Peroxisome biogenesis disorder 6A is the severe, classic-Zellweger end of the PEX10-related Zellweger spectrum. PEX10 encodes peroxin-10, a peroxisomal membrane protein with a C-terminal C3HC4 RING finger. In yeast, each of the three RING peroxins - Pex2, Pex10 and Pex12 - has ubiquitin-ligase activity towards Pex5, the matrix-protein receptor, and that ubiquitination is what determines whether the receptor is recycled or degraded. The human counterpart is inferred from that conserved architecture rather than demonstrated directly in the sources cited here, which is why the receptor-recycling node below is typed PROVISIONAL. Without a functional RING module the import cycle stalls. The cell-biological signature is what makes this a disorder of biogenesis rather than of any single peroxisomal enzyme, and it was established directly in patient cells: a PEX10-deficient Zellweger fibroblast line contains plenty of peroxisomes and imports peroxisomal membrane proteins perfectly well, but imports essentially no matrix proteins. The organelle is built and then left empty, so every matrix enzyme is missing at once. Very-long-chain fatty acid oxidation, plasmalogen synthesis and bile-acid intermediate processing all fail together, and the resulting damage to the developing brain, liver and kidney is largely complete before birth. What separates 6A from 6B at the same locus is how much peroxin-10 function the genotype leaves, and unusually for a spectrum disorder that claim rests on a direct genotype-phenotype survey rather than on inference: all four PEX10-deficient Zellweger patients in the founding survey carried nonsense, frameshift or splice alleles removing large parts of the coding region, while the one mildly affected patient carried a missense allele in the zinc-binding domain. The gene also reaches a third, much milder band at the other extreme, a late-onset ataxic form, so PEX10 spans the whole spectrum from neonatal lethality to adult-onset cerebellar disease. A caution belongs in this entry rather than in a footnote. The functional complementation assay that quantifies residual PEX10 activity was reported by its own authors to have serious flaws, after it returned nearly normal activity for alleles predicted to delete most of the protein. The severity-versus-residual-function account survives that, because it is supported independently by the mutational classes seen in the two phenotype groups, but any specific residual-activity number for a PEX10 allele should be treated with the caution its authors asked for. 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 PEX10-specific and what is specific to the severe band.
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Conditions with similar clinical presentations that must be differentiated from Peroxisome Biogenesis Disorder 6A (Zellweger):
name: Peroxisome Biogenesis Disorder 6A (Zellweger)
creation_date: "2026-09-10T00:00:00Z"
category: Mendelian
description: >-
Peroxisome biogenesis disorder 6A is the severe, classic-Zellweger end of the
PEX10-related Zellweger spectrum. PEX10 encodes peroxin-10, a peroxisomal membrane
protein with a C-terminal C3HC4 RING finger. In yeast, each of the three RING peroxins -
Pex2, Pex10 and Pex12 - has ubiquitin-ligase activity towards Pex5, the matrix-protein
receptor, and that ubiquitination is what determines whether the receptor is recycled or
degraded. The human counterpart is inferred from that conserved architecture rather than
demonstrated directly in the sources cited here, which is why the receptor-recycling node
below is typed PROVISIONAL. Without a functional RING module the import cycle stalls.
The cell-biological signature is what makes this a disorder of biogenesis rather than
of any single peroxisomal enzyme, and it was established directly in patient cells: a
PEX10-deficient Zellweger fibroblast line contains plenty of peroxisomes and imports
peroxisomal membrane proteins perfectly well, but imports essentially no matrix
proteins. The organelle is built and then left empty, so every matrix enzyme is missing
at once. Very-long-chain fatty acid oxidation, plasmalogen synthesis and bile-acid
intermediate processing all fail together, and the resulting damage to the developing
brain, liver and kidney is largely complete before birth.
What separates 6A from 6B at the same locus is how much peroxin-10 function the genotype
leaves, and unusually for a spectrum disorder that claim rests on a direct
genotype-phenotype survey rather than on inference: all four PEX10-deficient Zellweger
patients in the founding survey carried nonsense, frameshift or splice alleles removing
large parts of the coding region, while the one mildly affected patient carried a
missense allele in the zinc-binding domain. The gene also reaches a third, much milder
band at the other extreme, a late-onset ataxic form, so PEX10 spans the whole spectrum
from neonatal lethality to adult-onset cerebellar disease.
A caution belongs in this entry rather than in a footnote. The functional complementation
assay that quantifies residual PEX10 activity was reported by its own authors to have
serious flaws, after it returned nearly normal activity for alleles predicted to delete
most of the protein. The severity-versus-residual-function account survives that, because
it is supported independently by the mutational classes seen in the two phenotype groups,
but any specific residual-activity number for a PEX10 allele should be treated with the
caution its authors asked for.
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 PEX10-specific and
what is specific to the severe band.
synonyms:
- PBD6A
- PEX10-related Zellweger syndrome
- peroxisome biogenesis disorder, complementation group B
- peroxisome biogenesis disorder, complementation group 7
- Zellweger syndrome due to PEX10 deficiency
disease_term:
preferred_term: peroxisome biogenesis disorder 6A (Zellweger)
term:
id: MONDO:0013936
label: peroxisome biogenesis disorder 6A (Zellweger)
parents:
- Peroxisome Biogenesis Disorder
- Zellweger Spectrum Disorder
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
An autosomal recessive Mendelian disorder of organelle assembly, reached through
complementation grouping and then gene identification.
- classification_value: ENDOCRINOLOGY_METABOLISM
notes: >-
Also an inborn error of metabolism, and one whose biochemical signature is broad
rather than single-pathway: every peroxisomal matrix enzyme is simultaneously
mislocalised.
mappings:
mondo_mappings:
- term:
id: MONDO:0013936
label: peroxisome biogenesis disorder 6A (Zellweger)
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
The dismech entry and the MONDO class denote the same entity: the severe,
classic-Zellweger band of PEX10-related peroxisome biogenesis disorder. PBD6B and
the PEX10 ataxic form are separate concepts and are discussed here rather than
folded in.
references:
- reference: PMID:9683594
title: "Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders."
- reference: PMID:9700193
title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
- reference: PMID:10862081
title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
- reference: PMID:20301621
title: "Zellweger Spectrum Disorder."
tags:
- GeneReviews
- reference: PMID:26750748
title: "Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines."
- reference: PMID:28320181
title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
- reference: PMID:12794690
title: "Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: evidence for a founder haplotype for the most common PEX10 gene mutation."
- reference: PMID:18415699
title: Cerebral MRI as a valuable diagnostic tool in Zellweger spectrum patients.
- reference: PMID:19127411
title: "A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts."
