peroxisome biogenesis disorder 4B

Summary

peroxisome biogenesis disorder 4B (MONDO:0013931) is a disease caused by PEX6 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PEX6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 138
• Phenotypes (HPO): 19
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000524	Conjunctival telangiectasia	Frequent (30-79%)
HP:0000618	Blindness	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000763	Sensory neuropathy	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002346	Head tremor	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0005102	Cochlear degeneration	Frequent (30-79%)
HP:0006254	Elevated alpha-fetoprotein	Frequent (30-79%)
HP:0007126	Proximal amyotrophy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007263	Spinocerebellar atrophy	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 4B
Mondo ID	MONDO:0013931
MeSH	C537309
OMIM	271250, 614863
Orphanet	95433
DOID	DOID:0081433, DOID:0111612
NCIT	C155755
UMLS	C3553937
MedGen	766851
GARD	0015860
Is cancer (heuristic)	no

Also known as: autosomal recessive cerebellar ataxia - blindness - deafness · autosomal recessive cerebellar ataxia-blindness-deafness syndrome · autosomal recessive spinocerebellar ataxia type 3 · autosomal recessive spinocerebellar ataxia-blindness-hearing loss syndrome · non-classic peroxisome biogenesis disorder · PBD4B · peroxisome biogenesis disorder 4B · peroxisome biogenesis disorder type 4B · SCABD · SCAR3 · spinocerebellar ataxia autosomal recessive 3 · spinocerebellar ataxia, autosomal recessive 3

Data availability: 138 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive syndromic cerebellar ataxia › peroxisome biogenesis disorder 4B

Related subtypes (6): autosomal recessive cerebellar ataxia-saccadic intrusion syndrome, autosomal recessive spinocerebellar ataxia 11, ataxia - oculomotor apraxia type 4, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, Gemignani syndrome, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

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

138 retrieved; paginated sample, class counts are floors:

32 likely pathogenic, 30 uncertain significance, 26 pathogenic/likely pathogenic, 21 conflicting classifications of pathogenicity, 16 pathogenic, 7 benign, 4 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2627659	NM_000287.4(PEX6):c.[*438TAAA[1];2578C>T]		Pathogenic	no assertion criteria provided
1069504	NM_000287.4(PEX6):c.727C>T (p.Gln243Ter)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071121	NM_000287.4(PEX6):c.1691del (p.Cys564fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323439	NM_000287.4(PEX6):c.1313dup (p.Glu439fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
1324885	NM_000287.4(PEX6):c.1326dup (p.Ser443fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356707	NM_000287.4(PEX6):c.531del (p.Pro179fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1369876	NM_000287.4(PEX6):c.1415del (p.Pro472fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447140	NM_000287.4(PEX6):c.914_923del (p.Asp305fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1515421	NM_000287.4(PEX6):c.2734G>A (p.Ala912Thr)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194165	NM_000287.4(PEX6):c.2440C>T (p.Arg814Ter)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
2136394	NM_000287.4(PEX6):c.402del (p.Gly135fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
217424	NM_000287.4(PEX6):c.821C>T (p.Pro274Leu)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217426	NM_000287.4(PEX6):c.1841del (p.Leu614fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
224321	NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
224323	NM_000287.4(PEX6):c.1715C>T (p.Thr572Ile)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2837695	NM_000287.4(PEX6):c.1A>T (p.Met1Leu)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30195	NM_000287.4(PEX6):c.1601T>C (p.Leu534Pro)	PEX6	Pathogenic	no assertion criteria provided
3064919	NM_000287.4(PEX6):c.290T>G (p.Val97Gly)	PEX6	Pathogenic	criteria provided, single submitter
3593619	NM_000287.4(PEX6):c.2T>A (p.Met1Lys)	PEX6	Pathogenic	criteria provided, single submitter
3601634	NM_000287.4(PEX6):c.3G>T (p.Met1Ile)	PEX6	Pathogenic	criteria provided, single submitter
4277700	NM_000287.4(PEX6):c.1016del (p.Gly339fs)	PEX6	Pathogenic	criteria provided, single submitter
446026	NM_000287.4(PEX6):c.1287del (p.Trp430fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495796	NM_000287.4(PEX6):c.1947del (p.Ile650fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
498713	NM_000287.4(PEX6):c.273G>A (p.Trp91Ter)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
499109	NM_000287.4(PEX6):c.311del (p.Gly104fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550358	NM_000287.4(PEX6):c.1962-1G>A	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551023	NM_000287.4(PEX6):c.510dup (p.Gly171fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553235	NM_000287.4(PEX6):c.2082del (p.Gly695fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554303	NM_000287.4(PEX6):c.506_507del (p.Glu169fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555170	NM_000287.4(PEX6):c.2435G>A (p.Arg812Gln)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
PEX6	Definitive	Autosomal recessive	peroxisome biogenesis disorder	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEX6	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome
PEX6	Orphanet:44	Neonatal adrenoleukodystrophy
PEX6	Orphanet:772	Infantile Refsum disease
PEX6	Orphanet:912	Zellweger syndrome
PEX6	Orphanet:95433	Autosomal recessive spinocerebellar ataxia-blindness-deafness 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
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.

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)
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS

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
body of pancreas	1
mucosa of transverse colon	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX6	227	ubiquitous	marker	right uterine tube, body of pancreas, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEX6	2,620

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX6	Q13608	69.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Peroxisomal protein import	1	173.0×	0.006	PEX6

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
protein import into peroxisome matrix, translocation	1	4213.0×	1e-03	PEX6
protein unfolding	1	3370.4×	1e-03	PEX6
protein import into peroxisome matrix, receptor recycling	1	2407.4×	1e-03	PEX6
protein targeting to peroxisome	1	1685.2×	1e-03	PEX6
protein import into peroxisome matrix	1	1404.3×	1e-03	PEX6
peroxisome organization	1	802.5×	0.001	PEX6
protein stabilization	1	66.9×	0.015	PEX6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
PEX6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PEX6	3.6.4.7	peroxisome-assembly ATPase

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	1	PEX6
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)
PEX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01470729	Not specified	COMPLETED	Biomarkers in Autosomal Dominant Cerebellar Ataxia