Peroxisome Biogenesis Disorder 1B (PEX1-Related; Non-Classic Zellweger Spectrum Disorder — NALD/IRD Phenotype): Comprehensive Research Report

1. Disease Information

Overview. Peroxisome Biogenesis Disorder 1B (PBD1B) is the intermediate/mild end of the Zellweger spectrum disorder (ZSD) continuum caused by biallelic pathogenic variants in PEX1. Historically, PBD1B corresponded to the overlapping clinical entities neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) — the milder phenotypes of ZSD, as distinguished from classic/severe Zellweger syndrome (PBD1A, OMIM 214100), which is caused by the most severe, null PEX1 genotypes. Current clinical nosology (GeneReviews) treats ZSD as a single phenotypic continuum rather than three discrete diseases, because PEX1 (and PEX6) genotypes span the full severity range: "the term 'ZSD' is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype" (GeneReviews, NBK1448).

Key identifiers: - OMIM: #601539 (PBD1B), gene locus PEX1 *602136; related severe allelic disorder Zellweger syndrome PBD1A #214100 - MONDO: MONDO:0011101 - Orphanet: ORPHA912 (Zellweger spectrum disorder, umbrella term for the spectrum including this entity) - ICD-10-CM: E71.510 (Zellweger syndrome) / Q87.8 (other specified congenital malformation syndromes) is used generically for ZSD-spectrum entries - MeSH: Zellweger Syndrome (D019084) - Gene: PEX1 (HGNC:8850), chromosome 7q21.2 - Complementation group: CG1 (equivalent to complementation group E, CGE)

Synonyms: Peroxisome biogenesis disorder, complementation group 1 (CG1); Zellweger spectrum disorder (intermediate/mild forms); neonatal adrenoleukodystrophy (NALD); infantile Refsum disease (IRD); PEX1-related ZSD.

Evidence base: Information is drawn from aggregated disease-level clinical/genetic resources (OMIM, GeneReviews, Orphanet), longitudinal natural history cohort studies (e.g., NCT01668186), case reports/series, and mechanistic studies in cell and animal models — a mix of human-clinical, cohort-registry, and model-organism sources.

2. Etiology

Disease causal factor: Biallelic (homozygous or compound heterozygous) loss-of-function or hypomorphic pathogenic variants in PEX1 (7q21.2), encoding a peroxisomal AAA+ ATPase. PEX1 variants account for ~60–70% of all ZSD cases — the single most common genetic cause (GeneReviews; PMID 20301621).

Genetic risk factors / genotype determinants of severity: - p.Ile700Tyrfs*42 (a common frameshift/premature-truncation allele) — associated with severe disease when in trans with another null allele. - p.Gly843Asp (G843D, "Gly844Asp" in some mouse-model nomenclature offset by one residue) — the most common hypomorphic missense allele, present in ~30% of ZSD patients, producing a misfolded but partially functional PEX1 protein; homozygosity is associated with milder, degenerative-type phenotypes without major congenital malformations, with some patients surviving into adulthood (PMID 24503136; PMC4901203). - Together, p.Ile700Tyrfs*42 and p.Gly843Asp account for ~80% of PEX1 pathogenic alleles (GeneReviews NBK1448). - Genotype-phenotype correlation: "PEX1 mutations in complementation group 1 ... correlate with severity of disease" — complete loss-of-function (large deletions, nonsense, frameshift) genotypes → severe (PBD1A/Zellweger); missense/hypomorphic combinations (including G843D) → intermediate-to-mild (PBD1B/NALD-IRD) (Nature Pediatric Research, PMID reference "pr2002118"). - At least 114 distinct PEX1 mutations have been reported (MedlinePlus/GeneReviews).

Protective factors: No genetic or environmental protective factors are established; disease severity is governed almost entirely by residual PEX1 functional capacity conferred by the specific allele combination (allelic "dosage" of function). No modifier genes are formally established, though allelic background effects have been documented for PEX6 (p.Arg860Trp acts dominantly depending on allelic background), raising the possibility that similar background-dependent modifier effects could exist for PEX1, though this is not yet demonstrated.

Environmental/other factors: ZSD/PBD1B is a purely monogenic Mendelian disorder; no environmental, infectious, or lifestyle causal or risk factors are established. No gene-environment interaction data exist for PEX1.

Suggested ontology terms: Gene — hgnc:8850 (PEX1); Inheritance — HP:0000007 (Autosomal recessive inheritance).

