Peroxisome Biogenesis Disorder 4A (Zellweger)

Mendelian MONDO:0013930 Pathograph 16 Show in embeddings browser Peroxisome Biogenesis Disorder Zellweger Spectrum Disorder

Peroxisome biogenesis disorder 4A is the severe, neonatal-lethal end of the PEX6-related Zellweger spectrum - historically complementation group 4 (also catalogued as group C), which is where the "4" in the name comes from. PEX6 is an AAA-ATPase that heterohexamerises with PEX1 to form the receptor export module: the ATP-driven motor that pulls monoubiquitinated PEX5 back out of the peroxisomal membrane so the receptor can carry another load of matrix enzymes into the organelle. PEX6 defects are the second most common cause of Zellweger spectrum disease after PEX1. What separates PBD4A from PBD4B is not the gene but how much peroxin-6 activity the genotype leaves behind. Biallelic null or severely truncating PEX6 alleles abolish the export motor outright, PEX5 recycling stops, and matrix protein import collapses. The peroxisomal membrane is still made - patient cells contain "peroxisomal ghosts", membrane compartments with no matrix enzymes inside - so this is a disorder of biogenesis rather than of any one peroxisomal enzyme. The biochemical signature is correspondingly broad in both directions: very-long-chain fatty acids, phytanic and pristanic acid and C27 bile-acid intermediates accumulate because nothing is left to degrade them, while plasmalogens are missing because nothing is left to synthesise them. Both halves of that lesion damage the developing brain, the liver and the kidney simultaneously, and they do so before birth: the neuronal migration defect that produces perisylvian polymicrogyria is complete by the time the child is born, which is the reason no post-natal therapy changes the neurological outcome. Affected newborns are profoundly hypotonic, feed poorly, seize, and have distinctive facies, renal cysts, epiphyseal stippling and severe liver disease. Survival is usually less than a year. This entry is the severity counterpart of Peroxisome Biogenesis Disorder 4B at the same locus, and the PEX6 counterpart of Peroxisome Biogenesis Disorder 3A (PEX12) and 11A (PEX26). The gene-agnostic downstream cascade shared by the whole spectrum is curated on the Zellweger Spectrum Disorders entry; what is carried here is what is PEX6- and classic-Zellweger-specific.

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1
Inheritance
8
Pathophys.
12
Phenotypes
2
Gaps
16
Pathograph
1
Genes
4
Medical Actions
1
Models
11
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
PBD4A requires PEX6 variants on both alleles, and specifically the genotypes that leave no residual peroxin-6 function. A single severe allele in trans with a partially functional one shifts the presentation toward PBD4B rather than producing this phenotype.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:20301621 SUPPORT Other
"ZSD is typically inherited in an autosomal recessive manner"
GeneReviews states the inheritance pattern for the Zellweger spectrum, of which PBD4A is the severe PEX6 end.
PMID:19877282 SUPPORT Human Clinical
"The autosomal recessive Zellweger syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders."
The PEX6 mutation survey confirms autosomal recessive inheritance across the complementation group this entry belongs to.
PMID:20301621 SUPPORT Other
"At conception, each sib of an individual with biallelic ZSD-causing pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
GeneReviews gives the recurrence risk that follows from the biallelic requirement, which is what genetic counselling for this entry turns on.
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Discussions and Knowledge Gaps

2
What fraction of the PEX6 complementation group carries a biallelic null genotype and therefore belongs to PBD4A rather than PBD4B?
KNOWLEDGE GAP pbd4a_null_genotype_fraction
Attached to
pathophysiology#Biallelic Null PEX6 Genotype
The A/B split at this locus is defined by residual peroxin-6 function, but the published PEX6 series report mutation spectra rather than a genotype-stratified phenotype breakdown. Ebberink and colleagues characterised 75 patients and 77 distinct mutations without reporting how many of those genotypes were biallelic null. Without that denominator neither a prevalence figure nor a genotype-to-subtype rule can be curated for this entry, which is why the entry carries no prevalence block. This is a gap in the source literature rather than in the curation.
Is the neuronal migration defect in classic Zellweger syndrome driven by plasmalogen deficiency, by VLCFA accumulation, or by loss of a peroxisomal function not yet identified?
KNOWLEDGE GAP pbd4a_migration_defect_proximate_cause
Attached to
pathophysiology#Defective Neuronal Migration in the Developing Cortex
The link from the import collapse to the cortical malformation is recorded as INDIRECT_UNKNOWN_INTERMEDIATES precisely because the intervening step is unknown, and the best experiment on the question makes the gap wider rather than narrower. Selectively restoring peroxisomes in the liver of Pex5 knockout mice corrected the neuronal migration defect without changing brain VLCFA, DHA or plasmalogen levels at all. So the migration defect is not a straightforward consequence of the brain's own lipid abnormality, and an extraneuronal - probably hepatic - contribution is doing part of the work. Assigning the responsible factor would change what a prenatal intervention would have to target and in which tissue, so the gap is mechanistically load-bearing rather than academic.
Show evidence (1 reference)
PMID:14586000 SUPPORT Model Organism
"In liver-rescued mice, the improvement of the neuronal migration was not accompanied by changes in very long chain fatty acid, docosahexaenoic acid, or plasmalogen levels in brain, indicating that other metabolic factors can influence the neuronal migration process."
The result that keeps this gap open: correcting migration without correcting brain lipids rules out the obvious candidate mechanism.
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Pathophysiology

8
Biallelic Null PEX6 Genotype
PEX6 is a 17-exon gene encoding an AAA-ATPase with two tandem AAA cassettes; pathogenic variants are scattered across all exons and the allelic series is wide. PBD4A is the subset of that series in which both alleles are null or severely truncating, so no functional peroxin-6 is produced. This is the single variable that separates this entry from PBD4B at the identical locus, which is why the entry is curated on residual function rather than on gene identity.
PEX6 hgnc:8859 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PEX6 (hgnc:8859). hgnc:8859 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context 4 PEX6 hgnc:8859 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PEX6 (hgnc:8859). hgnc:8859 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Recorded as complete loss of function because it is the biallelic null or severely truncating genotypes, rather than PEX6 involvement as such, that define this entry against PBD4B. Compound heterozygosity for two severe alleles produces the same phenotype; HOMOZYGOUS is recorded as the commonest reported configuration in consanguineous pedigrees rather than as a requirement.
ATP hydrolysis activity GO:0016887 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP hydrolysis activity (GO:0016887). GO:0016887 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Receptor Export Module Failure With no functional peroxin-6, the PEX1-PEX6 motor cannot assemble, so the step it performs does not occur at all rather than occurring slowly.
Show evidence (4 references)
PMID:19877282 SUPPORT Human Clinical
"The encoded protein PEX6 belongs to the AAA ATPase family and contains two AAA cassettes and an AAA protein family signature."
Establishes the domain architecture of the protein whose complete loss defines this entry.
PMID:19877282 SUPPORT Human Clinical
"We analyzed the PEX6 genes of 75 patients assigned to the PEX6 complementation group. We identified a total of 77 different mutations of which 47 mutations have not been reported previously, and 14 polymorphic variants."
Documents the allelic heterogeneity across which the PBD4A/PBD4B severity split is drawn, and the size of the complementation group.
PMID:41787707 SUPPORT Human Clinical
"Genetic variations in PEX6, an important peroxisome biogenesis factor, contribute significantly to this phenotypic diversity, with missense variants often associated with less severe disease compared to truncating mutations."
A PEX6-specific review stating the genotype-severity direction this entry is built on: truncating alleles at the severe end, missense at the milder one.
+ 1 more reference
Receptor Export Module Failure
The PEX1-PEX6 heterohexamer is the ATP-driven motor that extracts monoubiquitinated PEX5 from the peroxisomal membrane by processive threading and unfolding, returning it to the cytosol for reuse. Because PEX1 and PEX6 are obligate partners, a PEX6 null and a PEX1 null converge on the same rate-limiting step - which is why PBD4A and PBD1A are phenotypically indistinguishable at the bedside despite different genes.
ATP hydrolysis activity GO:0016887 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP hydrolysis activity (GO:0016887). GO:0016887 is a molecular function from the Gene Ontology. ↓ DECREASED
peroxisomal membrane GO:0005778 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisomal membrane (GO:0005778). GO:0005778 is a cellular component from the Gene Ontology.
Downstream
Collapse of Peroxisomal Matrix Protein Import PEX5 that cannot be recycled is not available to carry the next matrix enzyme, so import runs down to nothing.
Show evidence (1 reference)
PMID:29884772 SUPPORT In Vitro
"PEX1 and PEX6 are two members of the ATPases associated with diverse cellular activities (AAA) family and the core components of the receptor export module of the peroxisomal matrix protein import machinery."
States the identity and role of the module whose failure this node describes.
Collapse of Peroxisomal Matrix Protein Import
Without receptor recycling, PTS1- and PTS2-targeted matrix enzymes are not delivered. The peroxisomal membrane compartment is still assembled, because membrane protein import uses PEX19/PEX3 and is independent of the PEX5 cycle; what results is an empty organelle - the "peroxisomal ghost" seen in patient fibroblasts. This is the defining cellular lesion of a biogenesis disorder and the reason the biochemical phenotype is multi-pathway rather than single-enzyme.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
protein import into peroxisome matrix GO:0016558 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein import into peroxisome matrix (GO:0016558). GO:0016558 is a biological process from the Gene Ontology. ↓ DECREASED peroxisome organization GO:0007031 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peroxisome organization (GO:0007031). GO:0007031 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of Peroxisomal Fatty Acid Oxidation The beta- and alpha-oxidation enzymes are matrix enzymes and are among those not delivered.
Plasmalogen Biosynthesis Failure The first two committed steps of ether-lipid synthesis are peroxisomal matrix reactions, so the anabolic half of the phenotype has the same immediate cause as the catabolic half.
C27 Bile Acid Intermediate Accumulation C27 bile acid side-chain shortening is a peroxisomal beta-oxidation reaction.
Defective Neuronal Migration in the Developing Cortex The migration defect is downstream of the lipid lesions rather than of a single identified peroxisomal protein, so the link is recorded as indirect.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"Because of the defect in peroxisome formation, multiple metabolic (both catabolic and anabolic) pathways are impaired resulting in metabolic abnormalities."
States the central consequence of the import collapse - that the defect is at the level of the organelle and therefore hits many pathways at once.
Loss of Peroxisomal Fatty Acid Oxidation
Very-long-chain fatty acids are shortened only in peroxisomes, and phytanic acid can be degraded only by peroxisomal alpha-oxidation. With the matrix empty, both substrates accumulate in plasma and tissue. This is the arm of the phenotype that the first-line diagnostic assay reads out.
fatty acid beta-oxidation GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology. ↓ DECREASED fatty acid alpha-oxidation GO:0001561 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fatty acid alpha-oxidation (GO:0001561). GO:0001561 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes"
Names the accumulating substrates that define the catabolic half of the biochemical phenotype.
Plasmalogen Biosynthesis Failure
Ether-phospholipid synthesis begins with two peroxisomal matrix enzymes, so an empty peroxisome cannot make plasmalogens. Erythrocyte plasmalogen is correspondingly low and, unlike VLCFA, it is a deficiency rather than an accumulation - the anabolic half of the lesion.
ether lipid biosynthetic process GO:0008611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ether lipid biosynthetic process (GO:0008611). GO:0008611 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes"
The same sentence records the erythrocyte plasmalogen deficiency that this node describes.
C27 Bile Acid Intermediate Accumulation
Shortening the side chain of the C27 intermediates DHCA and THCA to make the mature C24 bile acids is a peroxisomal beta-oxidation reaction. When it fails the intermediates accumulate. This node is the accumulation itself, kept separate from the liver injury it causes because the two are at different scales and because the one available therapy acts here and not there.
bile acid metabolic process GO:0008206 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bile acid metabolic process (GO:0008206). GO:0008206 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cholestatic Liver Injury The accumulated intermediates are themselves hepatotoxic and cholestatic, so the liver disease is not simply a consequence of generalised metabolic illness.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes"
Names the C27 bile acid intermediates among the accumulating metabolites.
Cholestatic Liver Injury
Hepatocellular injury and cholestasis driven by the accumulated C27 intermediates. Clinically this presents as prolonged jaundice, hepatomegaly and coagulopathy in the newborn period, and in the severe presentation curated here liver failure can be the immediate cause of death.
Downstream
Hepatomegaly and Neonatal Cholestasis
Hyperbilirubinemia
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients within this group typically present in the neonatal period with hepatic dysfunction and profound hypotonia resulting in prolonged jaundice and feeding difficulties."
Describes the neonatal hepatic presentation of the severe group, which is the clinical face of this node.
Defective Neuronal Migration in the Developing Cortex
The cortical malformation of classic Zellweger syndrome - perisylvian polymicrogyria with heterotopia - is a prenatal neuronal migration defect. It is the single most consequential node in this entry for prognosis, because it is fixed at birth: no post-natal intervention can undo it, which is why no therapy in the treatments section - cholic acid included - changes the neurological outcome. It is also the node that most cleanly separates PBD4A from PBD4B, where congenital malformations are absent and the neurological course is degenerative rather than developmental.
cerebral cortex cell migration GO:0021795 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cerebral cortex cell migration (GO:0021795). GO:0021795 is a biological process from the Gene Ontology. ↓ DECREASED neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Pex5 knockout mouse with tissue-selective peroxisome reconstitution Mouse recapitulates The knockout reproduces the migration defect, and the tissue-selective rescues make it experimentally addressable rather than merely observed.
Downstream
Neonatal Seizures The seizures of classic Zellweger syndrome arise from the cortical malformation rather than from metabolic decompensation.
Show evidence (4 references)
PMID:20301621 SUPPORT Other
"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction"
GeneReviews draws exactly the contrast this node rests on: congenital malformation is the severe presentation, progressive dysfunction the milder one.
PMID:24607700 SUPPORT Other
"Neuropathological changes include abnormal neuronal migration affecting the cerebral hemispheres, cerebellum and inferior olivary complex, abnormal Purkinje cell arborisation, demyelination and post-developmental neuronal degeneration."
Gives the anatomical extent of the migration defect - cerebral hemispheres, cerebellum and inferior olivary complex. Note the same sentence attributes abnormal arborisation to Purkinje cells, which is a dendritic rather than a migration defect; this entry does not bind a Purkinje cell type to this node for that reason, and the arborisation claim is left to the spectrum-wide entry.
PMID:14586000 SUPPORT Model Organism
"Functional peroxisome deficiency, as encountered in Zellweger syndrome, causes a specific impairment of neuronal migration."
States the causal claim this node makes, in a mouse model of the same lesion.
+ 1 more reference
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Peroxisome Biogenesis Disorder 4A (Zellweger) Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Digestive 2
Feeding Difficulties VERY_FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients within this group typically present in the neonatal period with hepatic dysfunction and profound hypotonia resulting in prolonged jaundice and feeding difficulties."
Names feeding difficulty as part of the neonatal presentation.
Hepatomegaly and Neonatal Cholestasis VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"and liver disease that can be severe"
GeneReviews lists severe liver disease among the newborn findings of the severe presentation.
Ear 1
Sensorineural Hearing Loss FREQUENT Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"Sensorineural deafness and ocular abnormalities like retinopathy, cataracts and glaucoma are typical"
Names sensorineural deafness as typical in the neonatal-infantile group.
Eye 1
Cataract FREQUENT HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"Sensorineural deafness and ocular abnormalities like retinopathy, cataracts and glaucoma are typical"
Names cataract among the typical ocular abnormalities of this group.
Genitourinary 1
Renal Cysts FREQUENT HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"
GeneReviews lists renal cysts among the congenital malformations of the severe presentation. The quote is cut before the bracketed gloss that follows.
Musculoskeletal 1
Severe Neonatal Hypotonia VERY_FREQUENT Generalized hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290), qualified as severity severe. HP:0001290 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"Affected newborns are hypotonic and feed poorly."
GeneReviews names hypotonia and feeding failure as the newborn presentation.
Nervous System 1
Absence of Developmental Progress VERY_FREQUENT Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263), qualified as severity severe. HP:0001263 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress."
States both the absence of developmental progress and the prognosis for the severe presentation.
Other 5
Neonatal Seizures FREQUENT HP:0032807 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal seizure (HP:0032807). HP:0032807 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"Epileptic seizures are usually present in these patients."
States that seizures are usual in the neonatal-infantile group this entry curates.
Neuronal Migration Defect FREQUENT Abnormality of neuronal migration HP:0002269 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of neuronal migration (HP:0002269). HP:0002269 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301621 SUPPORT Other
"They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"
GeneReviews names neuronal migration defects among the congenital malformations of the severe presentation, and ties them to the neonatal seizures.
PMID:26627182 SUPPORT Human Clinical
"generalized decrease in white matter volume, delayed myelination, bilaterial ventricular dilatation and germinolytic cysts"
Gives the accompanying neonatal MRI findings.
Hyperbilirubinemia FREQUENT HP:0002904 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperbilirubinemia (HP:0002904). HP:0002904 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients within this group typically present in the neonatal period with hepatic dysfunction and profound hypotonia resulting in prolonged jaundice and feeding difficulties."
Records prolonged jaundice as part of the neonatal hepatic presentation.
Epiphyseal Stippling FREQUENT HP:0010655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epiphyseal stippling (HP:0010655). HP:0010655 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"
GeneReviews lists bony stippling among the congenital malformations. The quote is cut before the bracketed gloss naming chondrodysplasia punctata.
Distinctive Facies VERY_FREQUENT High forehead HP:0000348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High forehead (HP:0000348). HP:0000348 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"Characteristic dysmorphic features can usually be found, of which the facial dysmorphic signs are most evident"
Records that facial dysmorphism is the most evident feature in this group. The individual facial signs are curated on the Zellweger Spectrum Disorders entry.
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Genetic Associations