- reference: PMID:19687296
title: "Pex2 and pex12 function as protein-ubiquitin ligases in peroxisomal protein import."
- reference: PMID:28784167
title: "Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report."
- reference: PMID:34521419
title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
PEX10 is one of the rarer complementation groups within an already rare spectrum. Two
severe-band series exist and they are of different sizes: the founding
genotype-phenotype survey assembled four Zellweger-phenotype PEX10 patients, and a
Japanese survey reported eleven, all sharing a founder allele. The Japanese survey also
gives a population rate, but it is for peroxisome biogenesis disorders as a whole in
Japan rather than for PBD6A, so it is recorded as context rather than as this entry's
prevalence.
evidence:
- reference: PMID:10862081
reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "All four PEX10-deficient Zellweger Syndrome (ZS) patients were found to have nonsense, frameshift, or splice site mutations that remove large portions of the PEX10 coding region."
explanation: >-
Quoted here for its denominator rather than its genotype claim. Four is the entire
severe-band population of that survey, and that is the number a reader should have in
mind for the genotype-phenotype statements it supports.
- reference: PMID:12794690
reference_title: "Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: evidence for a founder haplotype for the most common PEX10 gene mutation."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
we estimated the prevalence of PBD in Japan to be approximately one in 500,000 births.
explanation: >-
The only population rate available in the sources cited here. It is for peroxisome
biogenesis disorders as a class in one country, not for PBD6A, which is why this entry
still asserts no numeric prevalence of its own and carries the figure as context.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic PEX10 variants, and specifically the genotypes leaving little or no residual
peroxin-10 function. A severe allele in trans with a partially functional one shifts
the presentation out of this entry and toward PBD6B or the ataxic form.
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
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: >-
The recurrence risk that follows from the biallelic requirement, which is what genetic
counselling for this entry turns on. Quoted in preference to the diagnostic-strategy
sentence, which supports how the diagnosis is made rather than how the disease is
transmitted.
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
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: >-
States the biallelic requirement across the spectrum, of which PEX10 is one of the
13 genes.
- reference: PMID:9700193
reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
One patient (PBDB-01) possessed a homozygous, inactivating mutation, a 2 bp deletion
immediately upstream of the RING motif, which resulted in a frameshift, altering 65
amino acids from the normal.
explanation: >-
A worked homozygous genotype in a patient with the severe phenotype this entry
covers.
pathophysiology:
- name: Biallelic Severe PEX10 Genotype
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: >-
Both PEX10 alleles carry variants that remove or truncate the protein, in particular
the C-terminal C3HC4 RING finger that carries its function. PBD6A is the subset of the
PEX10 allelic series in which essentially no functional peroxin-10 is left, and that
residual-function threshold, rather than gene identity, is what separates this entry
from PBD6B and from the ataxic form at the same locus.
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
gene:
preferred_term: PEX10
term:
id: hgnc:8851
label: PEX10
description: >-
Nonsense, frameshift and splice-site alleles removing large portions of the coding
region. Compound heterozygosity occurs; the entry records HOMOZYGOUS because the
worked severe genotypes reported are homozygous, and the biologically operative
variable is the absence of residual function on both alleles rather than their
identity.
cellular_components:
- preferred_term: peroxisomal membrane
term:
id: GO:0005778
label: peroxisomal membrane
evidence:
- reference: PMID:9683594
reference_title: "Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
A Zellweger syndrome patient, PBD100, was homozygous for a splice donor-site mutation
that results in exon skipping and loss of 407 bp from the PEX10 open reading frame.
explanation: A worked severe genotype in a patient with the classic Zellweger phenotype.
- reference: PMID:9700193
reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "These results demonstrate that mutation in PEX10 is the genetic cause of complementation group B PBD."
explanation: >-
Establishes the gene-disease relationship by complementation, independently of the
US group that reached the same gene through complementation group 7.
- reference: PMID:10862081
reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "All four PEX10-deficient Zellweger Syndrome (ZS) patients were found to have nonsense, frameshift, or splice site mutations that remove large portions of the PEX10 coding region."
explanation: >-
The mutational class shared across the severe band, which is what defines this
entry against PBD6B.
downstream:
- target: Loss of Peroxin-10 RING Ligase Function
description: >-
The severe alleles converge on removing the C-terminal RING finger, which is the part
of the protein that carries its biological activity.
causal_link_type: DIRECT
evidence:
- reference: PMID:9700193
reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "This implies that the C-terminal part, including the RING finger, is required for biological function of Pex10p."
explanation: >-
Localises the essential function to the domain the severe alleles remove. The
authors' own "This implies" is preserved: the inference is theirs, from a
frameshift immediately upstream of the motif.
- name: Loss of Peroxin-10 RING Ligase Function
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: >-
Peroxin-10 is a peroxisomal membrane protein with two transmembrane segments and a
C3HC4 zinc-finger RING motif, with both termini facing the cytosol. The RING motif is
the functional business end, and it is what the severe alleles remove.
cellular_components:
- preferred_term: peroxisomal membrane
term:
id: GO:0005778
label: peroxisomal membrane
evidence:
- reference: PMID:9700193
reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: >-
Both the N- and C-terminal regions of Pex10p are exposed to the cytosol, as assessed
by an expression study of epitope-tagged Pex10p.
explanation: >-
Establishes the topology that puts the RING motif on the cytosolic face, where the
receptor it acts on arrives.
- reference: PMID:10862081
reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: >-
Although these results demonstrate serious flaws in the PEX10 functional
complementation assay, they do suggest that the C-terminal zinc-binding domain is
critical for PEX10 function.
explanation: >-
Supports the claim while carrying the authors' own caveat about the assay that
produced it. Quoted whole rather than trimmed to the supportive clause, because a
reader weighing this node needs the caveat as much as the conclusion. Marked
INDIRECT: with the assay called into question by its own authors, the domain claim
rests on the mutational pattern rather than on the activity measurements.
downstream:
- target: Failure of PEX5 Receptor Recycling
description: >-
The RING module's substrate is the matrix-protein receptor. Losing the ligase
activity is expected to leave the receptor unable to complete its cycle.
causal_link_type: DIRECT
evidence:
- reference: PMID:19687296
reference_title: "Pex2 and pex12 function as protein-ubiquitin ligases in peroxisomal protein import."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12
exhibits ubiquitin-protein isopeptide ligase activity.
explanation: >-
Demonstrates the ligase activity for Pex10 specifically, which is the step this edge
depends on. INDIRECT and MODEL_ORGANISM because the work is in yeast; no source
cited here demonstrates it for human PEX10, so the human claim rests on conservation.
