| Domain | PEX5/PBD2B-specific conclusion | Evidence scope/caveat |
|---|---|---|
| Identity | **Peroxisome biogenesis disorder 2B (PBD2B; OMIM 202370)** denotes the non-classic, milder end of **PEX5-related Zellweger spectrum disorder (ZSD)**; historical labels include neonatal adrenoleukodystrophy and infantile Refsum disease. It belongs to **complementation group 2** (Japanese group F), not PEX1- or PEX2-related disease. (pqac-00000002, pqac-00000003) | Historical phenotype labels overlap and are now generally treated as a severity continuum rather than discrete disorders. A dedicated MONDO term for PBD2B was not verified; broader ZSD is MONDO:0019609. (pqac-00000000) |
| Gene/protein | **PEX5** (12p13.31; OMIM *600414; ENSG00000139197) encodes the cytosolic receptor/chaperone for proteins bearing a C-terminal peroxisomal targeting signal type 1 (PTS1). PEX5L also supports PTS2 import through PEX7. (pqac-00000000, pqac-00000003, pqac-00000015) | This is specifically a PEX5 disorder; PEX1 and PEX2 encode different components of peroxisome biogenesis. |
| Inheritance | Autosomal recessive: disease results from **biallelic germline PEX5 variants**; PBD2B is expected to reflect hypomorphic alleles retaining partial receptor/import activity. (pqac-00000002, pqac-00000003) | Penetrance is expected to be high for pathogenic biallelic genotypes, but PEX5-specific estimates, modifier genes, founder effects, and carrier frequencies are unavailable. A reported 2025 homozygous stop-loss/frameshift allele remained an ACMG VUS without functional validation. (pqac-00000018, pqac-00000019) |
| Core mechanism | Reduced PEX5 function impairs PTS1-cargo recognition, docking at PEX13/PEX14, matrix translocation, or receptor recycling after Cys11 monoubiquitination and PEX1–PEX6–PEX26-mediated extraction; this reduces peroxisomal matrix-enzyme activity and perturbs lipid and redox metabolism. (pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000017) | Import failure is well established; the relative contribution of individual metabolites, mitochondrial dysfunction, oxidative stress, inflammation, and pexophagy to each human phenotype remains partly inferred from cells and models. |
| Biochemical signature | Expected ZSD profile: elevated plasma C26:0/C26:1 and C24:0/C22:0 or C26:0/C22:0 ratios, phytanic/pristanic acids, pipecolic acid, and C27 bile-acid intermediates (DHCA/THCA), with reduced erythrocyte plasmalogens; fibroblasts show impaired matrix-protein import. (pqac-00000003, pqac-00000007, pqac-00000008) | Results vary with age, diet, residual function, and tissue; mild disease may yield borderline or normal plasma results. These are general ZSD biomarkers, not validated PEX5-specific prognostic surrogates. |
| Mild-spectrum phenotypes | Typical features include infantile/childhood hypotonia and developmental delay, sensorineural hearing loss, progressive retinal dystrophy or visual loss, liver dysfunction, enamel hypoplasia, ataxia, peripheral neuropathy, spasticity, and stable or progressive leukodystrophy; renal stones/hyperoxaluria and adrenal insufficiency may emerge. (pqac-00000003, pqac-00000008, pqac-00000025) | PEX5-isolated frequencies are unavailable. General ZSD ophthalmic cohorts found abnormal ERGs in about 93%, macular cysts/schisis in 16/21 milder patients, and slow visual-acuity decline of approximately 0.01 LogMAR/year, but these cohorts were not PEX5-specific. (pqac-00000006, pqac-00000021) |
| Diagnosis | Confirm a compatible phenotype with a **multianalyte peroxisomal biochemical profile**, followed by a PEX/ZSD gene panel, exome, or genome sequencing demonstrating two clinically significant **PEX5** alleles in trans. Use fibroblast PTS1-import/localization and metabolic assays when biochemical or variant findings are equivocal. (pqac-00000005, pqac-00000007) | Single-marker VLCFA testing can miss mild PEX disorders. CMA, karyotyping, FISH, mitochondrial-DNA, and repeat-expansion testing are not first-line unless another diagnosis is suspected. |
| Treatment | No approved curative or **PEX5-targeted disease-modifying therapy** exists. Management is multidisciplinary and supportive: nutrition/gastrostomy when needed, antiseizure medication, hearing aids or cochlear implants, visual aids, physical/occupational/speech therapy, fat-soluble vitamins when deficient, adrenal replacement, vitamin K for coagulopathy, and renal-stone prevention. (pqac-00000008, pqac-00000010) | Evidence is based mainly on expert guidance and general ZSD practice; controlled PEX5-specific response rates and pharmacogenomic guidance are absent. |
| Prognosis | Hypomorphic PEX5 disease is expected to permit survival through childhood and potentially adulthood, with chronic sensory, neurologic, hepatic, and renal morbidity; leukodystrophy may remain stable or progress. (pqac-00000021, pqac-00000025) | No PEX5/PBD2B survival curve, median life expectancy, or validated prognostic biomarker exists. Severe-ZSD mortality within 1–2 years should not be directly applied to PBD2B. |
| Epidemiology | PBD2B is ultra-rare; no reliable PEX5-specific incidence, prevalence, sex ratio, ethnic distribution, or carrier-frequency estimate was identified. Both sexes should be affected equally under autosomal-recessive inheritance. | Published ZSD-wide or PEX1-specific estimates cannot be assigned to PEX5. Historical evidence identified only very small numbers of complementation-group-2 patients. (pqac-00000002, pqac-00000024) |
| Models/trials | Pex5-null and conditional mice reproduce absent matrix import, mitochondrial/ER abnormalities, neuronal-migration delay, dysmyelination, axonal degeneration, neuroinflammation, motor/cognitive impairment, and early death; CRISPR pex5 zebrafish show reduced import, hepatic lipid accumulation, demyelination, edema, impaired movement, and reduced survival. (pqac-00000004) | Null models resemble severe ZSD more than hypomorphic PBD2B. General ZSD studies include natural-history and retinal cohorts, while betaine and hydroxychloroquine trials targeted PEX1 or PEX1/PEX6/PEX26—not PEX5—and have not established disease-modifying efficacy. (pqac-00000011, pqac-00000028, pqac-00000029, pqac-00000030) |


*Table: Compact evidence summary distinguishing PEX5-specific conclusions from broader Zellweger-spectrum extrapolation. It highlights the scarcity of PEX5-isolated quantitative data and absence of a PEX5-targeted disease-modifying therapy.*