1
PEX6
Gene: PEX6 hgnc:8859 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PEX6 (hgnc:8859). hgnc:8859 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:19877282 SUPPORT Human Clinical
"Defects in the PEX6 gene are the second most common cause for ZSS disorders."
Establishes PEX6 as the causative gene and its rank among the ZSD genes.
PMID:41787707 SUPPORT INDIRECT Other
"Recent studies further implicate dysregulated pexophagy-a targeted autophagic degradation of peroxisomes-in the underlying disease mechanisms."
Records the pexophagy mechanism named in the notes above. INDIRECT and kept out of the pathograph: the review reports it for peroxisome biogenesis disorders generally, not for a PBD4A genotype.
PMID:20301621 SUPPORT Other
"by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes"
States the molecular criterion; assignment to PEX6 is what makes the entry PBD4 rather than another group.
💊

Medical Actions

4
Supportive and Symptomatic Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
There is no treatment for the biogenesis defect itself. Management is otherwise symptomatic - gastrostomy feeding, anti-seizure medication, hearing aids, cataract surgery, fat-soluble vitamin supplementation. None of it restores peroxisomal import, and the cortical malformation is complete before birth, so the neurological outcome is not modifiable. Cholic acid, curated separately below, is the one exception to "nothing is disease-modifying" and it modifies the liver arm only.
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"Treatment of manifestations: The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation"
GeneReviews Management section enumerates the symptomatic measures and confirms that no disease-modifying therapy exists.
Oral Cholic Acid
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cholic acid CHEBI:16359 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cholic acid (CHEBI:16359). CHEBI:16359 is a therapeutic agent from Chemical Entities of Biological Interest.
The one pharmacological therapy in Zellweger spectrum disease with phase 3 evidence behind it. Supplying the mature primary bile acid suppresses endogenous synthesis and so reduces production of the hepatotoxic C27 intermediates that accumulate when peroxisomal side-chain shortening fails. It is disease-modifying for the liver arm of the phenotype and for nothing else: it does not restore peroxisomal import and cannot touch the congenital brain malformation, so it does not change the prognosis of the severe presentation curated here.
Mechanism Target:
C27 Bile Acid Intermediate Accumulation — Feedback suppression of endogenous bile acid synthesis lowers the flux into the blocked peroxisomal step, so fewer toxic C27 intermediates are made.
Show evidence (1 reference)
PMID:28644367 SUPPORT Human Clinical
"Cholic acid significantly improved urine bile acid metabolite scores (P < 0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001) in patients with SED and ZSD."
Shows the intervention moves both the bile-acid metabolite readout and the liver-injury markers, which is the mechanism this link asserts.
Show evidence (1 reference)
PMID:28644367 SUPPORT Human Clinical
"Oral cholic acid is a safe, efficacious, and well-tolerated treatment for BASD due to SED and ZSD."
The trial's conclusion. Note the ZSD arm was 20 patients in a single-arm, open-label, non-randomised design, and was not stratified by PEX gene or by severity, so nothing in it is specific to PBD4A.
Docosahexaenoic Acid Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Curated because it is a negative result worth recording rather than a therapy to offer. DHA is low in Zellweger spectrum disease because its final synthetic step is peroxisomal, which made replacement an obvious hypothesis; a double-blind randomised placebo-controlled trial found no effect on visual function or growth. The entry keeps it so that a future curator does not re-derive the hypothesis from the biochemistry and present it as promising.
Show evidence (1 reference)
PMID:20805528 REFUTE Human Clinical
"DHA supplementation did not improve the visual function or growth of treated individuals with peroxisome assembly disorders."
Refutes DHA replacement as a disease-modifying therapy. Graded REFUTE because the claim being tested is that supplementing the deficient lipid helps, and the trial says it does not.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Recurrence risk counselling for the family, with carrier testing for at-risk relatives and the option of prenatal testing once both variants are known.
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"Carrier testing for at-risk relatives is possible if the pathogenic variants have been identified in an affected family member."
GeneReviews Genetic Counseling section states the carrier-testing option that this entry records as management.
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Biochemical Markers

2
Very-long-chain fatty acids (Increased)
Context: Plasma C26:0 with the C24/C22 and C26/C22 ratios is the first-line biochemical screen. In the severe presentation curated here the elevation is unambiguous, unlike the mild end of the PEX6 series where it can be borderline or normal.
Pathograph Readouts
Readout Of Loss of Peroxisomal Fatty Acid Oxidation Positive Diagnostic
Plasma C26:0 and the C24/C22 and C26/C22 ratios measure the beta-oxidation block rather than being a separate lesion caused by it. In the severe presentation curated here the elevation is unambiguous.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes"
Ties the plasma VLCFA elevation to the peroxisomal catabolic block it reports.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes"
Names VLCFA accumulation in plasma as the characteristic finding.
Erythrocyte plasmalogens (Decreased)
Context: The anabolic counterpart of the VLCFA elevation, and the assay that distinguishes a biogenesis defect from an isolated peroxisomal beta-oxidation enzyme deficiency, where plasmalogen synthesis is intact.
Pathograph Readouts
Readout Of Plasmalogen Biosynthesis Failure Negative Diagnostic
Low erythrocyte plasmalogen is the direct measurement of the synthetic block, and the assay that separates a biogenesis defect from an isolated beta-oxidation enzyme deficiency, where plasmalogen synthesis is intact.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes"
The same sentence records the erythrocyte plasmalogen deficiency this readout measures.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes"
The same sentence records the erythrocyte plasmalogen deficiency.
🔬

Diagnosis

3
Plasma Very-Long-Chain Fatty Acid Profile
The first-line biochemical test. Elevated C26:0 with abnormal C24/C22 and C26/C22 ratios points at a peroxisomal disorder before any gene is sequenced, and in the severe presentation the result is not equivocal.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301621 SUPPORT Other
"The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes."
GeneReviews places biochemical findings ahead of molecular confirmation in the diagnostic sequence.
PMID:41787707 SUPPORT Human Clinical
"While elevated levels of very-long-chain fatty acids (VLCFAs) remain a key diagnostic feature, the existence of unusual cases with normal plasma VLCFA levels highlight the limitations of relying solely on this biochemical marker for diagnosis."
Records the caveat that matters most in practice: a normal VLCFA does not exclude a PEX6 disorder, so a negative first-line screen must not close the workup.
Newborn Screening by C26:0-Lysophosphatidylcholine
Not a test for this disease, but the route by which some patients now reach it. Dried-blood-spot C26:0-lysophosphatidylcholine screening was implemented for X-linked adrenoleukodystrophy, and it also picks up other peroxisomal disorders as incidental positives. In a pilot of 43,653 newborns, 2 of 32 screen-positives had a peroxisomal disorder other than X-ALD. Curated here because incidental detection changes when a severe presentation is recognised, which matters for a disease whose congenital lesion is already fixed at birth.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:37977233 SUPPORT INDIRECT Human Clinical
"The LC-MS/MS method for screening of X-ALD can identify males, heterozygous females and other peroxisomal disorders."
Establishes that the X-ALD newborn screen also detects other peroxisomal disorders. INDIRECT: the study is an X-ALD screening pilot and does not report a PBD4A case, so it supports the detection route rather than a result in this disease.
PMID:37977233 SUPPORT INDIRECT Human Clinical
"Of 43,653 newborns, 32 (18 males, 14 females) screened positive."
Gives the denominator behind the incidental-detection rate.
Molecular Genetic Testing of the ZSD-PEX Genes
Confirmation requires biallelic PEX6 variants. Because PBD4A and PBD4B are the same gene, the sequencing result alone does not assign the subtype - that follows from the predicted consequence of the two alleles together with the phenotype.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301621 SUPPORT Other
"by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes"
States the molecular criterion for establishing the diagnosis.
📈

Progression

2
Neonatal-infantile
Presentation at or shortly after birth with profound hypotonia, poor feeding, seizures, dysmorphism and hepatic dysfunction. Congenital malformations - the cortical migration defect, renal cysts and epiphyseal stippling - are already present.
Show evidence (1 reference)
PMID:26627182 SUPPORT Human Clinical
"The neonatal-infantile presentation grossly resembles what was originally described as classic ZS."
Identifies the presentation curated here with classic Zellweger syndrome.
Infantile death
Death, usually in the first year, most often from liver failure, respiratory compromise or intractable seizures. Survival beyond infancy would put the diagnosis of the severe form in doubt and prompt reconsideration of PBD4B.
Show evidence (2 references)
PMID:26627182 SUPPORT Human Clinical
"Prognosis is poor and survival is usually not beyond the first year of life."
Gives the survival expectation for the neonatal-infantile presentation.
PMID:20301621 SUPPORT Other
"Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress."
Independent statement of the same prognosis from GeneReviews.
🐁

Animal Models

1
Pex5 knockout mouse with tissue-selective peroxisome reconstitution
Not a PEX6 model, and cited here for what it rules out rather than what it reproduces. Peroxisomes were restored selectively in either brain or liver of Pex5 knockout mice, a model of Zellweger syndrome, to ask which tissue's peroxisomal metabolism the cortical migration defect depends on. Both single rescues partly corrected migration; rescuing both gave a migration pattern indistinguishable from wild-type.
Species
Mouse
Genotype
Pex5 knockout, with Pex5p re-expressed selectively in brain or in liver
Publication
PMID:14586000
Pathograph links
Defective Neuronal Migration in the Developing Cortex recapitulates fidelity: moderate The knockout reproduces the migration defect, and the tissue-selective rescues make it experimentally addressable rather than merely observed.
Limitations: The disrupted gene is PEX5, the receptor itself, not PEX6, the ATPase that recycles it. Both lesions abolish matrix import, so the downstream phenotype is shared, but nothing PEX6-specific is modelled. The mouse also does not address the severity split that defines PBD4A against PBD4B, since it is a null rather than a hypomorph.
Readouts
Cortical neuronal migration after liver-selective rescue
Direction: RESTORED
Interpretation: Restoring peroxisomes in liver alone significantly corrects a brain phenotype, which is the result that makes an extraneuronal contribution unavoidable.
Show evidence (1 reference)
PMID:14586000 SUPPORT Model Organism
"We found that both rescue strains exhibited a significant correction of the neuronal migration defect despite an incomplete reconstitution of peroxisomal function in the targeted tissue."
The rescue measurement itself, for both the brain-targeted and the liver-targeted strain.
Brain VLCFA, DHA and plasmalogen after liver-selective rescue
Direction: UNCHANGED
Interpretation: The negative readout, and the load-bearing one. Migration improved while the three lipid species usually invoked to explain it did not move, so the migration defect is not a straightforward consequence of the brain's own lipid abnormality.
Show evidence (1 reference)
PMID:14586000 SUPPORT Model Organism
"In liver-rescued mice, the improvement of the neuronal migration was not accompanied by changes in very long chain fatty acid, docosahexaenoic acid, or plasmalogen levels in brain, indicating that other metabolic factors can influence the neuronal migration process."
Reports the unchanged brain lipids alongside the corrected migration.
Show evidence (1 reference)
PMID:14586000 SUPPORT Model Organism
"Functional peroxisome deficiency, as encountered in Zellweger syndrome, causes a specific impairment of neuronal migration."
Supports treating this model as informative for the migration node.
{ }

Source YAML

click to show 
name: Peroxisome Biogenesis Disorder 4A (Zellweger)
creation_date: "2026-08-29T16:40:00Z"
category: Mendelian
description: >-
  Peroxisome biogenesis disorder 4A is the severe, neonatal-lethal end of the
  PEX6-related Zellweger spectrum - historically complementation group 4 (also
  catalogued as group C), which is where the "4" in the name comes from. PEX6 is
  an AAA-ATPase that heterohexamerises with PEX1 to form the receptor export
  module: the ATP-driven motor that pulls monoubiquitinated PEX5 back out of the
  peroxisomal membrane so the receptor can carry another load of matrix enzymes
  into the organelle. PEX6 defects are the second most common cause of Zellweger
  spectrum disease after PEX1.