- target: Failure of Peroxisomal Matrix Protein Import
description: >-
Whether or not the receptor-recycling account is right, the import failure itself is
observed directly in patient cells, so this edge does not depend on it.
causal_link_type: DIRECT
evidence:
- reference: PMID:9683594
reference_title: "Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: >-
PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal
membrane proteins but do not import peroxisomal matrix proteins, indicating that
loss of PEX10 has its most pronounced effect on peroxisomal matrix-protein import.
explanation: >-
The central cell-biological observation of this entry, made in patient-derived
cells: the organelle is present and its membrane proteins arrive, and only matrix
import fails.
- name: Failure of PEX5 Receptor Recycling
biological_scale: MOLECULAR
mechanism_confidence: PROVISIONAL
description: >-
PEX5 carries matrix cargo to the peroxisome and must be ubiquitinated to be recycled
rather than degraded. The RING peroxins supply that ubiquitin-ligase activity. This
node is PROVISIONAL rather than ESTABLISHED because the demonstration is in yeast: the
human step is inferred from a conserved architecture, and no source cited here measures
PEX5 handling in PEX10-deficient human cells. The node is carried rather than dropped
because it is the accepted account of why the import machinery fails, and because
stating it as a node makes the inference visible instead of burying it in prose.
cellular_components:
- preferred_term: peroxisomal membrane
term:
id: GO:0005778
label: peroxisomal membrane
evidence:
- reference: PMID:19687296
reference_title: "Pex2 and pex12 function as protein-ubiquitin ligases in peroxisomal protein import."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is
destined for a new round of the receptor cycle.
explanation: >-
States the recycle-or-degrade switch this node describes. Yeast, hence INDIRECT.
downstream:
- target: Failure of Peroxisomal Matrix Protein Import
description: >-
A receptor that cannot be recycled cannot deliver further cargo.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:19687296
reference_title: "Pex2 and pex12 function as protein-ubiquitin ligases in peroxisomal protein import."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
The PTS1-dependent peroxisomal matrix protein import is facilitated by the receptor
protein Pex5 and can be divided into cargo recognition in the cytosol, membrane
docking of the cargo-receptor complex, cargo release, and recycling of the receptor.
explanation: >-
Places recycling as the final step of the import cycle, which is what makes its
failure a cause of import failure. INDIRECT: yeast, and the step from a stalled
cycle to the observed human import defect is not measured here.
- name: Failure of Peroxisomal Matrix Protein Import
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
description: >-
Peroxisomes are assembled and populated with membrane proteins but receive no matrix
enzymes. The result is an organelle that exists and is empty, which is why the
biochemical consequences are simultaneous across every peroxisomal pathway rather than
confined to one. This is also the defect shared by every PBD complementation group, and
it is what makes them one disease class.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: protein import into peroxisome matrix
modifier: DECREASED
term:
id: GO:0016558
label: protein import into peroxisome matrix
cellular_components:
- preferred_term: peroxisomal matrix
term:
id: GO:0005782
label: peroxisomal matrix
evidence:
- reference: PMID:9683594
reference_title: "Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "Cells from all PBD patients exhibit decreased import of one or more classes of peroxisome matrix proteins, a phenotype shared by yeast pex mutants."
explanation: >-
Places the PEX10 defect in the shared PBD cellular phenotype, which is the basis for
curating a gene-agnostic cascade on the spectrum entry rather than repeating it here.
- reference: PMID:9700193
reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: >-
HsPEX10 expression morphologically and biochemically restored peroxisome biogenesis
in fibroblasts from Zellweger patients of complementation group B in Japan
(complementation group VII in the USA).
explanation: >-
A rescue experiment: supplying wild-type PEX10 restores biogenesis in patient cells,
which is what makes the import failure attributable to the PEX10 lesion rather than
merely coincident with it.
downstream:
- target: Loss of Peroxisomal Metabolic Function
description: >-
Every matrix enzyme is absent from the compartment at once, so the metabolic
consequences arrive together rather than in sequence.
causal_link_type: DIRECT
evidence:
- reference: PMID:26750748
reference_title: "Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
As a result of impaired peroxisomal activities, individuals with PBD-ZSD can
manifest a complex spectrum of clinical phenotypes that typically result in
shortened life spans.
explanation: >-
States the step from impaired peroxisomal activity to clinical phenotype across
the spectrum.
- name: Loss of Peroxisomal Metabolic Function
biological_scale: ORGANISM
description: >-
The organism loses, simultaneously, very-long-chain fatty acid beta-oxidation,
plasmalogen synthesis and bile-acid intermediate processing. In the severe band this
happens throughout fetal development, which is why the brain malformation is present
at birth and why no post-natal intervention alters it.
biological_processes:
- preferred_term: peroxisome organization
modifier: DECREASED
term:
id: GO:0007031
label: peroxisome organization
evidence:
- reference: PMID:26750748
reference_title: "Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a
heterogeneous group of genetic disorders caused by mutations in PEX genes responsible
for normal peroxisome assembly and functions.
explanation: Establishes that the lesion is in assembly and therefore in function generally.
downstream:
- target: Neuronal Migration Defect
description: >-
Peroxisomal function is required during cortical development; its loss in the severe
band produces a migration defect that is complete before birth.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
They have distinctive facies, congenital malformations (neuronal migration defects
associated with neonatal-onset seizures, renal cysts, and bony stippling
explanation: >-
Establishes the migration defect as a congenital malformation of severe ZSD.
INDIRECT and with unknown intermediates: no source cited here traces the route from
absent matrix enzymes to arrested neuronal migration, and that route is genuinely
not established.
- target: Severe Neonatal Hypotonia
description: The presenting feature of the severe band.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: "Affected newborns are hypotonic and feed poorly."
explanation: States the neonatal presentation.
phenotypes:
- category: Neurologic
name: Neuronal Migration Defect
description: >-
Cortical neuronal migration defect, present at birth. It is the single most important
determinant of outcome in the severe band, and the reason therapy is symptomatic.
phenotype_term:
preferred_term: Abnormal neuronal migration
term:
id: HP:0002269
label: Abnormality of neuronal migration
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
They have distinctive facies, congenital malformations (neuronal migration defects
associated with neonatal-onset seizures, renal cysts, and bony stippling
explanation: Lists the migration defect among the congenital malformations of severe ZSD.
- category: Neurologic
name: Severe Neonatal Hypotonia
description: Profound hypotonia from birth, with poor feeding.
phenotype_term:
preferred_term: Neonatal hypotonia
term:
id: HP:0001319
label: Neonatal hypotonia
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: "Affected newborns are hypotonic and feed poorly."
explanation: States the finding in affected newborns.