3. Phenotypes

PBD1B (NALD/IRD-range ZSD) phenotypes are milder and more slowly progressive than classic Zellweger syndrome, but multisystemic. Suggested HPO terms and characteristics below (compiled from GeneReviews NBK1448, OMIM 601539, NORD, StatPearls NBK560676):

Table (click to expand)

Phenotype	HPO term	Onset	Severity/course	Frequency notes
Hypotonia	HP:0001252	Neonatal/infantile	Variable; less severe than classic Zellweger	Most affected children (near-universal)
Developmental delay / intellectual disability	HP:0001263 / HP:0001249	Infantile	Progressive in some; static in others; unlike Zellweger syndrome, some patients achieve head control, sit unsupported, or walk independently	Common but variable
Sensorineural hearing loss	HP:0000407	Infantile–childhood, progressive	Progressive	Frequent; often severe
Retinal dystrophy / pigmentary retinopathy	HP:0000556 / HP:0000510	Infantile–childhood	Progressive	Frequent
Cataracts	HP:0000518	Infantile	Variable	Reported
Hepatomegaly / hepatic dysfunction (elevated LFTs, coagulopathy)	HP:0002240 / HP:0001392	Infantile	Progressive to fibrosis in some	Common
Adrenal insufficiency	HP:0000846	Any age, often subclinical	Progressive; requires surveillance	Occurs in a subset; often subclinical, detected on ACTH stimulation
Ataxia / peripheral neuropathy	HP:0001251 / HP:0009830	Childhood	Progressive	Reported in milder/older survivors
Leukodystrophy / white matter disease on MRI	HP:0002352	Variable, can present later	Can be progressive, mimicking X-ALD	Present in NALD-range phenotype
Renal cysts	HP:0000107	Congenital-infantile	Static	Less common in milder forms than in classic Zellweger
Chondrodysplasia punctata (bone stippling, patella)	HP:0002832 / HP:0100255	Congenital	Static	More typical of severe Zellweger; occasionally seen in milder PBD1B
Failure to thrive / feeding difficulty	HP:0001508 / HP:0011968	Infantile	—	Common
Seizures	HP:0001250	Variable	—	Less frequent/less severe than classic Zellweger
Amelogenesis imperfecta (dental enamel defects)	HP:0000705	Childhood	—	Recognized secondary finding requiring dental surveillance
Nephrolithiasis (kidney stones)	HP:0000787	Childhood-onset	—	Recognized complication, monitored via urine oxalate/creatinine ratio
Osteopenia/osteoporosis	HP:0000939	Childhood	Progressive	Bone health surveillance recommended (vitamin D, bisphosphonate consideration)

Quality of life impact: Combined sensory loss (vision + hearing), motor impairment, and cognitive delay substantially affect adaptive functioning; disease-specific QOL instruments are not well established, but functional impact is described qualitatively across natural-history cohort studies (e.g., NCT01668186, and the ophthalmic natural-history cohort study, medRxiv 2022.11.06.22279732).

Distinguishing feature from classic Zellweger syndrome (PBD1A): Unlike Zellweger syndrome, PBD1B patients typically lack major congenital structural malformations and show a degree of psychomotor development — some achieve head control, independent sitting, or walking — with disease dominated instead by progressive sensorineural/degenerative features (vision, hearing, neurologic).

4. Genetic/Molecular Information

Causal gene: PEX1 (Peroxisome Biogenesis Factor 1), OMIM *602136, HGNC:8850, chromosome 7q21.2. Encodes a 1,283 amino acid, ~143–147 kDa protein, a AAA+ (ATPases Associated with diverse cellular Activities) family ATPase.

Variant classes causing PBD1B specifically: - Compound heterozygosity for one severe (null) and one hypomorphic allele, OR - Homozygosity/compound heterozygosity for hypomorphic missense alleles (classically p.Gly843Asp), OR - Combinations of hypomorphic alleles that retain partial PEX1 function. - Contrast: PBD1A (classic Zellweger, severe) results from biallelic null/loss-of-function genotypes (large deletions, nonsense, frameshift such as p.Ile700Tyrfs*42 in trans with another null allele).

Variant classification (ACMG/ClinVar): Missense (e.g., p.Gly843Asp — pathogenic/hypomorphic), frameshift (e.g., p.Ile700Tyrfs*42 — pathogenic/null), nonsense, splice-site, and small indels are all reported; large deletions/duplications also occur (example ClinVar record: NM_000466.3(PEX1):c.2097dup (p.Ile700fs) associated with "Peroxisome biogenesis disorder 1B").

Population/allele frequency: - The G843D hypomorphic allele is relatively common throughout Europe, less common in US cohorts; in Japan, p.Arg633Ter predominates instead, and the classic European alleles are largely absent (PMC12166394). - Molecular testing panels detect ~98% of PEX1 variants in affected individuals (GeneReviews).

Origin: Exclusively germline (autosomal recessive Mendelian); no somatic PBD1B has been reported (this is a developmental/congenital metabolic disease, not neoplastic).