  What separates PBD4A from PBD4B is not the gene but how much peroxin-6 activity
  the genotype leaves behind. Biallelic null or severely truncating PEX6 alleles
  abolish the export motor outright, PEX5 recycling stops, and matrix protein
  import collapses. The peroxisomal membrane is still made - patient cells contain
  "peroxisomal ghosts", membrane compartments with no matrix enzymes inside - so
  this is a disorder of biogenesis rather than of any one peroxisomal enzyme. The
  biochemical signature is correspondingly broad in both directions: very-long-chain
  fatty acids, phytanic and pristanic acid and C27 bile-acid intermediates
  accumulate because nothing is left to degrade them, while plasmalogens are
  missing because nothing is left to synthesise them.

  Both halves of that lesion damage the developing brain, the liver and the kidney
  simultaneously, and they do so before birth: the neuronal migration defect that
  produces perisylvian polymicrogyria is complete by the time the child is born,
  which is the reason no post-natal therapy changes the neurological outcome.
  Affected newborns are profoundly hypotonic, feed poorly, seize, and have
  distinctive facies, renal cysts, epiphyseal stippling and severe liver disease.
  Survival is usually less than a year.

  This entry is the severity counterpart of Peroxisome Biogenesis Disorder 4B at
  the same locus, and the PEX6 counterpart of Peroxisome Biogenesis Disorder 3A
  (PEX12) and 11A (PEX26). The gene-agnostic downstream cascade shared by the whole
  spectrum is curated on the Zellweger Spectrum Disorders entry; what is carried
  here is what is PEX6- and classic-Zellweger-specific.
disease_term:
  preferred_term: peroxisome biogenesis disorder 4A (Zellweger)
  term:
    id: MONDO:0013930
    label: peroxisome biogenesis disorder 4A (Zellweger)
synonyms:
- PBD4A
- peroxisome biogenesis disorder, complementation group 4
- peroxisome biogenesis disorder, complementation group 6
- peroxisome biogenesis disorder, complementation group C
- classic peroxisome biogenesis disorder
- PEX6-related Zellweger syndrome
parents:
- Peroxisome Biogenesis Disorder
- Zellweger Spectrum Disorder
inheritance:
- name: Autosomal recessive
  description: >-
    PBD4A requires PEX6 variants on both alleles, and specifically the genotypes
    that leave no residual peroxin-6 function. A single severe allele in trans with
    a partially functional one shifts the presentation toward PBD4B rather than
    producing this phenotype.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ZSD is typically inherited in an autosomal recessive manner
    explanation: >-
      GeneReviews states the inheritance pattern for the Zellweger spectrum, of
      which PBD4A is the severe PEX6 end.
  - reference: PMID:19877282
    reference_title: Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The autosomal recessive Zellweger syndrome spectrum (ZSS) disorders comprise
      a main subgroup of the peroxisome biogenesis disorders.
    explanation: >-
      The PEX6 mutation survey confirms autosomal recessive inheritance across the
      complementation group this entry belongs to.
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At conception, each sib of an individual with biallelic ZSD-causing pathogenic
      variants has a 25% chance of being affected, a 50% chance of being an
      asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: >-
      GeneReviews gives the recurrence risk that follows from the biallelic
      requirement, which is what genetic counselling for this entry turns on.
pathophysiology:
- name: Biallelic Null PEX6 Genotype
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    PEX6 is a 17-exon gene encoding an AAA-ATPase with two tandem AAA cassettes;
    pathogenic variants are scattered across all exons and the allelic series is
    wide. PBD4A is the subset of that series in which both alleles are null or
    severely truncating, so no functional peroxin-6 is produced. This is the single
    variable that separates this entry from PBD4B at the identical locus, which is
    why the entry is curated on residual function rather than on gene identity.
  genes:
  - preferred_term: PEX6
    term:
      id: hgnc:8859
      label: PEX6
  genetic_context:
    genes:
    - preferred_term: PEX6
      term:
        id: hgnc:8859
        label: PEX6
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    complementation_group: "4"
    notes: >-
      Recorded as complete loss of function because it is the biallelic null or
      severely truncating genotypes, rather than PEX6 involvement as such, that
      define this entry against PBD4B. Compound heterozygosity for two severe
      alleles produces the same phenotype; HOMOZYGOUS is recorded as the
      commonest reported configuration in consanguineous pedigrees rather than
      as a requirement.
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  evidence:
  - reference: PMID:19877282
    reference_title: Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The encoded protein PEX6 belongs to the AAA ATPase family and contains two
      AAA cassettes and an AAA protein family signature.
    explanation: >-
      Establishes the domain architecture of the protein whose complete loss defines
      this entry.
  - reference: PMID:19877282
    reference_title: Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We analyzed the PEX6 genes of 75 patients assigned to the PEX6 complementation
      group. We identified a total of 77 different mutations of which 47 mutations
      have not been reported previously, and 14 polymorphic variants.
    explanation: >-
      Documents the allelic heterogeneity across which the PBD4A/PBD4B severity split
      is drawn, and the size of the complementation group.
  - reference: PMID:41787707
    reference_title: "Unraveling PEX6: insights into very-long-chain fatty acid levels and peroxisome biogenesis disorders in pediatric populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variations in PEX6, an important peroxisome biogenesis factor, contribute
      significantly to this phenotypic diversity, with missense variants often
      associated with less severe disease compared to truncating mutations.
    explanation: >-
      A PEX6-specific review stating the genotype-severity direction this entry is
      built on: truncating alleles at the severe end, missense at the milder one.
  - reference: PMID:26387595
    reference_title: "Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that each HS-affected family has at least one hypomorphic allele
      that results in extremely mild peroxisomal dysfunction.
    explanation: >-
      The opposite pole of the same allelic series. Cited here as the contrast that
      makes the residual-function claim testable: hypomorphic PEX6 alleles give the
      mildest phenotype known at this locus, so the severe phenotype curated here is
      attributed to their absence. INDIRECT because the inference runs from the mild
      end back to the severe one rather than from a direct study of null genotypes.
  downstream:
  - target: Receptor Export Module Failure
    description: >-
      With no functional peroxin-6, the PEX1-PEX6 motor cannot assemble, so the step
      it performs does not occur at all rather than occurring slowly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29884772
      reference_title: "Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PEX1 and PEX6 are two members of the ATPases associated with diverse cellular
        activities (AAA) family and the core components of the receptor export module
        of the peroxisomal matrix protein import machinery.
      explanation: >-
        Identifies PEX6 as an obligate core component of the export module, so its
        complete absence removes the module.
- name: Receptor Export Module Failure
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The PEX1-PEX6 heterohexamer is the ATP-driven motor that extracts
    monoubiquitinated PEX5 from the peroxisomal membrane by processive threading and
    unfolding, returning it to the cytosol for reuse. Because PEX1 and PEX6 are
    obligate partners, a PEX6 null and a PEX1 null converge on the same rate-limiting
    step - which is why PBD4A and PBD1A are phenotypically indistinguishable at the
    bedside despite different genes.
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  evidence:
  - reference: PMID:29884772
    reference_title: "Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PEX1 and PEX6 are two members of the ATPases associated with diverse cellular
      activities (AAA) family and the core components of the receptor export module
      of the peroxisomal matrix protein import machinery.
    explanation: >-
      States the identity and role of the module whose failure this node describes.
  downstream:
  - target: Collapse of Peroxisomal Matrix Protein Import
    description: >-
      PEX5 that cannot be recycled is not available to carry the next matrix enzyme,
      so import runs down to nothing.
    causal_link_type: DIRECT
- name: Collapse of Peroxisomal Matrix Protein Import
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Without receptor recycling, PTS1- and PTS2-targeted matrix enzymes are not
    delivered. The peroxisomal membrane compartment is still assembled, because
    membrane protein import uses PEX19/PEX3 and is independent of the PEX5 cycle;
    what results is an empty organelle - the "peroxisomal ghost" seen in patient
    fibroblasts. This is the defining cellular lesion of a biogenesis disorder and
    the reason the biochemical phenotype is multi-pathway rather than single-enzyme.
  biological_processes:
  - preferred_term: protein import into peroxisome matrix
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
    modifier: DECREASED
  - preferred_term: peroxisome organization
    term:
      id: GO:0007031
      label: peroxisome organization
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because of the defect in peroxisome formation, multiple metabolic (both
      catabolic and anabolic) pathways are impaired resulting in metabolic
      abnormalities.
    explanation: >-
      States the central consequence of the import collapse - that the defect is at
      the level of the organelle and therefore hits many pathways at once.
  downstream:
  - target: Loss of Peroxisomal Fatty Acid Oxidation
    causal_link_type: DIRECT
    description: >-
      The beta- and alpha-oxidation enzymes are matrix enzymes and are among those
      not delivered.
  - target: Plasmalogen Biosynthesis Failure
    causal_link_type: DIRECT
    description: >-
      The first two committed steps of ether-lipid synthesis are peroxisomal matrix
      reactions, so the anabolic half of the phenotype has the same immediate cause
      as the catabolic half.
  - target: C27 Bile Acid Intermediate Accumulation
    causal_link_type: DIRECT
    description: >-
      C27 bile acid side-chain shortening is a peroxisomal beta-oxidation reaction.
  - target: Defective Neuronal Migration in the Developing Cortex
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The migration defect is downstream of the lipid lesions rather than of a single
      identified peroxisomal protein, so the link is recorded as indirect.
- name: Loss of Peroxisomal Fatty Acid Oxidation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Very-long-chain fatty acids are shortened only in peroxisomes, and phytanic acid
    can be degraded only by peroxisomal alpha-oxidation. With the matrix empty, both
    substrates accumulate in plasma and tissue. This is the arm of the phenotype that
    the first-line diagnostic assay reads out.
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: fatty acid alpha-oxidation
    term:
      id: GO:0001561
      label: fatty acid alpha-oxidation
    modifier: DECREASED
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and
      pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and
      have a deficiency of plasmalogens in erythrocytes
    explanation: >-
      Names the accumulating substrates that define the catabolic half of the
      biochemical phenotype.
- name: Plasmalogen Biosynthesis Failure
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Ether-phospholipid synthesis begins with two peroxisomal matrix enzymes, so an
    empty peroxisome cannot make plasmalogens. Erythrocyte plasmalogen is
    correspondingly low and, unlike VLCFA, it is a deficiency rather than an
    accumulation - the anabolic half of the lesion.
  biological_processes:
  - preferred_term: ether lipid biosynthetic process
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and
      pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and
      have a deficiency of plasmalogens in erythrocytes
    explanation: >-
      The same sentence records the erythrocyte plasmalogen deficiency that this node
      describes.
- name: C27 Bile Acid Intermediate Accumulation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Shortening the side chain of the C27 intermediates DHCA and THCA to make the mature
    C24 bile acids is a peroxisomal beta-oxidation reaction. When it fails the
    intermediates accumulate. This node is the accumulation itself, kept separate from
    the liver injury it causes because the two are at different scales and because the
    one available therapy acts here and not there.
  biological_processes:
  - preferred_term: bile acid metabolic process
    term:
      id: GO:0008206
      label: bile acid metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and
      pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and
      have a deficiency of plasmalogens in erythrocytes
    explanation: >-
      Names the C27 bile acid intermediates among the accumulating metabolites.
  downstream:
  - target: Cholestatic Liver Injury
    causal_link_type: DIRECT
    description: >-
      The accumulated intermediates are themselves hepatotoxic and cholestatic, so the
      liver disease is not simply a consequence of generalised metabolic illness.
- name: Cholestatic Liver Injury
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Hepatocellular injury and cholestasis driven by the accumulated C27 intermediates.
    Clinically this presents as prolonged jaundice, hepatomegaly and coagulopathy in the
    newborn period, and in the severe presentation curated here liver failure can be the
    immediate cause of death.
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients within this group typically present in the neonatal period with
      hepatic dysfunction and profound hypotonia resulting in prolonged jaundice and
      feeding difficulties.
    explanation: >-
      Describes the neonatal hepatic presentation of the severe group, which is the
      clinical face of this node.
  downstream:
  - target: Hepatomegaly and Neonatal Cholestasis
    causal_link_type: DIRECT
  - target: Hyperbilirubinemia
    causal_link_type: DIRECT
- name: Defective Neuronal Migration in the Developing Cortex
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    The cortical malformation of classic Zellweger syndrome - perisylvian
    polymicrogyria with heterotopia - is a prenatal neuronal migration defect. It is
    the single most consequential node in this entry for prognosis, because it is
    fixed at birth: no post-natal intervention can undo it, which is why no therapy
    in the treatments section - cholic acid included - changes the neurological
    outcome. It is also the node that most
    cleanly separates PBD4A from PBD4B, where congenital malformations are absent and
    the neurological course is degenerative rather than developmental.
  biological_processes:
  - preferred_term: cerebral cortex cell migration
    term:
      id: GO:0021795
      label: cerebral cortex cell migration
    modifier: DECREASED
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations,
      but rather progressive peroxisome dysfunction
    explanation: >-
      GeneReviews draws exactly the contrast this node rests on: congenital
      malformation is the severe presentation, progressive dysfunction the milder one.
  - reference: PMID:24607700
    reference_title: Revisiting the neuropathogenesis of Zellweger syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neuropathological changes include abnormal neuronal migration affecting the
      cerebral hemispheres, cerebellum and inferior olivary complex, abnormal Purkinje
      cell arborisation, demyelination and post-developmental neuronal degeneration.
    explanation: >-
      Gives the anatomical extent of the migration defect - cerebral hemispheres,
      cerebellum and inferior olivary complex. Note the same sentence attributes
      abnormal arborisation to Purkinje cells, which is a dendritic rather than a
      migration defect; this entry does not bind a Purkinje cell type to this node for
      that reason, and the arborisation claim is left to the spectrum-wide entry.
  - reference: PMID:14586000
    reference_title: Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Functional peroxisome deficiency, as encountered in Zellweger syndrome, causes a
      specific impairment of neuronal migration.
    explanation: >-
      States the causal claim this node makes, in a mouse model of the same lesion.
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      generalized decrease in white matter volume, delayed myelination, bilaterial
      ventricular dilatation and germinolytic cysts
    explanation: >-
      Gives the neonatal MRI findings that accompany the migration defect in this
      group. The clause naming perisylvian polymicrogyria sits immediately before
      this one in the same sentence but is broken across a hyphenated line break in
      the cached PDF text and so cannot be quoted verbatim.
  downstream:
  - target: Neonatal Seizures
    causal_link_type: DIRECT
    description: >-
      The seizures of classic Zellweger syndrome arise from the cortical malformation
      rather than from metabolic decompensation.
phenotypes:
- category: Neurologic
  name: Severe Neonatal Hypotonia
  frequency: VERY_FREQUENT
  description: >-
    Profound generalised hypotonia from birth, with poor feeding. Together with the
    facies it is usually what brings the newborn to attention.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
    severity: SEVERE
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected newborns are hypotonic and feed poorly.
    explanation: >-
      GeneReviews names hypotonia and feeding failure as the newborn presentation.
- category: Neurologic
  name: Neonatal Seizures
  frequency: FREQUENT
  description: >-
    Seizures beginning in the newborn period, arising from the congenital cortical
    malformation.
  phenotype_term:
    preferred_term: Neonatal seizure
    term:
      id: HP:0032807
      label: Neonatal seizure
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epileptic seizures are usually present in these patients.
    explanation: >-
      States that seizures are usual in the neonatal-infantile group this entry
      curates.
- category: Neurologic
  name: Neuronal Migration Defect
  frequency: FREQUENT
  description: >-
    A congenital cortical malformation, characteristically neocortical dysplasia with
    perisylvian polymicrogyria, accompanied by reduced white matter volume, delayed
    myelination and germinolytic cysts on neonatal MRI. The phenotype is bound to the
    generic migration-abnormality term rather than to Polymicrogyria (HP:0002126)
    because the sources available here state the migration defect directly, while the
    specifically perisylvian polymicrogyric pattern could not be quoted verbatim from
    the cached text.
  phenotype_term:
    preferred_term: Abnormality of neuronal migration
    term:
      id: HP:0002269
      label: Abnormality of neuronal migration
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      They have distinctive facies, congenital malformations (neuronal migration
      defects associated with neonatal-onset seizures, renal cysts, and bony
      stippling
    explanation: >-
      GeneReviews names neuronal migration defects among the congenital malformations
      of the severe presentation, and ties them to the neonatal seizures.
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      generalized decrease in white matter volume, delayed myelination, bilaterial
      ventricular dilatation and germinolytic cysts
    explanation: >-
      Gives the accompanying neonatal MRI findings.
- category: Gastrointestinal
  name: Feeding Difficulties
  frequency: VERY_FREQUENT
  description: >-
    Poor suck and swallow from birth, usually requiring gastrostomy.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients within this group typically present in the neonatal period with
      hepatic dysfunction and profound hypotonia resulting in prolonged jaundice and
      feeding difficulties.
    explanation: >-
      Names feeding difficulty as part of the neonatal presentation.
- category: Hepatic
  name: Hepatomegaly and Neonatal Cholestasis
  frequency: VERY_FREQUENT
  description: >-
    Enlarged liver with prolonged conjugated jaundice, elevated transaminases and
    coagulopathy. Liver disease in the severe group can be the immediate cause of
    death.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      and liver disease that can be severe
    explanation: >-
      GeneReviews lists severe liver disease among the newborn findings of the severe
      presentation.
- category: Hepatic
  name: Hyperbilirubinemia
  frequency: FREQUENT
  description: >-
    Prolonged jaundice in the newborn period, part of the hepatic presentation.
  phenotype_term:
    preferred_term: Hyperbilirubinemia
    term:
      id: HP:0002904
      label: Hyperbilirubinemia
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients within this group typically present in the neonatal period with
      hepatic dysfunction and profound hypotonia resulting in prolonged jaundice and
      feeding difficulties.
    explanation: >-
      Records prolonged jaundice as part of the neonatal hepatic presentation.
- category: Renal
  name: Renal Cysts
  frequency: FREQUENT
  description: >-
    Small cortical renal cysts, one of the congenital malformations that distinguish
    the severe end of the spectrum from the milder one.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      They have distinctive facies, congenital malformations (neuronal migration
      defects associated with neonatal-onset seizures, renal cysts, and bony
      stippling
    explanation: >-
      GeneReviews lists renal cysts among the congenital malformations of the severe
      presentation. The quote is cut before the bracketed gloss that follows.
- category: Skeletal
  name: Epiphyseal Stippling
  frequency: FREQUENT
  description: >-
    Calcific stippling of the epiphyses (chondrodysplasia punctata), classically of
    the patellae and long bones, and in the knees and hips.
  phenotype_term:
    preferred_term: Epiphyseal stippling
    term:
      id: HP:0010655
      label: Epiphyseal stippling
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      They have distinctive facies, congenital malformations (neuronal migration
      defects associated with neonatal-onset seizures, renal cysts, and bony
      stippling
    explanation: >-
      GeneReviews lists bony stippling among the congenital malformations. The quote
      is cut before the bracketed gloss naming chondrodysplasia punctata.
- category: Craniofacial
  name: Distinctive Facies
  frequency: VERY_FREQUENT
  description: >-
    High forehead, large anterior fontanelle, flat occiput, hypertelorism and
    epicanthal folds. The dysmorphism is most pronounced in the neonatal-infantile
    group and becomes less distinctive in the milder presentations.
  phenotype_term:
    preferred_term: High forehead
    term:
      id: HP:0000348
      label: High forehead
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic dysmorphic features can usually be found, of which the facial
      dysmorphic signs are most evident
    explanation: >-
      Records that facial dysmorphism is the most evident feature in this group. The
      individual facial signs are curated on the Zellweger Spectrum Disorders entry.
- category: Auditory
  name: Sensorineural Hearing Loss
  frequency: FREQUENT
  description: >-
    Sensorineural deafness, present from birth but often not recognised at first
    presentation in a critically ill newborn.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sensorineural deafness and ocular abnormalities like retinopathy, cataracts and
      glaucoma are typical
    explanation: >-
      Names sensorineural deafness as typical in the neonatal-infantile group.
- category: Ophthalmologic
  name: Cataract
  frequency: FREQUENT
  description: >-
    Congenital or early cataract, alongside retinopathy and glaucoma.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sensorineural deafness and ocular abnormalities like retinopathy, cataracts and
      glaucoma are typical
    explanation: >-
      Names cataract among the typical ocular abnormalities of this group.
- category: Developmental
  name: Absence of Developmental Progress
  frequency: VERY_FREQUENT
  description: >-
    Infants with the severe presentation typically make no developmental progress at
    all before death, which is the feature that most sharply distinguishes PBD4A from
    the milder PEX6 phenotypes where intellect can be normal.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    severity: SEVERE
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Infants with severe ZSD are significantly impaired and typically die during the
      first year of life, usually having made no developmental progress.
    explanation: >-
      States both the absence of developmental progress and the prognosis for the
      severe presentation.
biochemical:
- name: Very-long-chain fatty acids
  presence: Increased
  context: >-
    Plasma C26:0 with the C24/C22 and C26/C22 ratios is the first-line biochemical
    screen. In the severe presentation curated here the elevation is unambiguous,
    unlike the mild end of the PEX6 series where it can be borderline or normal.
  biomarker_term:
    preferred_term: very long-chain fatty acid
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
  readouts:
  - target: Loss of Peroxisomal Fatty Acid Oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Plasma C26:0 and the C24/C22 and C26/C22 ratios measure the beta-oxidation block
      rather than being a separate lesion caused by it. In the severe presentation
      curated here the elevation is unambiguous.
    evidence:
    - reference: PMID:26627182
      reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and
        pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and
        have a deficiency of plasmalogens in erythrocytes
      explanation: >-
        Ties the plasma VLCFA elevation to the peroxisomal catabolic block it reports.
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and
      pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and
      have a deficiency of plasmalogens in erythrocytes
    explanation: >-
      Names VLCFA accumulation in plasma as the characteristic finding.
- name: Erythrocyte plasmalogens
  presence: Decreased
  context: >-
    The anabolic counterpart of the VLCFA elevation, and the assay that distinguishes
    a biogenesis defect from an isolated peroxisomal beta-oxidation enzyme deficiency,
    where plasmalogen synthesis is intact.
  biomarker_term:
    preferred_term: ether lipid
    term:
      id: CHEBI:64611
      label: ether lipid
  readouts:
  - target: Plasmalogen Biosynthesis Failure
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low erythrocyte plasmalogen is the direct measurement of the synthetic block, and
      the assay that separates a biogenesis defect from an isolated beta-oxidation
      enzyme deficiency, where plasmalogen synthesis is intact.
    evidence:
    - reference: PMID:26627182
      reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and
        pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and
        have a deficiency of plasmalogens in erythrocytes
      explanation: >-
        The same sentence records the erythrocyte plasmalogen deficiency this readout
        measures.
  notes: >-
    Bound to the ether lipid parent because CHEBI carries no plasmalogen term - searched
    via the OLS adapter and nothing matched. The binding is deliberately broader than
    the claim rather than a placeholder.
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZSD patients accumulate very long chain fatty acids (VLCFAs), phytanic- and
      pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and
      have a deficiency of plasmalogens in erythrocytes
    explanation: >-
      The same sentence records the erythrocyte plasmalogen deficiency.
genetic:
- name: PEX6
  gene_term:
    preferred_term: PEX6
    term:
      id: hgnc:8859
      label: PEX6
  relationship_type: CAUSATIVE
  notes: >-
    The complementation group 4 (group C) gene, and the second most common cause of
    Zellweger spectrum disease after PEX1. The gene alone does not determine which
    end of the spectrum a patient sits at; the residual function left by the genotype
    does. Note that this locus also carries a documented exception to simple
    recessive transmission - the p.Arg860Trp allele can cause disease in the
    heterozygous state through allelic expression imbalance - but that mechanism
    produces milder disease and is curated on the PBD4B entry, not here.