- category: Neurologic
name: Neonatal Seizures
description: Seizures beginning in the newborn period, associated with the migration defect.
phenotype_term:
preferred_term: Neonatal seizure
term:
id: HP:0032807
label: Neonatal seizure
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
They have distinctive facies, congenital malformations (neuronal migration defects
associated with neonatal-onset seizures, renal cysts, and bony stippling
explanation: Same sentence; neonatal-onset seizures are named with the migration defect.
- category: Neurologic
name: Polymicrogyria and Pachygyria
description: >-
The specific cortical malformations behind the migration defect, and reported as more
common in the severe band specifically. Curated in addition to the general migration
defect rather than replacing it, because the general node is what the GeneReviews
sentence supports and this is what the imaging series adds.
phenotype_term:
preferred_term: Polymicrogyria
term:
id: HP:0002126
label: Polymicrogyria
evidence:
- reference: PMID:18415699
reference_title: Cerebral MRI as a valuable diagnostic tool in Zellweger spectrum patients.
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
Polymicrogyria and pachygyria were more common in patients with severe ZSS, while
leukencephalopathy increases with age in patients with longer survival.
explanation: >-
Assigns these malformations to the severe band specifically, which is what makes them
appropriate for this entry rather than for the spectrum entry. The second clause is
kept because it makes the severity contrast explicit.
- category: Renal
name: Renal Cysts
description: Renal cortical cysts, a congenital malformation of the severe band.
phenotype_term:
preferred_term: Renal cyst
term:
id: HP:0000107
label: Renal cyst
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
They have distinctive facies, congenital malformations (neuronal migration defects
associated with neonatal-onset seizures, renal cysts, and bony stippling
explanation: Same sentence; renal cysts are among the congenital malformations.
- category: Skeletal
name: Chondrodysplasia Punctata
description: >-
Stippled epiphyses of the patellae and long bones. Shared with the other post-squalene
and peroxisomal malformation syndromes and useful radiographically.
phenotype_term:
preferred_term: Chondrodysplasia punctata
term:
id: HP:0010655
label: Epiphyseal stippling
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
They have distinctive facies, congenital malformations (neuronal migration defects
associated with neonatal-onset seizures, renal cysts, and bony stippling
explanation: Same sentence; names the finding and the bones involved.
- category: Hepatic
name: Severe Liver Disease
description: Liver disease that can be severe, part of the classic triad of organ involvement.
phenotype_term:
preferred_term: Abnormal liver function
term:
id: HP:0001410
label: Decreased liver function
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "and liver disease that can be severe"
explanation: >-
States the liver involvement. The quote is short because the sentence it comes from
carries bracketed glosses that the reference validator strips, so only the clause
after them survives verbatim. Marked INDIRECT for the binding rather than the
finding: "liver disease" is broader than Decreased liver function, which is the
closest available HP term.
progression:
- phase: First year of life - death without developmental progress
notes: >-
This is the prognostic fact that defines the severe band and separates it from PBD6B and
the ataxic form at the same locus. It also explains the shape of the treatments section:
the neurological outcome is determined by a migration defect completed before birth, so
post-natal management is directed at comfort, feeding and the liver rather than at
development.
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
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 survival and developmental outcome for the severe band, which is the band this
entry is scoped to.
genetic:
- name: PEX10
gene_term:
preferred_term: PEX10
term:
id: hgnc:8851
label: PEX10
relationship_type: CAUSATIVE
variant_origin: GERMLINE
review_notes: >-
Peroxin-10, a 326-amino-acid peroxisomal membrane protein with two putative
transmembrane segments and a C-terminal C3HC4 zinc-finger RING motif, both termini
cytosolic. Reached independently by two groups in 1998, through complementation group
B in Japan and complementation group 7 in the USA, which is why this entry carries
both group designations as synonyms.
evidence:
- reference: PMID:9700193
reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "These results demonstrate that mutation in PEX10 is the genetic cause of complementation group B PBD."
explanation: Establishes the gene-disease relationship.
- reference: PMID:9683594
reference_title: "Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: >-
We identified the human orthologue of yeast PEX10 and observed that its expression
rescues peroxisomal matrix-protein import in PBD patients' fibroblasts from
complementation group 7 (CG7).
explanation: >-
Independent identification of the same gene through a different complementation
grouping, with functional rescue.
- reference: PMID:12794690
reference_title: "Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: evidence for a founder haplotype for the most common PEX10 gene mutation."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
All the 11 ZS patients with group-B PBD had a common mutation, i.e.
explanation: >-
Founder genetics specific to this gene and this severity band: every
Zellweger-phenotype PEX10 patient in the Japanese survey carried the same homozygous 2-bp
deletion, on a shared haplotype. It strengthens the truncating-allele
genotype-phenotype claim this entry makes, and it means Japanese severe-band
genotypes are not an independent sample of the allelic series. The quote stops at
"i.e." because the cached abstract breaks the sentence there.
diagnosis:
- name: Biochemical Peroxisomal Screen
description: >-
Plasma very-long-chain fatty acids with the ancillary peroxisomal analytes. Because the
lesion is in biogenesis rather than in one enzyme, several pathways are abnormal
together, which is what points to a PBD rather than to a single-enzyme peroxisomal
disorder.
evidence:
- reference: PMID:26750748
reference_title: "Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
Recent advances in biochemical methods for newborn screening and genetic testing have
provided unprecedented opportunities for identifying patients at the earliest possible
time and defining the molecular bases for their diseases.
explanation: >-
Supports biochemical screening as the entry route. INDIRECT: the quote states that
such methods exist and are used, rather than naming the analytes.
- name: PEX Gene Panel Sequencing
description: >-
Molecular confirmation, which for this entry means identifying biallelic PEX10
variants. Sequencing has replaced the cell-fusion complementation grouping through
which the gene was originally found.
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
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: States the confirmatory test and the gene set it covers.
treatments:
- name: Symptomatic and Supportive Management
description: >-
There is no disease-modifying therapy. Management is symptomatic across the affected
organs, and in the severe band its aims are comfort and feeding rather than
modification of the neurological outcome, which was determined before birth.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
therapeutic_modality: OTHER
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
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: >-
States the management approach and its components for the spectrum. Note the
list is spectrum-wide: several items (hearing aids, refractive correction) are
relevant to the milder bands rather than to this entry, and the entry does not
curate them as separate treatments here. The modality is OTHER rather than
BEHAVIORAL: this row spans gastrostomy, surgery and vitamin supplementation, none of
which is a behavioural intervention.