Functional consequences: Loss-of-function or partial loss-of-function of PEX1 ATPase activity → failure of the PEX1/PEX6 AAA-ATPase heterohexameric motor (the "Receptor Export Module," REM) to extract/recycle the PTS1-receptor PEX5 from the peroxisomal membrane after matrix-protein import, blocking further rounds of import and producing peroxisome-import-deficient "ghost peroxisomes" that carry the membrane but lack matrix enzymes (PMC6862443; PMC5762779; Nat Commun s41467-017-02474-4). The G843D variant specifically produces a PEX1 protein with partial retained ATPase/import-supporting activity but reduced stability, and is rapidly degraded by the proteasome — a defect amenable to pharmacologic chaperone rescue (biorxiv 2024.12.10.627778; PMC preprint).

Modifier genes: None formally validated for PEX1 itself, though the analogous PEX6 p.Arg860Trp allele shows allelic-background-dependent dominant behavior, illustrating that modifier/background effects are plausible in this gene family.

Epigenetic information: Not established/reported for PBD1B specifically; no disease-associated DNA methylation or histone modification signature has been characterized in the literature reviewed.

Chromosomal abnormalities: PBD1B is caused by intragenic PEX1 variants (point mutations, small indels) rather than large chromosomal rearrangements; large deletions/duplications of PEX1 are detected by deletion/duplication analysis as part of standard multigene panel testing but are not the predominant mutation type.

Suggested ontology terms: Gene — hgnc:8850 (PEX1); Protein function — GO:0016887 (ATP hydrolysis activity), GO:0016558 (protein import into peroxisome matrix); Molecular function — GO:0004396 (unfoldase-related AAA-ATPase activity, mechanistically analogous term).

5. Environmental Information

PBD1B is a monogenic disorder; there are no known environmental, toxic, occupational, or infectious causal or contributory factors. No lifestyle risk-modifying factors (diet, smoking, exercise) are documented in the literature. This section is largely not applicable for this disease beyond standard supportive nutritional management (below), which addresses disease consequences (fat-soluble vitamin malabsorption) rather than etiology.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Molecular/upstream lesion: Biallelic hypomorphic/partial-loss-of-function PEX1 variants (e.g., G843D) → misfolded, unstable, but partially active PEX1 protein.
Complex assembly failure: PEX1 heterohexamerizes with PEX6 to form the AAA-ATPase "Receptor Export Module" (REM) that recycles PEX5 (the peroxisomal targeting signal-1, PTS1, receptor) from the peroxisomal membrane back to the cytosol after each round of matrix-protein import (PMC6862443, Nat Commun 2023 s41467-023-41640-9 — cryo-EM structure of the substrate-bound complex).
Impaired matrix protein import: With reduced PEX1/PEX6 REM activity, PEX5 is not efficiently extracted/recycled → progressive failure to import newly synthesized PTS1/PTS2-tagged matrix enzymes → formation of peroxisomal "ghost" membrane remnants that lack the full complement of >50 resident matrix enzymes.
Biochemical consequences (multiple enzyme deficiencies in a single organelle):
Failure of β-oxidation of very-long-chain fatty acids (VLCFA, ≥C22) → accumulation of C26:0, C26:1 in plasma.
Failure of α-oxidation → accumulation of phytanic and pristanic acid.
Failure of bile-acid side-chain oxidation → accumulation of C27 bile-acid intermediates (DHCA, THCA).
Elevated pipecolic acid.
Deficient synthesis of plasmalogens (ether phospholipids) and docosahexaenoic acid (DHA), both of which require peroxisomal enzymatic steps.
Cellular consequences: ER stress response and activation of pexophagy (autophagic clearance of dysfunctional peroxisomes) have been demonstrated transcriptomically in the zebrafish pex1-null model (PMC12626956); lipid dysregulation (VLCFA accumulation, DHA/plasmalogen deficiency) drives membrane and myelin lipid abnormalities.
Tissue-level consequences:
CNS: impaired myelination/leukodystrophy, neuronal dysfunction, sensorineural hearing loss (documented mechanistically via cochlear hair-cell-specific Pex1 conditional knockout mouse — loss of Pex1 in inner ear hair cells causes cochlear synaptopathy and hearing loss, doi:10.3390/cells11243982).
Retina: photoreceptor/RPE lipid dysregulation and structural disruption (Pex1-G844D mouse RPE structural/lipid studies, biorxiv 2024.09.05.611330); disrupted outer nuclear/retinal layer architecture in zebrafish adults.
Liver: progressive hepatocellular injury/fibrosis (longitudinal Pex1-G844D mouse liver-disease-progression study, biorxiv 2025.05.08.652960).
Adrenal cortex: insufficiency from lipid-laden cortical dysfunction (mechanistically analogous to X-ALD adrenal involvement).
Bone: stippled epiphyses (chondrodysplasia punctata) in more affected individuals, reflecting disrupted plasmalogen-dependent cartilage/bone matrix processes.
Clinical manifestation: The cumulative multisystem, progressive, sensorineural/hepatic/neurologic phenotype characteristic of PBD1B (milder end of ZSD).

