| domain | high-confidence finding | evidence type | key quantitative/example data | ontology suggestions | evidence limitations |
|---|---|---|---|---|---|
| Identity / nomenclature | Peroxisome biogenesis disorder 4B is a PEX6-related autosomal recessive peroxisome biogenesis disorder within the Zellweger spectrum; mild presentations overlap with Heimler syndrome 2 / non-classic ZSD. SCAR3/SCABD1 is **not supported** as a synonym by retrieved disease-gene evidence and appears to be conflated nomenclature. (pqac-00000000, pqac-00000002, pqac-00000018) | Disease-gene database + human clinical/review | Open Targets maps MONDO:0013931 to **PEX6** with evidence from multiple publications; 2022 review states ZSD ranges from severe Zellweger syndrome to mild Heimler syndrome. (pqac-00000000, pqac-00000002) | MONDO:0013931; MONDO: Zellweger spectrum disorder; HP:0001417 | MONDO/OMIM cross-labeling for severe vs mild PEX6 entities is not fully resolved in retrieved sources; no direct source supporting SCAR3/SCABD1 was found. |
| Inheritance / gene | Cause is biallelic pathogenic variation in **PEX6**, encoding a peroxisomal AAA-ATPase complex component required for peroxisome biogenesis and matrix-protein import. (pqac-00000000, pqac-00000005, pqac-00000012) | Human disease-gene evidence + ACMG standard + review | Autosomal recessive; PEX6 acts with PEX1 and PEX26 in the AAA complex. Example severe neonatal variant: **c.1409G>C (p.Gly470Ala)** homozygous in 3 Mixteco infants. (pqac-00000018, pqac-00000016) | HGNC:8856; NCBI Gene: PEX6; GO:0016560 protein import into peroxisome matrix, GO:0005777 peroxisome | Most detailed mechanistic data are often shared across AAA-complex genes, not PEX6-only. |
| Severe phenotype | Severe neonatal PEX6 disease presents with hypotonia, craniofacial/ocular anomalies, abnormal liver tests, VLCFA abnormalities, feeding/respiratory problems, and early death. (pqac-00000018, pqac-00000017, pqac-00000016) | PEX6-specific human case series (2023) | 3 Mixteco neonates with homozygous **p.Gly470Ala**: all had elevated C26:0 (7.17–8.27 µmol/L), high C26/C22 ratios (0.424–0.592), hypotonia; 2/3 died by ~3–6 months; all had abnormal hepatic panels. (pqac-00000017, pqac-00000016) | HP:0001252 hypotonia; HP:0001508 failure to thrive; HP:0002240 hepatomegaly; HP:0000365 hearing impairment; HP:0000478 abnormality of the eye | Very small cohort; founder-effect population; not representative of full PEX6 spectrum. |
| Mild / non-classic phenotype | Mild ZSD / Heimler-like PEX6 disease can present with sensorineural hearing loss, enamel defects, retinal dystrophy, and sometimes late or adult diagnosis. (pqac-00000002, pqac-00000005) | Human clinical review / synthesis | 2022 review: mild phenotypes may show hearing loss, amelogenesis imperfecta, retinal dystrophy and only slight/normal biochemical abnormalities; adult diagnostic odyssey highlighted for mild ZSD. (pqac-00000002) | HP:0000365; HP:0000548 retinitis pigmentosa; HP:0000674 dental enamel abnormality | Retrieved mild examples were often PEX1-centered or review-level, not primary PEX6 cohorts. |
| Biochemical diagnostics | First-line testing relies on peroxisomal metabolites, especially VLCFAs; supportive markers include plasmalogens, phytanic/pristanic acid, bile-acid intermediates, pipecolic acid. (pqac-00000012, pqac-00000014) | ACMG technical standard + disease reviews | ACMG: current approach relies heavily on biochemical tests measuring plasma very-long-chain and branched-chain fatty acids and red-cell plasmalogens; trial protocols also monitor phytanic acid and plasmalogens. (pqac-00000012, pqac-00000010) | CHEBI: very long-chain fatty acid; CHEBI: phytanic acid; CHEBI: pristanic acid; LOINC concept suggestions for VLCFA/plasmalogen assays | Biomarker profile is generic to peroxisomal disorders and not specific to PEX6. |
| Diagnostic caveat | Normal plasma VLCFA does **not** exclude PEX6-related disease; integrated biochemical + molecular testing is needed, especially in mild phenotypes. (pqac-00000005, pqac-00000006, pqac-00000007) | PEX6-focused review/synthesis | Example cited PEX6 case: homozygous **c.1992G>C (p.Glu664Asp)** with developmental delay, dysmorphism, hearing loss, but **normal plasma VLCFA**. (pqac-00000005, pqac-00000006) | MAXO: genetic testing; GO:0005777 peroxisome | Evidence comes from review-level summary of individual cases, not a large cohort. |
| Mechanism | PEX6 forms, with PEX1 and PEX26, the peroxisomal AAA-ATPase complex that recycles ubiquitinated **PEX5** from the peroxisomal membrane; dysfunction leads to impaired matrix-protein import and increased pexophagy. (pqac-00000012, pqac-00000015, pqac-00000014) | Primary cell biology + ACMG background | Law 2017: loss of AAA-complex function causes accumulation of ubiquitinated PEX5 and signals pexophagy; Klouwer 2021 describes impaired PEX1/PEX6-complex function and defective matrix-protein import. (pqac-00000015, pqac-00000014) | GO:0016558 protein import into peroxisome matrix; GO:0000425 autophagy of peroxisome; GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process; CL:0000057 fibroblast | Core mechanistic experiments largely used PEX1/AAA-complex models rather than PEX6-mutant primary datasets. |