- name: Oral Cholic Acid
description: >-
The only therapy approved for Zellweger spectrum disorders, and the one item in the
management list that acts on a mechanism rather than on a symptom. Loss of peroxisomal
function disrupts bile acid synthesis, and the resulting liver disease can progress to
cirrhosis within the first year - which for the severe band is the same window in which
most affected infants die. It is adjunctive and it does not address the neurological
outcome, which was determined before birth.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_modality: SMALL_MOLECULE
evidence:
- reference: PMID:34521419
reference_title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
In the absence of functional peroxisomes, bile acid synthesis is disrupted, and
multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle,
eyes, ears, and nervous system.
explanation: >-
Gives the mechanistic rationale, and ties it to the matrix-import failure this entry
curates rather than to a symptom.
- reference: PMID:34521419
reference_title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
Liver disease may play an important role in morbidity and mortality, with hepatic
fibrosis that can develop as early as the postnatal period and often progressing to
cirrhosis within the first year of life.
explanation: >-
Establishes why the liver is the target, and on what timescale. For an entry whose
progression section records death within the first year, that timing matters.
differential_diagnoses:
- name: Peroxisome biogenesis disorder 6B
description: >-
The milder band at the same locus. Distinguished not by gene but by residual peroxin-10
function: the reported mildly affected patient carried a missense allele in the
zinc-binding domain rather than the truncating alleles seen in the severe band.
distinguishing_features:
- No congenital malformations; progressive rather than static disease
- At least one allele retaining residual peroxin-10 function
- Survival beyond infancy
evidence:
- reference: PMID:10862081
reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
In contrast, a more mildly affected PEX10-deficient neonatal adrenoleukodystrophy
patient expressed a PEX10 allele with a missense mutation, H290Q, affecting the
C-terminal zinc-binding domain of the PEX10 product.
explanation: >-
The genotype in the mild band, contrasted with the truncating alleles of the severe
band in the same survey.
- reference: PMID:28784167
reference_title: "Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report a case of a patient with Zellweger spectrum disorder due to a novel mutation
in the PEX10 gene, presenting with a mild late-onset neurological phenotype.
explanation: >-
A worked attenuated PEX10 case, which is what this differential row describes. Its
value here is showing how far the milder band departs from this entry: presentation at
age five with hearing impairment rather than at birth with hypotonia and seizures.
- name: PEX10-related ataxic form
description: >-
The mildest reported band at this locus: a late-onset cerebellar syndrome with mild
intellectual impairment, described with mydriasis, hyperreflexia and involuntary head
movement. It is the same gene reaching adulthood, and it is what makes PEX10 span the
full severity range of the spectrum.
distinguishing_features:
- Adult presentation with cerebellar ataxia rather than neonatal multisystem disease
- Compound heterozygosity including alleles that retain function
evidence:
- reference: PMID:28320181
reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal
matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome
biogenesis disorders, namely Zellweger syndrome (severe), neonatal
adrenoleukodystrophy (moderate) and an ataxic form (mild).
explanation: >-
States the three-band structure of the PEX10 allelic series, which is the framing
this entry and its two differential rows depend on.
- name: Peroxisome biogenesis disorders of other complementation groups
description: >-
PEX1, PEX6, PEX12, PEX26 and the other ZSD-PEX genes produce a clinically
indistinguishable severe phenotype. The distinction is molecular only, and clinically
it does not change management.
distinguishing_features:
- Different causal PEX gene on sequencing
- Clinically and biochemically indistinguishable in the severe band
evidence:
- reference: PMID:20301621
reference_title: "Zellweger Spectrum Disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: >-
the term "ZSD" is now used to refer to all individuals with a defect in one of the
ZSD-PEX genes regardless of phenotype
explanation: >-
States the current gene-agnostic framing, which is why the differential between
complementation groups is molecular rather than clinical.
discussions:
- discussion_id: residual_function_assay_reliability
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Loss of Peroxin-10 RING Ligase Function
- pathophysiology#Biallelic Severe PEX10 Genotype
prompt: >-
How much residual peroxin-10 activity does a given PEX10 allele actually leave, given
that the assay used to measure it was reported as unreliable by its own authors?
rationale: >-
The whole 6A-versus-6B distinction is a claim about residual function, and the
quantitative instrument for that claim is the PEX10 functional complementation assay.
That assay returned nearly normal activity for nonsense and frameshift alleles
predicted to delete a third or two thirds of the protein, and its authors described the
result as demonstrating serious flaws in the assay rather than as a finding about the
alleles. The severity-versus-residual-function account survives, because it is carried
independently by the mutational classes observed in the two phenotype groups. What does
not survive is any specific activity figure for a specific PEX10 allele, and the
consequence is practical: an allele of unknown severity cannot currently be assigned to
6A or 6B on functional grounds, only on the crude grounds of whether it truncates.
evidence:
- reference: PMID:10862081
reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: >-
Surprisingly, we observed that nonsense and frameshift mutations predicted to delete
the C-terminal 2/3 (R125X) or 1/3 (c.704insA) of the protein displayed nearly normal
PEX10 activity.
explanation: The anomalous result that called the assay into question.
- reference: PMID:10862081
reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: >-
Although these results demonstrate serious flaws in the PEX10 functional
complementation assay, they do suggest that the C-terminal zinc-binding domain is
critical for PEX10 function.
explanation: >-
The authors' own assessment of their instrument. This is the sentence the knowledge
gap exists to preserve: dismech has no structured way to attach a
method-reliability caveat to the evidence items derived from that assay, so it is
recorded here.
- reference: PMID:19127411
reference_title: "A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
Despite the abnormal metabolites detected in blood (phytanate, bile acid intermediates
and pipecolate), analysis of multiple peroxisomal pathways in fibroblasts yielded
normal results.
explanation: >-
A second, independent reason to distrust fibroblast assays for PEX10: a patient with a
real PEX10 defect and abnormal blood metabolites had entirely normal fibroblast
studies. That is a different failure mode from the complementation assay above -
here the cells look normal rather than the assay misreporting activity - and together
they are why this entry treats residual-function measurements as unreliable and why
molecular analysis is the diagnostic route.
- discussion_id: matrix_import_to_migration_defect
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Loss of Peroxisomal Metabolic Function
- phenotypes#Neuronal Migration Defect
prompt: >-
Which peroxisomal function, lost when matrix import fails, is the one that arrests
cortical neuronal migration?
rationale: >-
Matrix import failure removes every peroxisomal matrix enzyme simultaneously, so the
lesion offers no natural experiment: plasmalogen deficiency, very-long-chain fatty acid
accumulation and defective docosahexaenoic acid handling all arrive together and any of
them could be the operative one. Nothing cited here traces the route, and the causal
edge in this entry is typed with unknown intermediates for that reason rather than as a
hedge. It matters because it is the only place a therapy could act, and because the
window closes before birth.
evidence:
- reference: PMID:26750748
reference_title: "Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
Although we anticipate future progress in the development of more effective targeted
interventions, the current guidelines are meant to provide a starting point for the
management of these complex conditions in the context of personalized health care.
explanation: >-
A statement from a treatment-guideline review that targeted intervention remains
prospective, which is what one would expect while the operative mechanism is
unidentified. INDIRECT: it reports the state of therapy, not the state of mechanistic
knowledge, and the connection between them is the inference.
notes: >-
Lump/split decision: DISEASE, curated as the severe band of the PEX10 allelic series and
not as a subtype of a PEX10 parent entry. The stub is retired accordingly.