Cell types involved: hepatocyte (CL:0000182), cochlear hair cell (CL:0000855 or more specific inner/outer hair cell terms), retinal photoreceptor cell (CL:0000210) and retinal pigment epithelial cell (CL:0002586), adrenal cortex cell (CL:1000454), neuron (CL:0000540), oligodendrocyte (CL:0000128, for myelination defects), chondrocyte (CL:0000138, for stippled epiphyses).

Suggested GO Biological Process terms: GO:0016558 (protein import into peroxisome matrix), GO:0006635 (fatty acid beta-oxidation), GO:0001561 (fatty acid alpha-oxidation), GO:0097009 (energy homeostasis, less specific), GO:0008610 (lipid biosynthetic process), GO:0006687 (glycosphingolipid metabolic process — plasmalogen-adjacent), GO:0034389 (lipid droplet organization — peroxisome/pexophagy adjacent), GO:0044804 (autophagy of peroxisome/pexophagy).

Omics/advanced technologies: Transcriptomic profiling of pex1−/− zebrafish larvae shows upregulated ER-stress response genes and pexophagy pathway genes, and dysregulation of neurophysiological/visual-perception gene sets (PMC12626956; Frontiers 10.3389/fnmol.2025.1634536). Lipidomic studies in the zebrafish model reveal organ-specific accumulation of distinct fatty-acid species (bioRxiv 2021.01.03.425169). iPSC-derived models of ZSD show impaired peroxisome assembly and cell-type-specific lipid abnormalities (PMC4553005).

7. Anatomical Structures Affected

Organ level (primary): Brain/CNS, liver, adrenal glands, eye (retina, lens), inner ear (cochlea), kidney, skeletal system, peripheral nerves. Secondary/complications: Cardiovascular (less prominent than in classic Zellweger, where congenital heart disease is common), dental (enamel), skeletal (osteopenia). Body systems: Nervous, hepatobiliary, endocrine (adrenal), sensory (visual, auditory), skeletal, renal, digestive/nutritional (fat malabsorption).

Tissue/cell level: - Neurons and oligodendrocytes (CNS white matter/myelination) — UBERON:0002240/UBERON:0001869 - Hepatocytes — UBERON:0001114/CL:0000182 - Cochlear hair cells — UBERON:0001846 (cochlea), CL:0000855 (auditory hair cell) - Retinal photoreceptors, RPE — UBERON:0000966 (retina) - Adrenal cortical cells — UBERON:0002134 (adrenal cortex) - Chondrocytes at growth plate — UBERON:0002102 (epiphysis)

Subcellular level: The organelle itself — peroxisome (GO:0005777, cellular component) — is the primary site of dysfunction; downstream involvement of endoplasmic reticulum (ER stress, GO:0005783) and autophagosome/lysosome (pexophagy, GO:0005776) as clearance mechanisms for defective peroxisomes.

Localization/laterality: Disease is systemic/bilateral by nature (metabolic, not focal); hearing loss and retinopathy are bilateral and progressive; no meaningful lateralization pattern.

Suggested UBERON terms: UBERON:0002107 (liver), UBERON:0002369 (adrenal gland), UBERON:0000966 (retina), UBERON:0001846 (cochlea), UBERON:0001016 (nervous system), UBERON:0001474 (bone element).

8. Temporal Development

Onset: Typically infantile (many present as newborns/infants), though the intermediate/mild PBD1B phenotype can also present later in infancy or childhood; some very mild cases are recognized only in later childhood or, rarely, adulthood. Onset pattern: Insidious-to-subacute for most features; not typically acute.

Progression: - Disease course in PBD1B is variably progressive: sensorineural hearing loss and retinal dystrophy typically worsen over time; liver disease can progress to fibrosis; neurologic function may be relatively stable or slowly decline, in contrast to the rapidly fatal course of classic Zellweger syndrome. - Leukodystrophy (progressive white-matter degeneration) can develop in a subset, causing loss of previously acquired developmental skills — a NALD-like course reminiscent of, and clinically overlapping with, X-linked adrenoleukodystrophy. - 77% probability of reaching school age has been cited for children who survive infancy with a non-progressive/milder course (GeneReviews NBK1448).

Disease duration: Chronic, lifelong (in contrast to the typically fatal first-year course of severe Zellweger syndrome/PBD1A).

