogenic	criteria provided, single submitter
2680365	NM_004035.7(ACOX1):c.1603del (p.Val534_Val535insTer)	ACOX1	Likely pathogenic	criteria provided, single submitter
3240961	NM_004035.7(ACOX1):c.1362T>G (p.Tyr454Ter)	ACOX1	Likely pathogenic	criteria provided, single submitter
3240962	NM_004035.7(ACOX1):c.1584+1G>C	ACOX1	Likely pathogenic	criteria provided, single submitter
3583058	NM_004035.7(ACOX1):c.1654C>T (p.Gln552Ter)	ACOX1	Likely pathogenic	criteria provided, single submitter
3583059	NM_004035.7(ACOX1):c.1299-1G>C	ACOX1	Likely pathogenic	criteria provided, single submitter
3583060	NM_004035.7(ACOX1):c.748G>T (p.Glu250Ter)	ACOX1	Likely pathogenic	criteria provided, single submitter
3583062	NM_004035.7(ACOX1):c.430+1G>A	ACOX1	Likely pathogenic	criteria provided, single submitter
2187048	NM_004035.7(ACOX1):c.796G>A (p.Val266Met)	ACOX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3583061	NM_004035.7(ACOX1):c.692G>T (p.Gly231Val)	ACOX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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	Strong	Autosomal dominant	Mitchell syndrome	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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACOX1	HGNC:119	ENSG00000161533	Q15067	Peroxisomal acyl-coenzyme A oxidase 1	gencc,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.

Protein-family classification

Druggable: 1 · 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
Enzyme (other)	1	12.0×	0.083

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

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
buccal mucosa cell	1
duodenum	1
jejunal mucosa	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACOX1	3,503

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACOX1	Q15067	93.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
TYSND1 cleaves peroxisomal proteins	1	1427.5×	0.003	ACOX1
Beta-oxidation of very long chain fatty acids	1	878.5×	0.003	ACOX1
alpha-linolenic acid (ALA) metabolism	1	713.8×	0.003	ACOX1
Protein localization	1	190.3×	0.007	ACOX1
Peroxisomal protein import	1	173.0×	0.007	ACOX1
PPARA activates gene expression	1	94.4×	0.011	ACOX1

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
very long-chain fatty acid beta-oxidation	1	16852.0×	0.001	ACOX1
peroxisome fission	1	1532.0×	0.002	ACOX1
fatty acid derivative biosynthetic process	1	1532.0×	0.002	ACOX1
hydrogen peroxide biosynthetic process	1	1404.3×	0.002	ACOX1
fatty acid catabolic process	1	1296.3×	0.002	ACOX1
fatty acid beta-oxidation using acyl-CoA oxidase	1	1123.5×	0.002	ACOX1
fatty acid oxidation	1	1053.2×	0.002	ACOX1
alpha-linolenic acid metabolic process	1	887.0×	0.002	ACOX1
prostaglandin metabolic process	1	842.6×	0.002	ACOX1
very long-chain fatty acid metabolic process	1	766.0×	0.002	ACOX1
unsaturated fatty acid biosynthetic process	1	648.1×	0.002	ACOX1
long-chain fatty acid biosynthetic process	1	443.5×	0.003	ACOX1
generation of precursor metabolites and energy	1	343.9×	0.004	ACOX1
lipid homeostasis	1	337.0×	0.004	ACOX1
cholesterol homeostasis	1	156.0×	0.007	ACOX1
lipid metabolic process	1	91.6×	0.012	ACOX1
spermatogenesis	1	35.2×	0.028	ACOX1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 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
ACOX1	ALECTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACOX1	3	4

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: 1; 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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.