That decision follows repository precedent rather than being invented here. The KB
already carries Peroxisome_Biogenesis_Disorder_1B, _2B, _3A_Zellweger, _4A_Zellweger,
_4B, _11A_Zellweger and _11B as separate Disease entries at exactly this granularity,
alongside the Peroxisome_Biogenesis_Disorder and Zellweger_Spectrum_Disorders parents,
and the 4A/4B and 11A/11B pairs are the direct analogue of the 6A/6B pair. Nothing in
kb/ binds MONDO:0013936 or names "peroxisome biogenesis disorder 6", so this duplicates
nothing.
PBD6B is deliberately NOT folded in as a has_subtypes row. On the 4A/4B precedent it
would be a separate entry, and there is a substantive reason beyond consistency: the
severity bands here are defined by residual function, and the survey that establishes
that distinction found systematically different mutational classes in the two groups.
Collapsing them would lose that. The third band at this locus, the late-onset ataxic
form, is carried as a differential for the same reason.
Two limitations of the curation are worth naming, because both concern how the evidence
in this entry should be weighed and neither can be expressed structurally.
First, sample size. The genotype-phenotype claim that separates 6A from 6B rests on four
severe-band patients and one mild-band patient. The prevalence evidence item quotes the
sentence that carries the number rather than a cleaner summary sentence, so a reader
meets the denominator without having to look for it.
Second, method reliability. The functional complementation assay behind every
residual-activity statement about PEX10 was described by its own authors as seriously
flawed. dismech's EvidenceItem has no slot for a method caveat, so the caveat is carried
three ways instead: inside the quoted snippet (chosen whole rather than trimmed to its
supportive clause), in the explanation, and as its own knowledge gap. A reader who only
reads the node summary would not see it, which is the gap.
Neuronal migration defect is bound to HP:0002269 (Abnormality of neuronal migration)
rather than to a specific malformation term. The severe ZSD literature reports
perisylvian polymicrogyria, but the GeneReviews sentence quoted here says only "neuronal
migration defects", and binding the narrower term would assert more than the cited
sentence supports.
No animal models and no biochemical section. Neither is an omission of available content:
no PEX10-specific animal model is reported in the sources cited here, and the
peroxisomal biochemical panel is gene-agnostic and belongs on the spectrum entry.
The deep-research report generated for this entry is committed alongside it under
research/. Reference selection and every snippet were taken from the fetched reference
cache rather than from the report.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Lump/split decision: DISEASE, curated as the severe band of the PEX10 allelic series and not as a subtype of a PEX10 parent entry. The stub is retired accordingly. That decision follows repository precedent rather than being invented here. The KB already carries Peroxisome_Biogenesis_Disorder_1B, _2B, _3A_Zellweger, _4A_Zellweger, _4B, _11A_Zellweger and _11B as separate Disease entries at exactly this granularity, alongside the Peroxisome_Biogenesis_Disorder and Zellweger_Spectrum_Disorders parents, and the 4A/4B and 11A/11B pairs are the direct analogue of the 6A/6B pair. Nothing in kb/ binds MONDO:0013936 or names "peroxisome biogenesis disorder 6", so this duplicates nothing. PBD6B is deliberately NOT folded in as a has_subtypes row. On the 4A/4B precedent it would be a separate entry, and there is a substantive reason beyond consistency: the severity bands here are defined by residual function, and the survey that establishes that distinction found systematically different mutational classes in the two groups. Collapsing them would lose that. The third band at this locus, the late-onset ataxic form, is carried as a differential for the same reason. Two limitations of the curation are worth naming, because both concern how the evidence in this entry should be weighed and neither can be expressed structurally. First, sample size. The genotype-phenotype claim that separates 6A from 6B rests on four severe-band patients and one mild-band patient. The prevalence evidence item quotes the sentence that carries the number rather than a cleaner summary sentence, so a reader meets the denominator without having to look for it. Second, method reliability. The functional complementation assay behind every residual-activity statement about PEX10 was described by its own authors as seriously flawed. dismech's EvidenceItem has no slot for a method caveat, so the caveat is carried three ways instead: inside the quoted snippet (chosen whole rather than trimmed to its supportive clause), in the explanation, and as its own knowledge gap. A reader who only reads the node summary would not see it, which is the gap. Neuronal migration defect is bound to HP:0002269 (Abnormality of neuronal migration) rather than to a specific malformation term. The severe ZSD literature reports perisylvian polymicrogyria, but the GeneReviews sentence quoted here says only "neuronal migration defects", and binding the narrower term would assert more than the cited sentence supports. No animal models and no biochemical section. Neither is an omission of available content: no PEX10-specific animal model is reported in the sources cited here, and the peroxisomal biochemical panel is gene-agnostic and belongs on the spectrum entry. The deep-research report generated for this entry is committed alongside it under research/. Reference selection and every snippet were taken from the fetched reference cache rather than from the report.
Disease: Peroxisome Biogenesis Disorder 6A (Zellweger) — PBD6A MONDO ID: MONDO:0013936 · OMIM: #614870 (PBD6A) / #614871 (PBD6B, milder allelic form) · Gene: PEX10 (OMIM 602859, 1p36.32) Category: Mendelian, autosomal recessive
Peroxisome Biogenesis Disorder 6A (Zellweger) is the severe, PEX10-caused end of the Zellweger spectrum disorder (ZSD) continuum — a fatal, autosomal-recessive inborn error of organelle biogenesis. Biallelic loss-of-function mutations in PEX10, one of ~13–14 PEX genes required for peroxisome assembly, disable the peroxisomal matrix-protein import machinery. PEX10 is a C3HC4 zinc-RING-finger peroxin that, together with PEX2 and PEX12, forms the E3-ubiquitin-ligase core of the peroxisomal "importomer." This ligase mono- and poly-ubiquitinates the cycling receptor PEX5 to drive its recycling; when it fails, PEX5-mediated delivery of matrix enzymes collapses and peroxisomes become functionally empty ghosts. RING-finger missense substitutions (e.g., p.Cys307Tyr, p.Cys276Phe, p.Arg311Gln) map to this critical domain, and the most severe (Zellweger) phenotypes arise when residual function is minimal (PMID: 32069232, PMID: 28320181, PMID: 20679226).