Patterns: No spontaneous remission is described; disease is managed symptomatically rather than cured. No clearly defined "critical periods" beyond the general principle that earlier diagnosis enables earlier initiation of supportive/monitoring interventions (hearing aids, vision correction, cholic acid therapy, DHA supplementation) which may modify quality of life and possibly slow certain complications, though disease-modifying (curative) treatment does not yet exist.

9. Inheritance and Population

Epidemiology (for the PEX1-driven ZSD spectrum overall, PBD1A+1B combined, from recent population-genetics modeling, PMC12166394): - US birth incidence: - Core model (known pathogenic variants only): ~15 births/year (13.8–16.1), i.e., 3.8–4.4 per million births (~1 in 245,000). - Expanded model (including predicted pathogenic variants): ~32 births/year (29.7–34.7), i.e., 8.1–9.5 per million births (~1 in 114,000). - US population prevalence (patients <31 years old): ~200 (core model, mostly intermediate phenotype) to potentially ~900 (expanded model including undiagnosed mild cases). - Historical/older estimates of ZSD overall incidence: 1 in 133,000 births (US, confirmed via New York newborn screening data) vs. older literature estimate of 1 in 50,000 (now considered an overestimate) (GeneReviews NBK1448). - Japan: markedly lower incidence, ~1 in 500,000 births, attributable to the near-absence of the common European PEX1 alleles (G843D, Ile700fs) in the Japanese population, where p.Arg633Ter predominates instead. - A substantial proportion of intermediate/mild (PBD1B-range) patients are believed to be underdiagnosed/unrecognized by current biochemical screening practices, since VLCFA and plasmalogen levels can be normal or only mildly abnormal in milder cases.

Inheritance pattern: Autosomal recessive. Sibling recurrence risk 25% affected / 50% carrier / 25% unaffected; parents are obligate asymptomatic carriers.

Penetrance: Full penetrance is generally assumed for biallelic pathogenic genotypes, though expressivity is highly variable (severity ranges from neonatal death to adult survival) depending on the specific allele combination — this reflects variable expressivity more than incomplete penetrance.

Genetic anticipation: Not applicable (not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented for PEX1 in the reviewed literature, though it remains a theoretical possibility as in other autosomal recessive disorders and is relevant to recurrence-risk counseling when only one parent is confirmed as a carrier.

Founder effects / geographic variant distribution: - p.Gly843Asp: common throughout Europe and in US cohorts of European ancestry. - p.Arg633Ter: the predominant PEX1 allele in Japan. - These population-specific allele distributions materially affect regional incidence and the milder-vs-severe phenotype mix by geography.

Consanguinity: As an autosomal recessive disorder, consanguinity increases risk, though PEX1-ZSD is also frequently compound heterozygous (not homozygous) in outbred populations given the relatively high carrier frequency of common hypomorphic alleles like G843D.

Carrier frequency: Derivable from the birth-incidence modeling above (implicit in the population-genetics estimates); direct carrier frequency figures were not isolated from the excerpted sources but are being formally estimated in ongoing population-genetics modeling efforts (PMC12166394).

Sex ratio: No sex predilection is reported; autosomal recessive inheritance affects males and females equally.

10. Diagnostics

Biochemical screening (first-line): | Test | Finding in PBD1B | Caveat | |---|---|---| | Plasma VLCFA (C26:0, C26:1, C24:0/C22:0 and C26:0/C22:0 ratios) | Elevated | May be normal in milder cases — insufficient alone to exclude diagnosis | | Erythrocyte plasmalogens (C16-DMA, C18-DMA) | Reduced | Moderate-to-mild ZSD may show normal values | | Plasma/urine pipecolic acid | Elevated | More reliable in older children than neonates | | Plasma bile acid intermediates (DHCA, THCA) | Elevated | Plasma more sensitive than urine | | C26:0-lysophosphatidylcholine (dried blood spot) | Elevated | Emerging newborn-screening-compatible biomarker (adapted from X-ALD NBS assays; can flag "other peroxisomal disorders" alongside X-ALD in pilot NBS cohorts) |

Because "some individuals with ZSD do not have abnormalities of these screening assays," a normal biochemical panel does not exclude PBD1B — molecular testing is required for definitive diagnosis (GeneReviews).

Molecular genetic testing: - Multigene panel covering all 13–14 known ZSD-PEX genes (sequence + deletion/duplication analysis) is the preferred first-tier test when the phenotype suggests ZSD; detects ~98% of PEX1 variants. - Exome/genome sequencing preferred when the presentation is non-classic/doesn't strongly suggest ZSD. - Single-gene PEX1 sequencing alone is "rarely useful and typically NOT recommended" given genetic heterogeneity, unless a familial variant is already known. - Diagnosis is confirmed by identification of biallelic pathogenic/likely pathogenic PEX1 variants.