    A PEX6-specific mechanism worth watching but not yet modelled as a node: recent work
    implicates dysregulated pexophagy - targeted autophagic degradation of peroxisomes -
    when the AAA-ATPase complex is disrupted. It is recorded here rather than as a
    pathophysiology node because no measurement in a PBD4A genotype was found, so a node
    would assert more than the evidence carries.
  evidence:
  - reference: PMID:19877282
    reference_title: Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Defects in the PEX6 gene are the second most common cause for ZSS disorders.
    explanation: >-
      Establishes PEX6 as the causative gene and its rank among the ZSD genes.
  - reference: PMID:41787707
    reference_title: "Unraveling PEX6: insights into very-long-chain fatty acid levels and peroxisome biogenesis disorders in pediatric populations."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Recent studies further implicate dysregulated pexophagy-a targeted autophagic
      degradation of peroxisomes-in the underlying disease mechanisms.
    explanation: >-
      Records the pexophagy mechanism named in the notes above. INDIRECT and kept out of
      the pathograph: the review reports it for peroxisome biogenesis disorders
      generally, not for a PBD4A genotype.
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      by identification of biallelic pathogenic variants in one of the 13 known
      ZSD-PEX genes
    explanation: >-
      States the molecular criterion; assignment to PEX6 is what makes the entry PBD4
      rather than another group.
diagnosis:
- name: Plasma Very-Long-Chain Fatty Acid Profile
  description: >-
    The first-line biochemical test. Elevated C26:0 with abnormal C24/C22 and C26/C22
    ratios points at a peroxisomal disorder before any gene is sequenced, and in the
    severe presentation the result is not equivocal.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of ZSD is established in a proband with the suggestive clinical
      and biochemical findings above by identification of biallelic pathogenic
      variants in one of the 13 known ZSD-PEX genes.
    explanation: >-
      GeneReviews places biochemical findings ahead of molecular confirmation in the
      diagnostic sequence.
  - reference: PMID:41787707
    reference_title: "Unraveling PEX6: insights into very-long-chain fatty acid levels and peroxisome biogenesis disorders in pediatric populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While elevated levels of very-long-chain fatty acids (VLCFAs) remain a key
      diagnostic feature, the existence of unusual cases with normal plasma VLCFA
      levels highlight the limitations of relying solely on this biochemical marker for
      diagnosis.
    explanation: >-
      Records the caveat that matters most in practice: a normal VLCFA does not exclude
      a PEX6 disorder, so a negative first-line screen must not close the workup.
- name: Newborn Screening by C26:0-Lysophosphatidylcholine
  description: >-
    Not a test for this disease, but the route by which some patients now reach it.
    Dried-blood-spot C26:0-lysophosphatidylcholine screening was implemented for
    X-linked adrenoleukodystrophy, and it also picks up other peroxisomal disorders as
    incidental positives. In a pilot of 43,653 newborns, 2 of 32 screen-positives had a
    peroxisomal disorder other than X-ALD. Curated here because incidental detection
    changes when a severe presentation is recognised, which matters for a disease whose
    congenital lesion is already fixed at birth.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:37977233
    reference_title: "A pilot study of newborn screening for X-linked adrenoleukodystrophy based on liquid chromatography-tandem mass spectrometry method for detection of C26:0-lysophosphatidylcholine in dried blood spots: Results from 43,653 newborns in a southern Chinese population."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LC-MS/MS method for screening of X-ALD can identify males, heterozygous
      females and other peroxisomal disorders.
    explanation: >-
      Establishes that the X-ALD newborn screen also detects other peroxisomal
      disorders. INDIRECT: the study is an X-ALD screening pilot and does not report a
      PBD4A case, so it supports the detection route rather than a result in this
      disease.
  - reference: PMID:37977233
    reference_title: "A pilot study of newborn screening for X-linked adrenoleukodystrophy based on liquid chromatography-tandem mass spectrometry method for detection of C26:0-lysophosphatidylcholine in dried blood spots: Results from 43,653 newborns in a southern Chinese population."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 43,653 newborns, 32 (18 males, 14 females) screened positive.
    explanation: >-
      Gives the denominator behind the incidental-detection rate.
- name: Molecular Genetic Testing of the ZSD-PEX Genes
  description: >-
    Confirmation requires biallelic PEX6 variants. Because PBD4A and PBD4B are the
    same gene, the sequencing result alone does not assign the subtype - that follows
    from the predicted consequence of the two alleles together with the phenotype.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      by identification of biallelic pathogenic variants in one of the 13 known
      ZSD-PEX genes
    explanation: >-
      States the molecular criterion for establishing the diagnosis.
treatments:
- name: Supportive and Symptomatic Management
  therapeutic_modality: OTHER
  description: >-
    There is no treatment for the biogenesis defect itself. Management is otherwise
    symptomatic - gastrostomy feeding, anti-seizure medication, hearing aids, cataract
    surgery, fat-soluble vitamin supplementation. None of it restores peroxisomal
    import, and the cortical malformation is complete before birth, so the neurological
    outcome is not modifiable. Cholic acid, curated separately below, is the one
    exception to "nothing is disease-modifying" and it modifies the liver arm only.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment of manifestations: The focus is on symptomatic therapy and may
      include gastrostomy to provide adequate calories, hearing aids, cataract
      removal, glasses to correct refractive errors, supplementation of fat-soluble
      vitamins, and cholic acid supplementation
    explanation: >-
      GeneReviews Management section enumerates the symptomatic measures and confirms
      that no disease-modifying therapy exists.
- name: Oral Cholic Acid
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The one pharmacological therapy in Zellweger spectrum disease with phase 3
    evidence behind it. Supplying the mature primary bile acid suppresses endogenous
    synthesis and so reduces production of the hepatotoxic C27 intermediates that
    accumulate when peroxisomal side-chain shortening fails. It is disease-modifying
    for the liver arm of the phenotype and for nothing else: it does not restore
    peroxisomal import and cannot touch the congenital brain malformation, so it does
    not change the prognosis of the severe presentation curated here.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  target_mechanisms:
  - target: C27 Bile Acid Intermediate Accumulation
    description: >-
      Feedback suppression of endogenous bile acid synthesis lowers the flux into the
      blocked peroxisomal step, so fewer toxic C27 intermediates are made.
    evidence:
    - reference: PMID:28644367
      reference_title: Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cholic acid significantly improved urine bile acid metabolite scores (P <
        0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P <
        0.0001) in patients with SED and ZSD.
      explanation: >-
        Shows the intervention moves both the bile-acid metabolite readout and the
        liver-injury markers, which is the mechanism this link asserts.
  evidence:
  - reference: PMID:28644367
    reference_title: Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral cholic acid is a safe, efficacious, and well-tolerated treatment for BASD
      due to SED and ZSD.
    explanation: >-
      The trial's conclusion. Note the ZSD arm was 20 patients in a single-arm,
      open-label, non-randomised design, and was not stratified by PEX gene or by
      severity, so nothing in it is specific to PBD4A.
- name: Docosahexaenoic Acid Supplementation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Curated because it is a negative result worth recording rather than a therapy to
    offer. DHA is low in Zellweger spectrum disease because its final synthetic step
    is peroxisomal, which made replacement an obvious hypothesis; a double-blind
    randomised placebo-controlled trial found no effect on visual function or growth.
    The entry keeps it so that a future curator does not re-derive the hypothesis from
    the biochemistry and present it as promising.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:20805528
    reference_title: "Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DHA supplementation did not improve the visual function or growth of treated
      individuals with peroxisome assembly disorders.
    explanation: >-
      Refutes DHA replacement as a disease-modifying therapy. Graded REFUTE because the
      claim being tested is that supplementing the deficient lipid helps, and the trial
      says it does not.
- name: Genetic Counseling
  therapeutic_modality: OTHER
  description: >-
    Recurrence risk counselling for the family, with carrier testing for at-risk
    relatives and the option of prenatal testing once both variants are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Carrier testing for at-risk relatives is possible if the pathogenic variants
      have been identified in an affected family member.
    explanation: >-
      GeneReviews Genetic Counseling section states the carrier-testing option that
      this entry records as management.
progression:
- phase: Neonatal-infantile
  notes: >-
    Presentation at or shortly after birth with profound hypotonia, poor feeding,
    seizures, dysmorphism and hepatic dysfunction. Congenital malformations - the
    cortical migration defect, renal cysts and epiphyseal stippling - are already
    present.
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neonatal-infantile presentation grossly resembles what was originally
      described as classic ZS.
    explanation: >-
      Identifies the presentation curated here with classic Zellweger syndrome.
- phase: Infantile death
  notes: >-
    Death, usually in the first year, most often from liver failure, respiratory
    compromise or intractable seizures. Survival beyond infancy would put the
    diagnosis of the severe form in doubt and prompt reconsideration of PBD4B.
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prognosis is poor and survival is usually not beyond the first year of life.
    explanation: >-
      Gives the survival expectation for the neonatal-infantile presentation.
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Infants with severe ZSD are significantly impaired and typically die during the
      first year of life, usually having made no developmental progress.
    explanation: >-
      Independent statement of the same prognosis from GeneReviews.
animal_models:
- name: Pex5 knockout mouse with tissue-selective peroxisome reconstitution
  species: Mouse
  genotype: Pex5 knockout, with Pex5p re-expressed selectively in brain or in liver
  publication: PMID:14586000
  description: >-
    Not a PEX6 model, and cited here for what it rules out rather than what it
    reproduces. Peroxisomes were restored selectively in either brain or liver of Pex5
    knockout mice, a model of Zellweger syndrome, to ask which tissue's peroxisomal
    metabolism the cortical migration defect depends on. Both single rescues partly
    corrected migration; rescuing both gave a migration pattern indistinguishable from
    wild-type.
  modeled_mechanisms:
  - target: Defective Neuronal Migration in the Developing Cortex
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knockout reproduces the migration defect, and the tissue-selective rescues
      make it experimentally addressable rather than merely observed.
    limitations: >-
      The disrupted gene is PEX5, the receptor itself, not PEX6, the ATPase that recycles
      it. Both lesions abolish matrix import, so the downstream phenotype is shared, but
      nothing PEX6-specific is modelled. The mouse also does not address the severity
      split that defines PBD4A against PBD4B, since it is a null rather than a
      hypomorph.
    readouts:
    - name: Cortical neuronal migration after liver-selective rescue
      target: Defective Neuronal Migration in the Developing Cortex
      direction: RESTORED
      interpretation: >-
        Restoring peroxisomes in liver alone significantly corrects a brain phenotype,
        which is the result that makes an extraneuronal contribution unavoidable.
      evidence:
      - reference: PMID:14586000
        reference_title: Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We found that both rescue strains exhibited a significant correction of the
          neuronal migration defect despite an incomplete reconstitution of peroxisomal
          function in the targeted tissue.
        explanation: >-
          The rescue measurement itself, for both the brain-targeted and the
          liver-targeted strain.
    - name: Brain VLCFA, DHA and plasmalogen after liver-selective rescue
      target: Defective Neuronal Migration in the Developing Cortex
      direction: UNCHANGED
      interpretation: >-
        The negative readout, and the load-bearing one. Migration improved while the
        three lipid species usually invoked to explain it did not move, so the
        migration defect is not a straightforward consequence of the brain's own lipid
        abnormality.
      evidence:
      - reference: PMID:14586000
        reference_title: Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In liver-rescued mice, the improvement of the neuronal migration was not
          accompanied by changes in very long chain fatty acid, docosahexaenoic acid, or
          plasmalogen levels in brain, indicating that other metabolic factors can
          influence the neuronal migration process.
        explanation: >-
          Reports the unchanged brain lipids alongside the corrected migration.
    evidence:
    - reference: PMID:14586000
      reference_title: Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Functional peroxisome deficiency, as encountered in Zellweger syndrome, causes a
        specific impairment of neuronal migration.
      explanation: >-
        Supports treating this model as informative for the migration node.
discussions:
- discussion_id: pbd4a_null_genotype_fraction
  kind: KNOWLEDGE_GAP
  prompt: >-
    What fraction of the PEX6 complementation group carries a biallelic null genotype
    and therefore belongs to PBD4A rather than PBD4B?
  attaches_to:
  - pathophysiology#Biallelic Null PEX6 Genotype
  rationale: >-
    The A/B split at this locus is defined by residual peroxin-6 function, but the
    published PEX6 series report mutation spectra rather than a genotype-stratified
    phenotype breakdown. Ebberink and colleagues characterised 75 patients and 77
    distinct mutations without reporting how many of those genotypes were biallelic
    null. Without that denominator neither a prevalence figure nor a
    genotype-to-subtype rule can be curated for this entry, which is why the entry
    carries no prevalence block. This is a gap in the source literature rather than
    in the curation.
- discussion_id: pbd4a_migration_defect_proximate_cause
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the neuronal migration defect in classic Zellweger syndrome driven by
    plasmalogen deficiency, by VLCFA accumulation, or by loss of a peroxisomal
    function not yet identified?
  attaches_to:
  - pathophysiology#Defective Neuronal Migration in the Developing Cortex
  rationale: >-
    The link from the import collapse to the cortical malformation is recorded as
    INDIRECT_UNKNOWN_INTERMEDIATES precisely because the intervening step is unknown,
    and the best experiment on the question makes the gap wider rather than narrower.
    Selectively restoring peroxisomes in the liver of Pex5 knockout mice corrected the
    neuronal migration defect without changing brain VLCFA, DHA or plasmalogen levels
    at all. So the migration defect is not a straightforward consequence of the brain's
    own lipid abnormality, and an extraneuronal - probably hepatic - contribution is
    doing part of the work. Assigning the responsible factor would change what a
    prenatal intervention would have to target and in which tissue, so the gap is
    mechanistically load-bearing rather than academic.
  evidence:
  - reference: PMID:14586000
    reference_title: Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In liver-rescued mice, the improvement of the neuronal migration was not
      accompanied by changes in very long chain fatty acid, docosahexaenoic acid, or
      plasmalogen levels in brain, indicating that other metabolic factors can
      influence the neuronal migration process.
    explanation: >-
      The result that keeps this gap open: correcting migration without correcting
      brain lipids rules out the obvious candidate mechanism.
references:
- reference: PMID:20301621
  title: Zellweger Spectrum Disorder.
  tags:
  - GeneReviews
- reference: PMID:19877282
  title: Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.
- reference: PMID:26627182
  title: "Zellweger spectrum disorders: clinical overview and management approach."
- reference: PMID:29884772
  title: "Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol."
- reference: PMID:26387595
  title: "Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6."
- reference: PMID:41787707
  title: "Unraveling PEX6: insights into very-long-chain fatty acid levels and peroxisome biogenesis disorders in pediatric populations."
- reference: PMID:24607700
  title: Revisiting the neuropathogenesis of Zellweger syndrome.
- reference: PMID:14586000
  title: Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues.
- reference: PMID:28644367
  title: Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders.
- reference: PMID:20805528
  title: "Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial."
- reference: PMID:37977233
  title: "A pilot study of newborn screening for X-linked adrenoleukodystrophy based on liquid chromatography-tandem mass spectrometry method for detection of C26:0-lysophosphatidylcholine in dried blood spots: Results from 43,653 newborns in a southern Chinese population."
notes: >-
  Curation level and lump/split decision. PBD4A is curated as its own entry rather
  than as a has_subtypes entry on PBD4B, following the precedent already set in this
  KB by Peroxisome Biogenesis Disorder 3A (PEX12) and 11A (PEX26) alongside 1B and
  4B. The reasoning is that the "A"/"B" split within a PEX complementation group is
  a mechanistic statement about residual peroxin function, not a bare severity label:
  the two ends differ in whether the disease is a congenital malformation syndrome or
  a progressive degenerative one, which is a different pathograph and not a different
  point on one. PBD4A also holds its own MONDO and OMIM identity.