The downstream biochemistry is a multi-pathway metabolic failure: impaired α- and β-oxidation of very-long-chain fatty acids (VLCFA), defective bile-acid synthesis with accumulation of toxic C27 intermediates (DHCA, THCA), and deficient ether-phospholipid (plasmalogen) and DHA synthesis (PMID: 34625341). These lesions converge on mitochondria-mediated oxidative stress and neuronal death, producing the hallmark neuronal-migration defects (polymicrogyria, pachygyria, germinolytic cysts) alongside hepatic, renal, retinal, auditory, adrenal and skeletal disease (PMID: 20959636). Classic Zellweger neonates present at birth with profound hypotonia, seizures, craniofacial dysmorphism and failure to thrive, and most die within the first year (PMID: 28784167, PMID: 12069541).
ZSD is rare (~1 in 50,000–90,000 births, with regional founder effects), diagnosed by elevated plasma VLCFA (C26:0, C26:0/C22:0) and the dried-blood-spot marker C26:0-lysophosphatidylcholine confirmed by PEX-gene sequencing (PMID: 28677031, PMID: 30846882). Management is supportive; oral cholic acid (Cholbam®) is the sole FDA-approved therapy, and gene/base-editing approaches show preclinical rescue in mouse models (PMID: 34521419, PMID: 41981313). Prevention is limited to genetic counseling, carrier testing and prenatal diagnosis (PMID: 23327810).
Overview. Zellweger syndrome (ZS), historically the "cerebro-hepato-renal syndrome," was first described in 1964 as a familial syndrome of multiple congenital defects, and is the severest of the peroxisome biogenesis disorders (PBDs) (PMID: 12069541, PMID: 23327810). PBD6A is the specific designation for the PEX10-caused severe (Zellweger) form; PBD6B is the milder PEX10 form (neonatal adrenoleukodystrophy / infantile-Refsum-like). The three classic clinical labels — Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate), and infantile Refsum disease / ataxic form (mild) — are now recognized as a continuum, the Zellweger spectrum disorder (ZSD) (PMID: 28320181).
Key identifiers.
| Resource | Identifier |
|---|---|
| OMIM | #614870 (PBD6A) · #614871 (PBD6B) · 602859 (PEX10 gene) |
| MONDO | MONDO:0013936 (PBD6A) |
| Orphanet | ORPHA:912 (Zellweger syndrome) |
| MeSH | D015211 (Zellweger Syndrome) |
| ICD-10 | Q87.8 / E71.5x (peroxisomal disorders) |
| ICD-11 | 5C57.0 |
Synonyms / alternative names. Zellweger syndrome; cerebro-hepato-renal syndrome (CHRS); PBD, Zellweger type; peroxisome biogenesis disorder 6A; PEX10-related ZSD (PMID: 23327810, PMID: 12069541).
Information source. Content is drawn from aggregated disease-level resources (OMIM, Orphanet, natural-history cohorts, scoping reviews) supplemented by individual patient case reports and small clinical cohorts; there is no large EHR-derived dataset given rarity.
Primary cause — genetic. PBD6A is caused by biallelic (homozygous or compound-heterozygous) pathogenic variants in PEX10 (PMID: 32069232). "Mutations of 13 different PEX genes lead to PBDs including Zellweger syndrome (ZS)" and "different types of mutations of PEX1 and PEX10 genes are correlated with broad-range phenotypes of PBDs" (PMID: 32069232). There is no environmental or infectious cause; the disease is fully genetically determined.
Genetic risk factors. The causal factor is the loss-of-function PEX10 genotype itself. Genotype–phenotype correlation is central: RING-domain missense changes and severe truncating alleles yield Zellweger; hypomorphic/milder alleles yield NALD or the ataxic form (PMID: 28320181, PMID: 27230853). Consanguinity and membership in founder populations (see §9) increase risk.
Environmental / lifestyle / infectious factors. None causative. This is not a multifactorial or exposure-driven disease. Infections (e.g., neonatal sepsis) are complications, not causes (PMID: 33213396).
Protective factors. No established genetic or environmental protective factors. Within the spectrum, residual PEX10 function (hypomorphic alleles) is the principal modifier that "protects" against the severe Zellweger phenotype, shifting patients toward milder, longer-surviving disease (PMID: 27230853).
Gene–environment interactions. Not applicable in a conventional sense; phenotype is modulated chiefly by allele severity and, in prolonged-survival cases, likely by unknown modifier factors (PMID: 15098231).
Classic (severe) Zellweger presents in the neonatal period with a stereotyped, multisystem, progressive phenotype. A scoping review/meta-analysis (107 studies, 307 patients) and a 136-patient natural-history chart review found clinical findings differing significantly across severity categories (PMID: 35741019).
| Phenotype | Type | HPO term | Onset | Frequency / severity |
|---|---|---|---|---|
| Severe hypotonia | Clinical sign | HP:0001319 (neonatal hypotonia) | Neonatal | Near-universal, severe |
| Seizures | Clinical sign | HP:0001250 | Neonatal | Very common |
| Craniofacial dysmorphism (high forehead, large fontanelle, flat face, epicanthus, broad nasal bridge, micrognathia) | Physical | HP:0000280 / HP:0000239 | Congenital | Characteristic |
| Retinal degeneration → blindness | Lab/clinical | HP:0000546 | Infancy | "Almost all" (PMID: 37541626); median VA ~0.93 logMAR (~20/320) |
| Sensorineural hearing loss | Clinical | HP:0000407 | Infancy | Moderately-severe to severe, slowly progressive (PMID: 34534157) |
| Hepatic dysfunction (hepatomegaly, cholestasis, fibrosis, coagulopathy) | Lab/clinical | HP:0002240 / HP:0001394 | Neonatal | Common |
| Renal cysts, hyperoxaluria/stones | Imaging/lab | HP:0000107 | Congenital | Common |
| Adrenal insufficiency | Lab | HP:0000846 | Variable | Reported |
| Global developmental delay / no milestones | Behavioral/developmental | HP:0001263 | Infancy | Severe form reaches no milestones (PMID: 28784167) |
| Feeding difficulties / failure to thrive / GERD | Clinical | HP:0011968 / HP:0001508 | Neonatal | Common |
| Chondrodysplasia punctata / epiphyseal stippling, fractures | Imaging | HP:0000943 | Congenital | Reported |
"Common clinical findings that were significantly different across severity categories included seizures, hypotonia, reduced mobility, feeding difficulties, renal cysts, adrenal insufficiency, hearing and vision loss, and a shortened lifespan" (PMID: 35741019).