| Downstream metabolic consequences | Peroxisome dysfunction causes accumulation of VLCFAs and other substrates plus reduced plasmalogens, mature bile acids, and DHA, affecting liver, nervous system, retina, and hearing. (pqac-00000012, pqac-00000014, pqac-00000005) | ACMG standard + review + case evidence | ACMG lists increased VLCFAs, pristanic acid and bile-acid precursors, and decreased plasmalogens, mature bile acids and DHA in PBD-ZSD. (pqac-00000014, pqac-00000012) | UBERON:0002107 liver; UBERON:0000955 brain; UBERON:0000966 retina; UBERON:0001723 cochlea; HP:0001290 developmental delay | Not all abnormalities are present in every mild PEX6 patient. |
| Epidemiology / founder effect | ZSD is rare; a 2023 PEX6-specific report suggests a possible Mixteco founder effect for **p.Gly470Ala**. (pqac-00000018, pqac-00000008) | Human case series / epidemiologic observation | Report states ZSD incidence ~**1/50,000** newborns in the U.S.; all 3 cases were born to Mixteco mothers and shared homozygous **PEX6 c.1409G>C (p.Gly470Ala)**. (pqac-00000018) | HP:0034341 founder effect (concept suggestion) | Founder-effect inference is preliminary and based on 3 cases plus cited prior literature. |
| Prognosis | Prognosis is highly variable: neonatal presentations often have survival <1 year, whereas milder ZSD can persist into adolescence/adulthood. (pqac-00000018, pqac-00000002, pqac-00000007) | Human case series + clinical reviews | 2023 PEX6 neonatal report: 2/3 infants died before 1 year; review notes some ZSD patients survive into adulthood, especially mild forms. (pqac-00000018, pqac-00000002) | HP:0003819 neonatal onset; HP:0011463 childhood onset; HP:0003581 adult onset | No PEX6-specific longitudinal natural-history cohort with survival estimates was retrieved. |
| Supportive treatment | No curative therapy is established; management is supportive and organ-directed, including nutritional, hepatic, audiologic, ophthalmologic, developmental, and palliative care. (pqac-00000002, pqac-00000018) | Clinical review + human case reports | 2023 case report notes no curative treatment; neonatal patients received comfort-focused care; ZSD reviews emphasize supportive care across systems. (pqac-00000018, pqac-00000002) | MAXO: supportive care; MAXO: hearing aid/cochlear management; MAXO: ophthalmologic monitoring; MAXO: physical therapy | PEX6-specific treatment guidelines were not separately retrieved from generic ZSD management guidance. |
| Cholic acid / liver-directed therapy | Cholic acid is used in ZSD liver disease contexts, but evidence is **generic ZSD**, not PEX6-specific, and benefit may be incomplete. (pqac-00000018) | Review-level mention in retrieved PEX6 report | 2023 report cites “promising” prior study for cholic acid; not evaluated in the reported PEX6 neonatal series. (pqac-00000018) | CHEBI: cholic acid; MAXO: bile acid replacement | No direct PEX6-stratified efficacy data retrieved here. |
| Experimental therapy / hydroxychloroquine | Hydroxychloroquine was clinically tested for PEX1/PEX6/PEX26 PBD-ZSD eligibility, but in-vitro evidence does **not** support autophagy inhibitors as effective restoration therapy. (pqac-00000010, pqac-00000014) | Phase II clinical trial registry + in-vitro study | **NCT03856866**: randomized double-blind crossover N-of-1 HCQ trial, enrollment **3**, included **PEX6** patients with abnormal VLCFAs; Klouwer 2021 found no improvement and worsening of peroxisomal functions with HCQ/chloroquine/3-MA. (pqac-00000010, pqac-00000014) | MAXO: hydroxychloroquine administration; GO:0000425 pexophagy | Trial record available, but no retrieved peer-reviewed clinical outcomes by genotype; lab evidence mainly PEX1-G843D cells. |
| Other trials / real-world implementation | Active observational infrastructure exists for natural history, caregiver QoL, and retinopathy, but not proven disease-modifying PEX6 therapy. (pqac-00000009, pqac-00000004) | ClinicalTrials.gov observational studies | **NCT01668186** natural history: enrollment **244**, recruiting; **NCT03440905** caregiver QoL: **92** completed; **NCT06190626** retinopathy study: **30** recruiting; **NCT03115086** Cholbam registry: **55** active-not-recruiting. (pqac-00000004, pqac-00000009) | MAXO: natural history study participation; MAXO: retinal monitoring | Most studies are pan-ZSD/PBD and not PEX6-specific. |
| Model systems | Mechanistic understanding comes from patient fibroblasts and generic ZSD animal models (mouse, zebrafish, Drosophila), with strong relevance to AAA-complex/peroxisome biology. (pqac-00000015, pqac-00000014) | In vitro + animal model/review | Patient-cell and fibroblast work support AAA-complex/pexophagy model; Drosophila and zebrafish peroxisome models show conserved import, lipid, and neurodevelopmental phenotypes. (pqac-00000015, pqac-00000014) | CL:0000057 fibroblast; NCBITaxon:10090 mouse; NCBITaxon:7955 zebrafish; NCBITaxon:7227 Drosophila | Retrieved animal models were mostly PEX1 or non-PEX6 peroxisome models, so disease recapitulation is indirect for PEX6-PBD4B. |


*Table: This table condenses high-confidence knowledge-base facts for PEX6-related peroxisome biogenesis disorder 4B, separating PEX6-specific findings from broader Zellweger spectrum evidence. It is useful for rapid curation of nomenclature, phenotypes, diagnostics, mechanism, prognosis, treatment status, and model-system evidence.*