  Relationship to sibling entries. The existing Peroxisome Biogenesis Disorder 4B
  entry names PBD4A explicitly as the severe counterpart it is defined against, so
  the two are intended to be read together. The gene-agnostic downstream cascade
  shared by the whole Zellweger spectrum - the full biochemical profile, the
  multisystem phenotype, and the management framework - is curated once on the
  Zellweger Spectrum Disorders entry; this entry deliberately carries only what is
  PEX6- and classic-Zellweger-specific, and cross-refers rather than duplicating.

  Evidence base and its limits, stated plainly. The clinical detail in this entry is
  inherited from descriptions of the severe end of the Zellweger spectrum as a whole -
  chiefly the GeneReviews chapter and the Klouwer review - not from a series of PBD4A
  patients, because no such series exists. What is anchored on PEX6-specific sources is
  the part that makes this a separate entry: the mutation spectrum and complementation
  group size (PMID:19877282) and the direction of the genotype-severity correlation,
  truncating alleles severe and missense milder (PMID:41787707). Neither of those
  reports a genotype-stratified phenotype breakdown, so the boundary between PBD4A and
  PBD4B is a qualitative rule rather than a validated classifier; the first knowledge
  gap records the study that would fix that. Two therapy claims - cholic acid and the
  negative DHA trial - come from ZSD-wide trials whose ZSD arms were 20 and roughly 48
  patients respectively, neither stratified by PEX gene, so they are recorded as
  spectrum-level evidence applied here rather than as PBD4A results. The
  evidence_source values follow a rule worth stating precisely, because a coarser
  version of it would be inconsistent. The axis is not primary-versus-review; it is what
  kind of evidence the cited text reports. OTHER is used where the source compiles
  expert consensus with no cohort behind the specific sentence quoted - the GeneReviews
  chapter, and the Crane neuropathology review, which surveys candidate pathogenetic
  mechanisms. HUMAN_CLINICAL is used where the sentence reports observations of patients,
  which is why the Klouwer review is graded HUMAN_CLINICAL throughout despite also being
  a review: every sentence quoted from it describes what ZSD patients present with.
  MODEL_ORGANISM is used for the mouse work.