Imaging: Brain MRI (for white matter changes/leukodystrophy — recommended annual surveillance); abdominal ultrasound/liver elastography (fibroscan) for hepatic fibrosis surveillance.

Functional/other tests: Audiology (annual), ophthalmologic exam (annual, including ERG for retinal dystrophy), adrenal function testing (ACTH stimulation/cortisol by age 1 year and annually), urine oxalate-to-creatinine ratio (nephrolithiasis risk), coagulation studies and liver function tests, dental exam every 6 months (amelogenesis imperfecta).

Histopathology/biopsy: Not typically required for diagnosis in the genomic-testing era; historically, liver biopsy showed absence/reduction of peroxisomes and cholestatic changes; skin fibroblast culture allows complementation-group and peroxisome-import functional studies (used historically and still useful for VUS functional confirmation, e.g., PMC6968987 "Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants").

Prenatal/carrier/preimplantation testing: Once the familial pathogenic variants are known, DNA-based prenatal or preimplantation genetic testing is available; biochemical prenatal testing (VLCFA/plasmalogens in chorionic villus/amniocyte samples) can supplement equivocal molecular results. Carrier testing must be molecular — "biochemical testing is not accurate for carrier testing, as the biochemical markers in carriers are normal."

Differential diagnosis: X-linked adrenoleukodystrophy (elevated VLCFA but distinct biochemical profile — isolated β-oxidation defect, not multi-enzyme), D-bifunctional protein (HSD17B4) deficiency, acyl-CoA oxidase 1 (ACOX1) deficiency (both single peroxisomal enzyme deficiencies that can mimic ZSD biochemically and clinically — the "pseudo-ZSD" single-enzyme disorders), congenital myotonic dystrophy, X-linked myotubular myopathy, spinal muscular atrophy, mitochondrial disease, Usher syndrome, other hereditary leukodystrophies.

Screening programs: No universal newborn screening for ZSD/PBD1B currently exists in most jurisdictions, but pilot programs adapting the C26:0-lysoPC LC-MS/MS assay used for X-ALD NBS have identified incidental "other peroxisomal disorders" cases, suggesting a path toward future ZSD-inclusive NBS.

Suggested LOINC/ontology anchors: VLCFA panel, erythrocyte plasmalogens, pipecolic acid, bile acid intermediates (specific LOINC codes not enumerated in sources reviewed — recommend confirming via LOINC search at curation time).

11. Outcome/Prognosis

Survival: Prognosis in PBD1B is markedly better than in classic/severe Zellweger syndrome (PBD1A), where death typically occurs within the first year of life. PBD1B patients (NALD/IRD-range) can survive into childhood, adolescence, and — particularly with the milder G843D-homozygous genotype — into early adulthood.

School-age survival: For children surviving infancy with a non-progressive/milder course, GeneReviews cites a 77% probability of reaching school age.

Morbidity/functional outcomes: Progressive sensorineural hearing loss and retinal dystrophy commonly lead to combined visual and auditory impairment over time; motor and cognitive function are variably affected — unlike classic Zellweger syndrome, some individuals achieve independent ambulation and normal-range cognition. Leukodystrophy, when it develops, can cause loss of previously acquired skills (regression), analogous to childhood cerebral X-ALD.

Complications: Hepatic fibrosis/dysfunction, adrenal insufficiency (can be life-threatening if unrecognized during acute illness — "adrenal crisis" risk), nephrolithiasis, osteopenia/fracture risk, dental complications (amelogenesis imperfecta), feeding difficulties/failure to thrive.

Prognostic factors: Genotype is the dominant prognostic determinant — null/null genotypes → severe/lethal; hypomorphic combinations (e.g., G843D homozygosity) → milder, longer-surviving phenotype. Early recognition and proactive multisystem surveillance/supportive care (per management guidelines, e.g., PMID 26750748 Braverman et al. 2016 consensus guideline) likely improve functional outcomes, though disease-modifying therapy remains limited.

12. Treatment

There is currently no curative or disease-reversing therapy; management is multidisciplinary and supportive/preventive, targeting downstream consequences of peroxisomal dysfunction.