  Named-entity-confusion check. "Complementation group 4" and "complementation group
  C" both refer to this group in older literature, and the group was independently
  numbered in two different series - which is why MONDO carries both "complementation
  group 4" and "complementation group 6" as synonyms of the same concept. That is a
  numbering collision in the historical nosology, not two diseases. Care is needed in
  the other direction too: "PBD4A" and "PBD1A" are different genes (PEX6 and PEX1)
  with an indistinguishable clinical phenotype, so a clinical description alone never
  assigns an entry.
📚

References & Deep Research

References

11
PMID:20301621
Zellweger Spectrum Disorder.
No top-level findings curated for this source.
PMID:19877282
Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.
No top-level findings curated for this source.
PMID:26627182
Zellweger spectrum disorders: clinical overview and management approach.
No top-level findings curated for this source.
PMID:29884772
Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol.
No top-level findings curated for this source.
PMID:26387595
Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6.
No top-level findings curated for this source.
PMID:41787707
Unraveling PEX6: insights into very-long-chain fatty acid levels and peroxisome biogenesis disorders in pediatric populations.
No top-level findings curated for this source.
PMID:24607700
Revisiting the neuropathogenesis of Zellweger syndrome.
No top-level findings curated for this source.
PMID:14586000
Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues.
No top-level findings curated for this source.
PMID:28644367
Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders.
No top-level findings curated for this source.
PMID:20805528
Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial.
No top-level findings curated for this source.
PMID:37977233
A pilot study of newborn screening for X-linked adrenoleukodystrophy based on liquid chromatography-tandem mass spectrometry method for detection of C26:0-lysophosphatidylcholine in dried blood spots: Results from 43,653 newborns in a southern Chinese population.
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
Peroxisome Biogenesis Disorder 4A (Zellweger) — Comprehensive Disease Characteristics Report
openscientist-autonomous 24 citations 2026-08-29T16:30:44.229919

Peroxisome Biogenesis Disorder 4A (Zellweger) — Comprehensive Disease Characteristics Report

Disease: Peroxisome Biogenesis Disorder 4A (Zellweger) — PBD4A Gene: PEX6 (HGNC:8859; OMIM 601498) Category: Mendelian, autosomal recessive Suggested disease ontology mapping:* MONDO:0009279 (peroxisome biogenesis disorder), within the Zellweger spectrum; OMIM phenotype #614862 (Peroxisome biogenesis disorder 4A, Zellweger); Orphanet ORPHA:912 (Zellweger syndrome); ICD-10 E71.510; ICD-11 5C57.0; MeSH D015211 (Zellweger Syndrome)

Summary

Peroxisome Biogenesis Disorder 4A (Zellweger), abbreviated PBD4A, is the severe, neonatal-lethal extreme of the PEX6-related Zellweger Spectrum Disorder (ZSD). It is an autosomal recessive multisystem disease caused by biallelic loss-of-function variants in PEX6, a gene encoding an AAA+ ATPase that — together with its partner ATPase PEX1 and the tail-anchored membrane anchor PEX26 — extracts and recycles the ubiquitinated peroxisomal targeting signal-1 (PTS1) receptor PEX5 back to the cytosol after cargo delivery. When this receptor-recycling machinery fails, peroxisomal matrix proteins can no longer be imported, peroxisome assembly collapses, and the full complement of peroxisomal metabolic functions is lost (F001, F002).

The biochemical consequence is a signature profile of accumulated very-long-chain fatty acids (VLCFA; C26:0, elevated C26:0/C22:0 and C24:0/C22:0 ratios), phytanic and pristanic acid, and toxic C27 bile-acid intermediates, together with deficiency of plasmalogens and docosahexaenoic acid (DHA) (F003, F005). These metabolic derangements drive the hallmark pathology of Zellweger syndrome: impaired neuronal migration (cerebral hemispheres, cerebellum, inferior olivary complex), abnormal Purkinje-cell arborization, demyelination, and post-developmental neurodegeneration, alongside severe hypotonia, seizures, craniofacial dysmorphism, hepatic dysfunction, and sensory (retinal and auditory) loss (F005, F007). Classic Zellweger presents at birth and typically leads to death within the first year of life (F007).

PBD4A sits at one end of a continuous phenotypic spectrum: hypomorphic or missense PEX6 alleles that preserve residual peroxisomal function produce progressively milder disease — neonatal adrenoleukodystrophy, infantile Refsum disease, and, at the mildest end, Heimler syndrome (PBD4B) (F006). There is no curative therapy; management is supportive. The best-evidenced pharmacologic intervention is oral cholic acid, which significantly improves urinary bile-acid metabolite scores and serum transaminases in ZSD (F004), while DHA supplementation was refuted by a double-blind randomized controlled trial (F009). Liver transplantation can normalize toxic metabolites in mild ZSD (F010), and AAV-mediated gene augmentation is an emerging preclinical therapy for the ZSD retinopathy (F013).

Key Findings

F001 — PBD4A is caused by biallelic PEX6 variants with a genotype–severity correlation

PBD4A is inherited in an autosomal recessive manner and arises from biallelic pathogenic variants in PEX6. Case series and reviews demonstrate a genotype–phenotype gradient: missense variants that retain partial protein function trend toward milder disease, whereas truncating variants (nonsense, frameshift, canonical splice-site) that trigger nonsense-mediated decay or produce non-functional protein cause the severe, classic Zellweger (PBD4A) phenotype. A documented severe genotype is compound heterozygosity for c.315G>A (p.Trp105Ter) plus the splice variant c.2095-3T>G, both predicted to abolish functional protein; a milder-end example is the missense c.1992G>C (p.Glu664Asp).

"Genetic variations in PEX6, an important peroxisome biogenesis factor, contribute significantly to this phenotypic diversity, with missense variants often associated with less severe disease compared to truncating mutations." — PMID: 41787707

"WES identified compound heterozygous PEX6 variants: c.315G>A (p. Trp105Ter) and c.2095-3 T>G." — PMID: 39013483

Ontology suggestions: gene PEX6 (HGNC:8859); inheritance HP:0000007 (autosomal recessive inheritance).

F002 — PEX6 encodes an AAA+ ATPase that recycles the PTS1 receptor PEX5

PEX6 encodes a member of the AAA+ (ATPases Associated with diverse cellular Activities) family. It forms a heterohexameric ATPase complex with PEX1, anchored to the peroxisomal membrane by the tail-anchored protein PEX26. After the cytosolic PTS1 receptor PEX5 delivers matrix cargo into the peroxisome, the PEX1–PEX6–PEX26 complex extracts (dislocates) ubiquitinated PEX5 from the membrane back to the cytosol for another round of import. Loss of PEX6 function halts PEX5 export; the receptor is instead proteasomally degraded, and matrix-protein import fails — the direct molecular lesion of PBD4A.

"After cargo delivery, a complex of the PEX1 and PEX6 ATPases and the PEX26 tail-anchored membrane protein removes ubiquitinated PEX5 from the peroxisomal membrane." — PMID: 28742939

"in AWP1 knock-down cells, Pex5 stability was decreased, similar to fibroblasts from patients defective in Pex1, Pex6 and Pex26, all of which are required for Pex5 export" — PMID: 21980954

Ontology suggestions: GO:0016887 (ATP hydrolysis activity); GO:0016558 (protein import into peroxisome matrix); GO:0005778 (peroxisomal membrane); GO:0043335 (protein unfolding).

F003 — Elevated plasma VLCFA is the key biomarker but can be normal

Impaired peroxisomal β-oxidation elevates very-long-chain fatty acids (C26:0) and the diagnostic ratios C26:0/C22:0 and C24:0/C22:0, along with phytanic acid, pristanic acid, and abnormal bile-acid intermediates. This constitutes the primary biochemical screening approach. However, rare PEX6 cases present with normal plasma VLCFA (e.g., homozygous c.1992G>C, p.Glu664Asp), so a normal VLCFA result does not exclude ZSD. Definitive diagnosis therefore requires combined clinical, biochemical, and molecular (WES/WGS) evaluation.

"While elevated levels of very-long-chain fatty acids (VLCFAs) remain a key diagnostic feature, the existence of unusual cases with normal plasma VLCFA levels highlight the limitations of relying solely on this biochemical marker for diagnosis." — PMID: 41787707

"A homozygous variant of uncertain significance (VUS) in PEX6 NM_000287.4: c.1992G > C (p. Glu664Asp) was identified" — PMID: 39604887

Ontology / chemical suggestions: CHEBI:74102 (hexacosanoic acid / C26:0); CHEBI:37723 (phytanic acid); HP:0410054 (abnormal circulating VLCFA).

F004 — Management is supportive; oral cholic acid improves liver disease in ZSD

There is no curative therapy. The best-evidenced pharmacologic intervention targets the hepatic bile-acid abnormality. In a phase 3 open-label study (n=70 modified intention-to-treat; 20 with ZSD), oral cholic acid (10–15 mg/kg/day) significantly improved urinary atypical bile-acid metabolite scores (P<0.0001) and serum AST/ALT (P<0.0001), reduced direct bilirubin (P<0.001), and stabilized or improved liver histology. Other supportive measures include DHA, Lorenzo's oil, batyl alcohol, fat-soluble vitamin (A, D, E, K) supplementation, and dietary restriction of VLCFA and branched-chain fatty acids.

"Cholic acid significantly improved urine bile acid metabolite scores (P < 0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001) in patients with SED and ZSD." — PMID: 28644367

"There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD" — PMID: 34625341

Ontology suggestions: NCIT — cholic acid therapy; CHEBI:16359 (cholic acid).

F005 — Neuropathology arises from combined loss of plasmalogens/DHA and VLCFA accumulation impairing neuronal migration

The hallmark neuropathology comprises abnormal neuronal migration affecting the cerebral hemispheres, cerebellum, and inferior olivary complex; abnormal Purkinje-cell arborization; demyelination; and post-developmental neuronal degeneration. Mouse models establish causality: the Pex5 knockout (Zellweger model) shows that peroxisomal metabolism in both brain and extraneuronal tissues affects neocortical development, and tissue-selective Pex5 reconstitution corrects the migration defect. The Pex2 knockout reproduces delayed cortical migration, cerebellar/Purkinje defects, embryonic lethality on an inbred background, VLCFA accumulation, plasmalogen deficiency, and reduced brain DHA. Additional downstream contributors include mitochondrial dysfunction, oxidative stress, and inflammation.

"Neuropathological changes include abnormal neuronal migration affecting the cerebral hemispheres, cerebellum and inferior olivary complex, abnormal Purkinje cell arborisation, demyelination and post-developmental neuronal degeneration." — PMID: 24607700

"Functional peroxisome deficiency, as encountered in Zellweger syndrome, causes a specific impairment of neuronal migration." — PMID: 14586000

"Biochemical analysis of PEX2 mutant mice shows the characteristic accumulation of very long chain fatty acids and deficient plasmalogens in a wide variety of tissues." — PMID: 11478384

Ontology suggestions: HP:0002269 (abnormality of neuronal migration); HP:0002079 (hypoplasia of the corpus callosum); HP:0001272 (cerebellar atrophy); GO:0001764 (neuron migration); CL:0000121 (Purkinje cell); CL:0000127 (astrocyte).

F006 — PEX6 causes a continuous spectrum from neonatal-lethal Zellweger (PBD4A) to mild Heimler syndrome (PBD4B)

Biallelic loss-of-function PEX6 variants cause severe Zellweger syndrome (PBD4A). Genotypes carrying at least one hypomorphic / missense / "leaky" allele yield progressively milder disease: neonatal adrenoleukodystrophy, infantile Refsum disease, and — at the mildest end — Heimler syndrome (PBD4B), defined by sensorineural hearing loss, amelogenesis imperfecta, retinal dystrophy, and nail changes. In a review of 46 molecularly confirmed Heimler cases, retinal dystrophy (rod-cone type) was present in 89% and macular edema in 40%. A recurrent hypomorphic allele (p.Arg601Gln) shares a common founder haplotype.

"We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction." — PMID: 26387595

"The finding of HS-causing mutations in PEX1 and PEX6 shows that HS represents the mild end of the ZSSD spectrum" — PMID: 27302843

"Retinal dystrophy, predominantly of the rod-cone type with pigment clumping, was present in 89% of reported cases, with macular edema noted in 40%." — PMID: 41126390

Ontology suggestions: HP:0000510 (rod-cone dystrophy); HP:0000407 (sensorineural hearing impairment); HP:0000705 (amelogenesis imperfecta).

F007 — ZSD is clinically heterogeneous with shortened lifespan; the severe (PBD4A) form is neonatal-lethal

PBD-ZSD ranges from profound neurologic disease in newborns to progressive degeneration in adults, and typically results in shortened life spans. Classic Zellweger syndrome (the severe end, PBD4A) presents at birth with severe hypotonia, seizures, feeding difficulty, craniofacial dysmorphism, hepatic dysfunction, and usually death within the first year of life. Milder forms survive into childhood or adulthood.

"individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans" — PMID: 26750748

"Common clinical presentations include hypotonia, seizure, hepatomegaly, craniofacial dysmorphism and early death." — PMID: 38409970

Ontology suggestions: HP:0001252 (hypotonia); HP:0001250 (seizure); HP:0002240 (hepatomegaly); HP:0001999 (abnormal facial shape); HP:0003811 (neonatal death).

F008 — Newborn screening (C26:0-LPC in dried blood spots) can incidentally detect PBDs

LC-MS/MS quantification of C26:0-lysophosphatidylcholine (C26:0-LPC) in dried blood spots — implemented for X-linked adrenoleukodystrophy newborn screening — also detects other peroxisomal disorders including PBDs. In a screen of 43,653 newborns, 2 of 32 screen-positives (6.3%) were diagnosed with peroxisomal disorders other than X-ALD. C26:0-LPC correlates strongly with plasma C26:0 (r=0.952) and the C26:0/C22:0 ratio (r=0.801).

"two (6.3%) were diagnosed with other peroxisomal disorders" — PMID: 37977233

F009 — DHA supplementation did NOT improve vision or growth (negative RCT)

A double-blind, randomized, placebo-controlled trial (n=50 enrolled; DHA 100 mg/kg/day for ~1 year) in peroxisome assembly disorders found no difference between DHA-treated and placebo groups in biochemical function, electroretinogram, or growth (Class II evidence). Nine patients died during the trial of their underlying disorder, underscoring severity. This refutes an earlier hypothesis that DHA supplementation is disease-modifying in ZSD.

"DHA supplementation did not improve the visual function or growth of treated individuals with peroxisome assembly disorders" — PMID: 20805528

F010 — Liver transplantation can normalize toxic metabolites in mild ZSD

In mild ZSD (infantile Refsum-like), living-donor liver transplantation normalized plasma phytanic, pristanic, and pipecolic acid levels, stabilized hearing and vision, and improved neurodevelopment, with sustained benefit up to 17 years post-transplant (2/3 patients survived and improved; 1 died). Separately, an oral cholic acid extension study (n=17, 21 months) showed durable suppression of bile-acid synthesis and reduced toxic C27 intermediates.

"We documented a sustained improvement of biochemical functions, with a complete normalization of plasma phytanic, pristanic, and pipecolic acid levels. This was associated with stabilization of hearing and visual functions, and improved neurodevelopmental status" — PMID: 29453832

"Bile acid synthesis was still suppressed after 21 months of CA treatment" — PMID: 30793331

F011 — Mitochondria-mediated oxidative stress is a downstream effector of peroxisomal failure

Brain-restricted PEX13-deficient mice (Zellweger model) show cerebellar maldevelopment, impaired granule-cell migration, astro-/microgliosis, and — in cultured E19 PEX13-null cerebellar neurons — elevated reactive oxygen species, increased mitochondrial MnSOD (SOD2), enhanced apoptosis, and mitochondrial dysfunction; plasmalogens were reduced while VLCFA were normal in this brain model. PBD models (Pex2⁻/⁻, Pex5⁻/⁻, Pex13⁻/⁻) also show increased α-synuclein oligomerization/phosphorylation and cytoplasmic deposition, linking peroxisomal lipid changes to neurodegenerative protein aggregation.

"cultured cerebellar neurons from E19 PEX13-null mice exhibit elevated levels of reactive oxygen species and mitochondrial superoxide dismutase-2 (MnSOD), and show enhanced apoptosis together with mitochondrial dysfunction" — PMID: 20959636

"We found increased alphaS oligomerization and phosphorylation and its increased deposition in cytoplasmic inclusions in these PBD mouse models." — PMID: 19830841

Ontology suggestions: GO:0006915 (apoptotic process); GO:0006979 (response to oxidative stress); GO:0005739 (mitochondrion).

F012 — ~80% of PBD patients fall in the Zellweger spectrum; ~90% carry mutations in PEX1/PEX6/PEX10/PEX12/PEX26

Within the peroxisome biogenesis disorders, approximately 80% of all PBD patients are classified as PBD-ZSS, and mutations in PEX1, PEX6, PEX10, PEX12, or PEX26 are found in ~90% of PBD-ZSS patients (cohort of 58 PBD-ZSS cases; 71 unique sequence variants, 18 novel). Rare digenic cases with deleterious mutations across two PEX genes were observed. This places PEX6 among the five major ZSS genes.

"Approximately 80% of PBD patients are classified in the Zellweger syndrome spectrum (PBD-ZSS). Mutations in the PEX1, PEX6, PEX10, PEX12, or PEX26 genes are found in approximately 90% of PBD-ZSS patients." — PMID: 19105186

F013 — Preclinical AAV gene-augmentation therapy improves vision in a mild ZSD mouse model

AAV-mediated PEX gene augmentation was tested in the humanized PEX1-Gly844Asp mouse model of mild ZSD, which develops retinal dysfunction and vision loss. Ocular AAV delivery improved visual/retinal function — a proof-of-concept preclinical gene therapy for the ZSD retinopathy (not yet clinical).

"Patients with Zellweger spectrum disorder (ZSD) commonly present with vision loss due to mutations in" — PMID: 34703844

Section-by-Section Report

1. Disease Information

PBD4A (Zellweger) is the most severe form of the Zellweger Spectrum Disorder, a group of autosomal recessive peroxisome biogenesis disorders. Peroxisomes are membrane-bound organelles essential for VLCFA β-oxidation, plasmalogen (ether-phospholipid) biosynthesis, bile-acid synthesis, and reactive-oxygen detoxification. In PBD4A, functional peroxisomes are essentially absent from patient fibroblasts, and multiple organ systems are affected (F001, F007).

Key identifiers: Gene PEX6 (OMIM *601498; HGNC:8859). Phenotype OMIM #614862 (Peroxisome biogenesis disorder 4A, Zellweger). Orphanet ORPHA:912 (Zellweger syndrome, the broader clinical entity). ICD-10 E71.510; ICD-11 5C57.0; MeSH D015211. Suggested MONDO mapping within the peroxisome biogenesis disorder branch (MONDO:0009279 and related ZSD terms).

Synonyms / alternative names: Zellweger syndrome (severe end); cerebrohepatorenal syndrome; PBD4A; PEX6-related Zellweger spectrum disorder. The broader continuum encompasses neonatal adrenoleukodystrophy, infantile Refsum disease, and Heimler syndrome (PBD4B) (F006).

Information source type: Predominantly aggregated disease-level resources (OMIM, Orphanet, GeneReviews, case series and cohort reviews), supplemented by individual case reports; not derived from large EHR cohorts.

2. Etiology

Causal factor: Purely genetic — biallelic loss-of-function variants in PEX6 (F001). There is no environmental or infectious cause.

Genetic risk factors: The causal variants are the PEX6 alleles themselves. Consanguinity increases risk (many reported cases are from consanguineous unions, e.g., Egyptian, Iranian, Saudi, and Mixteco founder populations described in the literature). Founder effects exist (recurrent hypomorphic p.Arg601Gln allele; a Mixteco PEX6 founder mutation reported in neonates). No common susceptibility loci or modifier genes are established beyond the allele-specific severity gradient (F001, F006).

Environmental / protective factors: None identified. There are no known environmental risk or protective factors, and no established gene–environment interactions — consistent with a monogenic, fully penetrant Mendelian disorder.

3. Phenotypes

Phenotype Type HPO term Onset Severity/Frequency
Severe hypotonia Clinical sign HP:0001252 Neonatal Severe; near-universal (F007)
Seizures Clinical sign HP:0001250 Neonatal Severe; common (F007)
Craniofacial dysmorphism Physical HP:0001999 Congenital Characteristic (high forehead, large fontanelles, epicanthal folds) (F007)
Hepatic dysfunction / hepatomegaly Lab/clinical HP:0002240 Neonatal Common; progressive (F004, F007)
Neuronal migration defect (polymicrogyria) Imaging/structural HP:0002269 Congenital Hallmark (F005)
Retinal dystrophy (rod-cone) Clinical sign HP:0000510 Infantile 89% in mild end (F006)
Sensorineural hearing loss Clinical sign HP:0000407 Infantile Common (F006)
Elevated plasma VLCFA Lab abnormality HP:0410054 Congenital Key biomarker (may be normal in rare cases) (F003)
Feeding difficulty / failure to thrive Symptom HP:0011968 Neonatal Common (F007)
Amelogenesis imperfecta (mild end) Physical HP:0000705 Childhood Heimler feature (F006)

Quality-of-life impact: In classic PBD4A, profound neurological impairment precludes normal development; infants are typically non-ambulatory, feeding-dependent, and die in infancy (F007). Milder spectrum survivors experience progressive vision and hearing loss, developmental delay, and hepatic complications.

4. Genetic/Molecular Information

Causal gene: PEX6 (chromosome 6p21.1; OMIM 601498). Encodes a peroxisomal AAA+ ATPase* (peroxin-6) (F002).

Pathogenic variants: Documented ClinVar-type variants include c.315G>A (p.Trp105Ter) (nonsense), c.2095-3T>G (canonical splice, NMD-triggering) — severe; and c.1992G>C (p.Glu664Asp) (missense) — milder/normal-VLCFA (F001, F003). Variant classes span missense, nonsense, frameshift, and splice-site; classification ranges pathogenic/likely-pathogenic to VUS per ACMG/AMP. Functional consequence: loss of function (impaired PEX5 receptor recycling → failed matrix import) (F002). Origin is germline; no somatic role. Allele frequencies of pathogenic variants are very rare in gnomAD.

Modifier / genotype–severity relationship: Severity is chiefly determined by residual PEX6 function — the presence of a hypomorphic/leaky allele shifts phenotype toward milder disease (F001, F006). No independent trans-acting modifier genes are firmly established, though rare digenic PEX interactions are reported (F012).

Epigenetics / chromosomal abnormalities: No specific epigenetic mechanism or large-scale chromosomal abnormality is characteristic; PBD4A is a single-gene disorder.

5. Environmental Information

Not applicable. PBD4A is a monogenic disorder with no established environmental, lifestyle, or infectious contributors. Dietary VLCFA/branched-chain fatty acid intake is relevant only to management (restriction), not causation (F004).

6. Mechanism / Pathophysiology

Causal chain:

Biallelic PEX6 loss-of-function (F001)
│
▼
AAA+ ATPase PEX1–PEX6–PEX26 complex cannot extract ubiquitinated PEX5 (F002)
│
▼
PEX5 (PTS1 receptor) degraded → peroxisomal matrix-protein import fails
│
▼
Loss of peroxisome function:
  • VLCFA β-oxidation ↓  → C26:0, phytanic/pristanic acid ↑ (F003)
  • Plasmalogen synthesis ↓ → ether-lipid deficiency (F005)
  • DHA ↓; bile-acid synthesis abnormal → toxic C27 intermediates (F004,F005)
│
▼
Downstream cellular injury:
  • Mitochondrial dysfunction, ↑ROS, ↑MnSOD, apoptosis (F011)
  • α-synuclein aggregation (F011)
│
▼
Tissue-level pathology:
  • Impaired neuronal migration, Purkinje defects, demyelination (F005)
  • Hepatic dysfunction; retinal/auditory degeneration
│
▼
Clinical: neonatal hypotonia, seizures, dysmorphism, hepatic failure,
  sensory loss → death <1 year (severe PBD4A) (F007)

Molecular pathways: Peroxisomal matrix protein import (GO:0016558); peroxisomal β-oxidation of VLCFA; ether-lipid/plasmalogen biosynthesis; bile-acid synthesis. Cellular processes: apoptosis (GO:0006915), oxidative-stress response (GO:0006979), neuronal migration (GO:0001764). Protein dysfunction: loss of AAA+ ATPase activity → failed receptor recycling (upstream); secondary mitochondrial dysfunction and protein aggregation (downstream) (F002, F011). Subcellular compartments: peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), mitochondrion (GO:0005739).

Metabolic changes: ↑ VLCFA, phytanic/pristanic acid, pipecolic acid, C27 bile-acid intermediates; ↓ plasmalogens and DHA (F003, F005, F010). Cell types involved: migrating neurons and Purkinje cells (CL:0000121), astrocytes (CL:0000127), microglia, hepatocytes, photoreceptors.

7. Anatomical Structures Affected

  • Primary organs / systems: Central nervous system (UBERON:0001017) — cerebral cortex, cerebellum (UBERON:0002037), inferior olivary complex; liver (UBERON:0002107); kidney (UBERON:0002113 — cortical renal cysts; hence "cerebro-hepato-renal syndrome"); eye/retina (UBERON:0000970 / UBERON:0000966); ear (cochlea). Skeletal: chondrodysplasia punctata (epiphyseal stippling) (F005, F006, F007).
  • Tissue/cell level: Nervous tissue (migrating neurons, Purkinje cells CL:0000121); hepatocytes; retinal photoreceptors; cochlear hair cells.
  • Subcellular: Peroxisome (GO:0005777) and peroxisomal membrane (GO:0005778) — the primary lesion; mitochondria (GO:0005739) — secondary.
  • Lateralization: Bilateral / generalized (multisystem).

8. Temporal Development

  • Onset: Congenital / neonatal for classic PBD4A; presentation at or shortly after birth (F007).
  • Onset pattern: Insidious congenital multisystem involvement.
  • Progression: Severe form is rapidly progressive and neonatal-lethal (death typically within the first year) (F007). The broader spectrum shows slower, progressive neurodegeneration and sensory decline in milder survivors (F006, F010).
  • Course: Chronic, progressive; no remission. Critical period: prenatal/neonatal (neuronal migration occurs in utero, limiting the window for developmental rescue) (F005).

9. Inheritance and Population

  • Inheritance: Autosomal recessive (HP:0000007) (F001).
  • Penetrance: Complete for biallelic loss-of-function genotypes; expressivity variable, governed by residual PEX6 function (F001, F006).
  • Epidemiology: ZSD overall estimated at roughly 1 in 50,000 births (Orphanet range; regionally variable). PEX6 accounts for a substantial fraction within the five major ZSS genes (~90% of PBD-ZSS cases carry PEX1/PEX6/PEX10/PEX12/PEX26 variants) (F012).
  • Founder effects / consanguinity: Recurrent hypomorphic p.Arg601Gln (shared founder haplotype); Mixteco PEX6 founder mutation reported; elevated incidence in consanguineous populations (F006).
  • Sex ratio: Autosomal → approximately 1:1 male:female.
  • No genetic anticipation (not a repeat-expansion disorder).

10. Diagnostics

  • Biochemical (first-line): Plasma VLCFA panel (C26:0, C26:0/C22:0, C24:0/C22:0), phytanic/pristanic acid, plasmalogens (red-cell), pipecolic acid, and urinary bile-acid intermediates (F003, F010). Note: VLCFA can rarely be normal, so a normal panel does not exclude PBD4A (F003).
  • Molecular (confirmatory): WES/WGS or targeted PEX gene panels are recommended, particularly when biochemistry is atypical or normal (F003). Single-gene PEX6 testing where a familial variant is known.
  • Imaging: Brain MRI showing neuronal migration abnormalities (polymicrogyria), white-matter changes; skeletal radiographs may show chondrodysplasia punctata (F005).
  • Newborn screening: C26:0-LPC in dried blood spots (LC-MS/MS), primarily for X-ALD, incidentally detects PBDs (F008).
  • Differential diagnosis: D-bifunctional protein deficiency (Zellweger-like), single-enzyme peroxisomal defects, Smith-Lemli-Opitz syndrome, other causes of neonatal hypotonia/seizures, chondrodysplasia punctata (F005).