Pharmacotherapy: - Cholic acid (Cholbam®) — FDA-approved (2015) as adjunctive treatment for peroxisomal disorders including Zellweger spectrum disorders in patients with manifestations of liver disease, steatorrhea, or fat-soluble vitamin malabsorption complications. Dosing: 10–15 mg/kg orally once daily or in two divided doses (pediatric and adult). Approval was based on a long-term single-arm trial + extension + case reports in 34 patients with peroxisomal disorders (including ZSD), showing improvement/normalization of liver-function labs, weight gain, developmental improvement, and prolonged survival in cholic-acid-responsive patients (PMC5065608; FDA NDA 205750; Travere Therapeutics press release). - Suggested MAXO term: MAXO:0000647-adjacent pharmacotherapy category; treatment_term = NCIT:C15986 (Pharmacotherapy); therapeutic_agent = CHEBI cholic acid (CHEBI:16359). - Fat-soluble vitamin supplementation (A, D, E, K) for malabsorption; vitamin K especially for coagulopathy. - DHA (docosahexaenoic acid) supplementation — studied in a randomized, double-blind, placebo-controlled trial at Johns Hopkins (100 mg/kg/day; 50 enrolled, 34 completed 1-year follow-up) targeting visual function and growth; results were inconsistent — earlier open-label case reports suggested improved tone and visual function, but the controlled trial did not yield a clear, consistent benefit (PMC3013498; PMID 8729110; Neurology 1993 43(7):1389). - Anti-seizure medications — standard agents for the subset with seizures. - Bisphosphonates — considered for osteopenia/bone fragility.

Advanced/experimental therapeutics: - AAV-mediated PEX1 gene augmentation — proof-of-concept subretinal gene therapy (AAV8.CMV.HsPEX1.HA) tested in the Pex1-G844D mouse model of mild ZSD; improved peroxisomal function and electroretinogram (ERG) response (1.6–2.5-fold improvement in treated eyes; ~2-fold ffERG amplitude at 32 weeks vs. control) — first proof-of-concept gene augmentation therapy for a peroxisome biogenesis disorder, targeting the retina specifically (PMC8516995; Molecular Therapy Methods & Clinical Development, S2329-0501(21)00137-6). Not yet in human clinical trials. - Pharmacologic chaperones — skin fibroblasts from G843D-genotype patients respond to chaperone-like small molecules that stabilize the mutant PEX1 protein and normalize peroxisomal β-oxidation in vitro, a promising precision approach specifically for the hypomorphic-allele (PBD1B-range) genotype (preclinical, biorxiv 2024.12.10.627778 and related literature). - Allogeneic hematopoietic stem cell transplantation (HSCT) — reported in a single pediatric case report (PEX1-related ZSD, IRD phenotype) with significant clinical, biochemical (VLCFA normalization), and brain MRI improvement, and no abnormal findings at 2-year follow-up (PMC8424192, Frontiers in Pediatrics 2021). This is an isolated case, not a standard-of-care recommendation, and requires cautious interpretation pending larger series.

Surgical/interventional: Gastrostomy tube placement for persistent feeding difficulty; cataract extraction; lithotripsy or surgical management of kidney stones.

Supportive/rehabilitative: Hearing aids (or cochlear implantation in appropriate candidates) for hearing loss; vision correction; physical/occupational/speech therapy for developmental support; nutritional management.

Treatment strategy: A structured annual surveillance protocol underlies management — audiology, ophthalmology, liver panel + coagulation + ultrasound/fibroscan, brain MRI, adrenal function (ACTH/cortisol from age 1 year), urine oxalate/creatinine, and 6-monthly dental exams — enabling early detection and management of emerging complications (Braverman et al. 2016 consensus management guideline, PMID 26750748; GeneReviews NBK1448).

Suggested MAXO terms: MAXO:0000950 (supportive care), MAXO:0009030 (hearing aid usage), MAXO:0001001 (gene therapy — experimental), MAXO:0000747 (hematopoietic stem cell transplantation — case-report only), MAXO:0000088 (dietary intervention, DHA/vitamin supplementation).

13. Prevention

Primary prevention: Not applicable in the classic sense (no modifiable etiologic risk factor to intervene on); the sole primary-prevention lever is reproductive/genetic — carrier screening and reproductive planning in families with a known PEX1 pathogenic variant.

Secondary prevention (early detection): Molecular carrier screening in at-risk relatives; prenatal diagnosis (DNA-based, once familial variants are known) and preimplantation genetic testing for at-risk couples; potential future expanded newborn screening leveraging C26:0-lysoPC or related biomarkers (currently piloted primarily for X-ALD but incidentally detects some "other peroxisomal disorders").

Tertiary prevention: The entire annual multisystem surveillance protocol described above (Section 12) functions as tertiary prevention — early detection of adrenal insufficiency, hepatic fibrosis, hearing/vision decline, bone fragility, and nephrolithiasis to enable early intervention and reduce morbidity.

Genetic counseling: Central to family management — includes carrier-status clarification via molecular testing (biochemical carrier testing is unreliable), discussion of the 25%/50%/25% recurrence risk pattern for future pregnancies, and availability of prenatal/preimplantation genetic testing once the familial variants are identified.