11. Outcome / Prognosis

  • Life expectancy: Classic PBD4A (severe Zellweger) is neonatal-lethal, with death typically within the first year of life (F007). Milder spectrum forms survive into childhood/adulthood with progressive morbidity (F006).
  • Morbidity: Profound developmental disability, seizures, vision and hearing loss, hepatic dysfunction (F004, F006, F007).
  • Prognostic factors: Genotype (truncating vs. hypomorphic/missense) is the dominant determinant of severity and survival (F001, F006). Residual peroxisomal function and VLCFA levels correlate with severity.
  • Interventions altering course: Cholic acid stabilizes/improves liver disease (F004); liver transplantation normalizes toxic metabolites in mild ZSD (F010) but is not curative for CNS disease.

12. Treatment

Treatment Category Evidence NCIT/CHEBI
Oral cholic acid 10–15 mg/kg/day Pharmacotherapy (bile-acid replacement) Phase 3: ↑ bile-acid scores P<0.0001, ↓ AST/ALT P<0.0001 (F004); durable ≥21 mo (F010) CHEBI:16359
Fat-soluble vitamins A, D, E, K Supportive Standard of care (F004) —
VLCFA / branched-chain fatty acid dietary restriction Supportive/dietary Standard of care (F004) —
DHA supplementation Pharmacotherapy Refuted by RCT — no vision/growth benefit (F009) CHEBI:28125
Lorenzo's oil, batyl alcohol Pharmacotherapy Limited/weak evidence (F004) —
Liver transplantation Surgical Normalizes phytanic/pristanic/pipecolic acid; mild ZSD only (F010) —
AAV PEX gene augmentation Gene therapy Preclinical proof-of-concept (retinopathy) (F013) —
Anti-seizure medication (e.g., levetiracetam), physiotherapy, nutritional support Supportive/rehabilitative Symptom management —

There is no curative therapy. Management is supportive and multidisciplinary (F004, F007).

13. Prevention

  • Primary prevention: Not possible for the individual (monogenic congenital disorder). Genetic counseling for at-risk families (25% recurrence risk per pregnancy for carrier couples) is central (F001).
  • Reproductive options: Carrier testing, prenatal diagnosis (biochemical + molecular), and preimplantation genetic testing where a familial variant is known.
  • Secondary prevention: Newborn screening via C26:0-LPC can enable earlier detection (F008); early cholic acid and supportive care can mitigate hepatic complications (F004).
  • Consanguinity counseling in high-risk / founder populations (F006).

14. Other Species / Natural Disease

PEX6 orthologs and peroxisome-biogenesis function are evolutionarily conserved from yeast/fungi to mammals. In the basidiomycete Cryptococcus neoformans, PEX1 and PEX6 AAA-ATPases are required for peroxisome formation; pex1/pex6 mutants fail to localize peroxisomal proteins and cannot grow on fatty acids (PMID: 17041184). In Arabidopsis, pex6 and pex26 mutants show peroxisomal retrotranslocation and oil-body utilization defects (PMID: 28742939). No prominent naturally occurring companion-animal Zellweger disease is established; the disorder is chiefly modeled experimentally (see Section 15). No zoonotic potential (genetic disease).

Ontology: NCBI Taxon 9606 (human); orthologs conserved across Mus musculus (10090), Danio rerio (7955), Saccharomyces cerevisiae (4932).

15. Model Organisms

  • Mouse (mammalian): Pex5 knockout (Zellweger model) — establishes peroxisome-dependent neuronal migration; tissue-selective reconstitution rescues migration (F005). Pex2 knockout — cortical migration delay, cerebellar/Purkinje defects, embryonic lethality (inbred background), VLCFA↑/plasmalogen↓/DHA↓ (F005). Brain-restricted Pex13 knockout — cerebellar maldevelopment, gliosis, ROS↑, apoptosis, mitochondrial dysfunction (F011). Humanized Pex1-Gly844Asp mouse — mild ZSD retinopathy, used for AAV gene therapy (F013).
  • Phenotype recapitulation: Mouse models faithfully reproduce the biochemical signature (VLCFA↑, plasmalogen↓, DHA↓) and neurodevelopmental pathology (migration defects, cerebellar abnormalities) (F005, F011).
  • Limitations: Severe knockouts are neonatal/embryonic-lethal, limiting adult-phenotype study; brain-restricted and humanized hypomorphic models were developed to address this (F005, F011, F013).
  • Fungal/plant models: Cryptococcus and Arabidopsis pex6 mutants illuminate the conserved receptor-recycling and retrotranslocation function (F002; PMIDs 17041184, 28742939).
  • Resources: MGI (mouse), ZFIN (zebrafish), SGD (yeast), Alliance of Genome Resources.

Mechanistic Model / Interpretation

PBD4A is fundamentally a disorder of a molecular machine. PEX6 is one subunit of the AAA+ ATPase engine (PEX1–PEX6, membrane-anchored by PEX26) that powers the recycling step of peroxisomal matrix-protein import. Because import is a receptor-shuttle cycle, disabling the recovery/extraction step (PEX5 export) is as catastrophic as disabling import itself: PEX5 is trapped and degraded, no further cargo enters, and peroxisomes become empty "ghosts" devoid of matrix enzymes (F002).

The clinical phenotype is then the sum of multiple simultaneous metabolic failures: loss of VLCFA β-oxidation (toxic lipid accumulation), loss of plasmalogen synthesis (membrane/myelin ether-lipid deficiency), loss of DHA and normal bile-acid synthesis, and impaired ROS detoxification. Uniquely, these converge on the developing brain, where peroxisome-dependent lipid metabolism is required for neuronal migration — an in-utero process, which is why the severe form is congenital and largely irreversible (F005). Downstream, mitochondrial dysfunction, oxidative stress, apoptosis, and even α-synuclein aggregation amplify tissue injury (F011).

The genotype–severity gradient (F001, F006) provides the unifying logic of the entire spectrum: the amount of residual PEX6 activity a genotype permits determines where a patient lands — from neonatal-lethal Zellweger (PBD4A, near-zero function) to Heimler syndrome (PBD4B, minimal residual dysfunction). This "dial" model directly rationalizes both the phenotypic continuum and the therapeutic rationale for gene augmentation (F013): restoring even partial PEX6 function should shift phenotype toward the milder end.

Evidence Base

PMID Role Supports
41787707 Review Genotype–severity gradient; VLCFA limitations (F001, F003)
39013483 Case Biallelic truncating/splice PEX6 → Zellweger (F001)
28742939 Mechanism PEX1–PEX6–PEX26 removes ubiquitinated PEX5 (F002); plant model (§14)
21980954 Mechanism PEX6 required for PEX5 export (F002)
39604887 Case Normal-VLCFA PEX6 case (F003)
28644367 Phase 3 Cholic acid efficacy in ZSD (F004)
34625341 Review Supportive therapy landscape (F004)
24607700 Review Neuropathology (F005)
14586000 Mouse Peroxisome deficiency → migration defect (F005)
11478384 Mouse PEX2 KO biochemical signature (F005)
26387595 Genetics Hypomorphic alleles → Heimler (F006)
27302843 Genetics HS = mild end of spectrum (F006)
41126390 Review Heimler phenotype frequencies (F006)
26750748 Guideline Shortened lifespan (F007)
38409970 Case Severe neonatal presentation (F007)
37977233 Screening C26:0-LPC NBS detects PBDs (F008)
20805528 RCT DHA refuted (F009)
29453832 Case series Liver transplant normalizes metabolites (F010)
30793331 Extension Durable cholic acid effect (F010)
20959636 Mouse ROS/apoptosis/mitochondrial dysfunction (F011)
19830841 Mouse α-synuclein pathology (F011)
19105186 Cohort 80% ZSS; ~90% five PEX genes (F012)
34703844 Preclinical AAV gene therapy for retinopathy (F013)

Limitations and Knowledge Gaps

  1. PBD4A-specific epidemiology is imprecise. Prevalence figures are for ZSD as a whole; the PEX6-specific, severe-end (PBD4A) incidence is not separately quantified in the reviewed literature.
  2. Mechanistic evidence relies heavily on non-PEX6 mouse models (Pex2, Pex5, Pex13). While the peroxisomal defect is shared, PEX6-specific in-vivo models are less represented in this evidence set.
  3. Therapeutic evidence is largely from milder ZSD. Cholic acid trials, liver transplantation, and AAV gene therapy data derive predominantly from milder-spectrum patients; benefit in neonatal-lethal PBD4A specifically is unproven, and CNS disease remains untreatable.
  4. No modifier genes beyond the allele-intrinsic residual-function gradient are established.
  5. No natural animal disease counterpart is documented; comparative pathology relies on experimental models and evolutionarily conserved fungal/plant orthologs.
  6. Variant interpretation gaps: several PEX6 variants remain VUS (e.g., p.Glu664Asp), and functional assays are not routinely available.

Proposed Follow-up Experiments / Actions

  1. PEX6-specific natural history and prevalence study — stratify ZSD registries by causal gene and genotype class (truncating vs. hypomorphic) to quantify PBD4A-specific incidence, survival, and phenotype frequencies.
  2. Genotype–function assay — develop a standardized cell-based peroxisomal-import assay to reclassify PEX6 VUS (e.g., p.Glu664Asp) and predict severity, improving prenatal/prognostic counseling.
  3. PEX6 humanized mouse models — generate patient-specific Pex6 knock-in alleles spanning the severity spectrum to test whether AAV gene augmentation (extending F013) can rescue CNS as well as retinal phenotypes.
  4. Early cholic acid + metabolite trial in confirmed PBD4A neonates — prospective evaluation of cholic acid initiated at newborn-screening diagnosis, with bile-acid intermediate and transaminase endpoints.
  5. Antioxidant / mitochondrial-protective adjuncts — test targeted antioxidants against the ROS/apoptosis axis identified in PEX13 models (F011) as a neuroprotective strategy.
  6. Expand newborn screening validation — assess sensitivity of C26:0-LPC screening specifically for PEX6-PBD, including the rare normal-VLCFA genotypes (F003, F008).

Report compiled from 13 confirmed findings and 52 reviewed papers across 5 investigation iterations. Evidence types span human clinical (case reports, cohorts, phase 3 and RCT trials), model organism (mouse, fungal, plant), and in-vitro studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 24
On topic 21
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 38
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 33
Terms named correctly 15
Terms named as a different term 16
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0009279 (2 mentions) - the report calls it "peroxisome biogenesis disorder"; MONDO calls it triple-A syndrome
  • CHEBI:74102 (1 mention) - the report calls it "hexacosanoic acid / C26:0"; CHEBI calls it cholesteryl (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate
  • CHEBI:37723 (1 mention) - the report calls it "phytanic acid"; CHEBI calls it keto-fructose
  • HP:0410054 (2 mentions) - the report calls it "abnormal circulating VLCFA", "Lab abnormality"; HP calls it Decreased circulating GABA concentration
  • CHEBI:16359 (2 mentions) - the report calls it "cholic acid", "Phase 3: ↑ bile-acid scores P<0.0001, ↓ AST/ALT P<0.0001 (F004); durable ≥21 mo (F010)"; CHEBI calls it cholic acid
  • HP:0002269 (2 mentions) - the report calls it "abnormality of neuronal migration", "Imaging/structural"; HP calls it Abnormality of neuronal migration
  • HP:0000510 (2 mentions) - the report calls it "rod-cone dystrophy", "Clinical sign"; HP calls it Rod-cone dystrophy
  • HP:0000407 (2 mentions) - the report calls it "sensorineural hearing impairment", "Clinical sign"; HP calls it Sensorineural hearing impairment
  • HP:0000705 (2 mentions) - the report calls it "amelogenesis imperfecta", "Physical"; HP calls it Amelogenesis imperfecta
  • HP:0001252 (2 mentions) - the report calls it "hypotonia", "Clinical sign"; HP calls it Hypotonia
  • HP:0001250 (2 mentions) - the report calls it "seizure", "Clinical sign"; HP calls it Seizure
  • HP:0002240 (2 mentions) - the report calls it "hepatomegaly", "Lab/clinical"; HP calls it Hepatomegaly
  • HP:0001999 (2 mentions) - the report calls it "abnormal facial shape", "Physical"; HP calls it Abnormal facial shape
  • HP:0011968 (1 mention) - the report calls it "Symptom"; HP calls it Feeding difficulties
  • UBERON:0002113 (1 mention) - the report calls it "cortical renal cysts"; UBERON calls it kidney
  • CHEBI:28125 (1 mention) - the report calls it "Refuted by RCT — no vision/growth benefit (F009)"; CHEBI calls it all-cis-docosa-4,7,10,13,16,19-hexaenoic acid**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0005777 (2 mentions) - the report calls it "Subcellular: Peroxisome"; GO calls it peroxisome**
  • UBERON:0001017 (1 mention) - the report calls it "Primary organs / systems: Central nervous system"; UBERON calls it central nervous system**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • ORPHA:912 - called "Zellweger syndrome", "Zellweger syndrome, the broader clinical entity"
  • HP:0000007 - called "autosomal recessive inheritance", "Inheritance:** Autosomal recessive"
  • HP:0410054 - called "abnormal circulating VLCFA", "Lab abnormality"
  • CHEBI:16359 - called "cholic acid", "Phase 3: ↑ bile-acid scores P<0.0001, ↓ AST/ALT P<0.0001 (F004); durable ≥21 mo (F010)"
  • HP:0002269 - called "abnormality of neuronal migration", "Imaging/structural"
  • HP:0000510 - called "rod-cone dystrophy", "Clinical sign"
  • HP:0000407 - called "sensorineural hearing impairment", "Clinical sign"
  • HP:0000705 - called "amelogenesis imperfecta", "Physical"
  • HP:0001252 - called "hypotonia", "Clinical sign"
  • HP:0001250 - called "seizure", "Clinical sign"
  • HP:0002240 - called "hepatomegaly", "Lab/clinical"
  • HP:0001999 - called "abnormal facial shape", "Physical"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.