Immunization/public health/prophylaxis: Not applicable — this is a purely monogenic metabolic disorder with no infectious, vaccine-preventable, or public-health-intervention dimension.

14. Other Species / Natural Disease

Taxonomy of studied model species: Mouse (Mus musculus, NCBITaxon:10090), zebrafish (Danio rerio, NCBITaxon:7955).

Orthologous gene: Mouse Pex1 (MGI:1339959); note the mouse numbering convention places the orthologous hypomorphic allele at Gly844Asp (one residue offset from human G843D) due to a minor sequence-length difference between species.

Natural disease in other species: No naturally occurring (spontaneous) veterinary PEX1-deficiency disease has been identified in the literature reviewed (no OMIA entry surfaced in this search) — all animal data derive from engineered/induced genetic models, not spontaneously occurring veterinary disease. This section is therefore largely not applicable; PBD1B does not have documented natural companion-animal or wildlife counterparts analogous to, e.g., naturally occurring lysosomal storage diseases in dogs/cats.

Comparative biology: Peroxisome biogenesis and the PEX1/PEX6 AAA-ATPase mechanism are evolutionarily conserved from yeast to humans (the REM/receptor-recycling mechanism was first characterized in yeast peroxisome biology), underlying the utility of zebrafish and mouse models as translationally relevant systems.

Zoonotic potential/transmission: Not applicable — this is a non-infectious, monogenic disorder.

15. Model Organisms

Mouse models: - Pex1 global/null knockout mouse — global deletion is neonatal lethal, precluding postnatal phenotypic study; this severe lethality models the human null/null (classic Zellweger, PBD1A) genotype and has driven development of conditional and hypomorphic alternatives. - Pex1-G844D hypomorphic knock-in mouse — the primary translational model for mild human ZSD (i.e., the PBD1B-range phenotype), recapitulating the human hypomorphic G843D genotype; viable postnatally (PMID 24503136; PMC4901203, "The Pex1-G844D mouse: A model for mild human Zellweger spectrum disorder"). Used extensively for: - Retinal/RPE structural and lipid characterization (biorxiv 2024.09.05.611330) - Liver disease progression natural history (biorxiv 2025.05.08.652960) - AAV-PEX1 gene augmentation proof-of-concept therapy (PMC8516995) - Conditional (floxed) Pex1 mouse crossed with cell-type-specific Cre lines (e.g., Gfi1-Cre, VGlut3-Cre for inner-ear hair cells) — used to dissect tissue-specific consequences (e.g., cochlear synaptopathy and hearing loss) while circumventing the neonatal lethality of the global knockout (doi:10.3390/cells11243982).

Zebrafish model: - pex1−/− loss-of-function zebrafish — a recently reported (2025) model that is viable (unlike the mouse global knockout) and recapitulates hallmark ZSD features: ghost peroxisome formation, VLCFA/phytanic/pristanic acid accumulation, DHA/plasmalogen deficiency, ER-stress and pexophagy transcriptomic signatures, abnormal larval locomotor behavior, and disrupted adult retinal architecture (PMC12626956; Frontiers 10.3389/fnmol.2025.1634536). Its viability beyond early development is a key advantage over the mouse null model, enabling study of later-onset/progressive disease stages and serving as a preclinical drug-screening platform. - A separate zebrafish Zellweger model study demonstrated organ-specific accumulation of distinct fatty-acid species and widespread gene-expression changes (bioRxiv 2021.01.03.425169).

Cellular/iPSC models: - Patient-derived induced pluripotent stem cells (iPSCs) differentiated into relevant lineages show impaired peroxisome assembly and cell-type-specific lipid abnormalities, providing a human-cell-based platform complementary to animal models (PMC4553005). - Patient skin fibroblasts (including from G843D-genotype patients) are used for complementation-group assignment, functional variant confirmation, and pharmacologic chaperone-response studies.

Model recapitulation/limitations: The Pex1-G844D mouse and zebrafish pex1-null models each capture different facets of the human mild-ZSD (PBD1B) phenotype — the mouse being the more established model for liver/retina longitudinal study and gene-therapy proof-of-concept, and zebrafish offering higher-throughput, viable, whole-organism assessment including behavior. Neither model fully recapitulates the human combination of progressive sensorineural (hearing + vision) decline together with hepatic and adrenal involvement in one system; cross-model and iPSC-based validation is used to build a fuller mechanistic picture.

Research applications: These models collectively support (1) natural-history/longitudinal organ-specific disease-progression studies, (2) mechanistic dissection of tissue-specific peroxisomal dysfunction (retina, liver, cochlea), and (3) preclinical testing of therapeutic candidates (AAV-PEX1 gene augmentation, pharmacologic chaperones, and potential future small-molecule or antisense approaches).

Summary Table: Key Ontology Term Suggestions for Curation