Quality-of-life impact. In severe Zellweger, QoL is profoundly limited: affected infants reach no developmental milestones, are cortically blind and deaf, feed poorly and rarely survive infancy (PMID: 28784167). Milder spectrum survivors may achieve supported employment and partly independent living, but face progressive gait disorders and sensory loss (PMID: 26287655).
Causal gene. PEX10 (HGNC gene, OMIM 602859), chromosome 1p36.32, encoding an integral peroxisomal-membrane peroxin. PEX10 is "involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild)" (PMID: 28320181).
Pathogenic variants. - Variant types: missense (esp. RING-domain), frameshift, nonsense/truncating, and small deletions. Representative pathogenic changes: p.Cys307Tyr (p.C307Y) in the RING finger (PMID: 28320181); p.Cys276Phe and p.Arg311Gln in the ataxic form (PMID: 27230853); a homozygous 2-bp deletion as a Japanese founder allele (PMID: 12794690). - Classification (ACMG/AMP): null/frameshift/nonsense alleles are pathogenic (PVS1); RING-domain missense in a well-established functional domain are typically pathogenic/likely pathogenic. Milder cases may carry one hypomorphic allele. - Allele frequency: individually very rare in gnomAD; carrier frequencies elevated in founder populations (see §9). - Origin: germline; no somatic relevance. - Functional consequence: loss of function (impaired E3-ligase/importomer activity). No gain-of-function or dominant-negative mechanism is described (PMID: 20679226).
Modifier genes. Allele severity is the dominant modifier; unidentified factors influence phenotype even for identical genotypes ("next to the PEX1 genotype other yet unknown factors determine the ultimate phenotype," PMID: 15098231 — an observation that generalizes across ZSD).
Epigenetic information. No disease-specific DNA-methylation or histone-modification signatures have been established for PBD6A.
Chromosomal abnormalities. None characteristic; PBD6A is a single-gene disorder, not a copy-number/structural syndrome.
Environmental factors: none causative — PBD6A is a purely genetic disorder. Lifestyle factors: not applicable. Infectious agents: not causative; however, neonates are vulnerable to overwhelming Gram-negative sepsis as a complication, consistent with an emerging role of peroxisomes in immune modulation (PMID: 33213396). Dietary considerations (VLCFA restriction, DHA and fat-soluble-vitamin supplementation) are therapeutic/supportive rather than etiologic.
(Steps 1–4 are mechanistically demonstrated in cell/animal models; the oxidative-stress neurodegeneration step is directly demonstrated in a PEX13 brain model and inferred to generalize to PEX10.)
Suggested ontology terms. GO:0016558 (protein import into peroxisome matrix); GO:0007031 (peroxisome organization); GO:0006635 (fatty-acid β-oxidation); GO:0008203 (cholesterol/bile-acid metabolism); GO:0006979 (response to oxidative stress); GO:0001764 (neuron migration). CL:0000540 (neuron); CL:0000121 (Purkinje cell); CL:0000573 (retinal photoreceptor); CL:0000182 (hepatocyte). CHEBI:76724 (very-long-chain fatty acid); CHEBI:36021 (plasmalogen); CHEBI:3098 (bile acid).
Organ / body-system level. Multisystem — the name cerebro-hepato-renal enumerates the three primary organs. Primary: brain/CNS (nervous system), liver (digestive/hepatobiliary), kidney (urinary). Secondary/associated: eyes (retina, lens, optic nerve), ears (cochlea), adrenal glands (endocrine), skeleton, GI tract (PMID: 37144748, PMID: 33213396).
Tissue / cell level. Neurons and neuronal-migration units (cortex, cerebellar granule and Purkinje cells), hepatocytes and biliary epithelium, renal tubular/cortical tissue, retinal photoreceptors and RPE, cochlear sensory cells. The PEX13 brain model shows "impaired cerebellar fissure/cortical layer formation, defective granule cell migration and Purkinje cell layer development" (PMID: 20959636).
Subcellular level. The peroxisome (GO:0005777) is absent/reduced (membrane ghosts persist); secondary mitochondrial dysfunction (GO:0005739) contributes to oxidative injury.
Localization / lateralization. Bilateral, symmetric multisystem involvement; brain malformations (polymicrogyria, pachygyria, germinolytic subependymal cysts) are typically bilateral. Suggested UBERON terms: UBERON:0000955 (brain), UBERON:0002037 (cerebellum), UBERON:0002107 (liver), UBERON:0002113 (kidney), UBERON:0000966 (retina), UBERON:0001846 (inner ear), UBERON:0002369 (adrenal gland).
Onset. Congenital / neonatal. Severe Zellweger presents at or shortly after birth with hypotonia and seizures (PMID: 28784167); the pattern is chronic-progressive from birth.
Progression. In the severe form the course is rapidly progressive, with failure to thrive and early death, usually before age 1 year; patients reach no developmental milestones (PMID: 12069541). Across the broader spectrum, intermediate/mild patients survive into childhood or adulthood (cohorts to 24–35 years) with variable courses — stable, slowly declining, or with adolescent-onset progressive gait disorder/leukodystrophy (PMID: 26287655, PMID: 15098231).
Patterns. No spontaneous remission. Critical periods: the neonatal window is the period of greatest vulnerability and the target window for any disease-modifying intervention; leukoencephalopathy accrues with age in longer survivors (PMID: 18415699, PMID: 14872027).
Epidemiology. ZSD incidence ~1 in 50,000–90,000 births. New-York newborn screening estimated ~1 in 90,000 (from 1.08 million screenings) — "Our results are close to current newborn screening estimates in New York of 1 in 90,000 births, estimated from 1.08 million screenings"; an ExAC-based bioinformatic estimate gave ~1 in 83,841 (PMID: 30846882). Japan overall ~1 in 500,000–800,000, but Okinawa 1 in 30,000 (PMID: 8914632).
Inheritance. Autosomal recessive, complete penetrance for the biochemical/genetic phenotype; variable expressivity governed by allele severity. No anticipation (not a repeat-expansion disorder). Germline mosaicism not a notable feature.
Founder effects / consanguinity. A PEX6 founder mutation in Saguenay-Lac-St-Jean, Quebec gives "Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55" (PMID: 22894767). A homozygous 2-bp PEX10 deletion is a founder allele among Japanese complementation-group-B patients — "All the 11 ZS patients with group-B PBD had a common mutation, i.e., a homozygous 2-base-pair deletion in PEX10" (PMID: 12794690). Consanguinity increases risk.
Population demographics. Panethnic; regional clustering where founder alleles exist (French-Canadian Quebec; Okinawa). Sex ratio ~1:1 (autosomal). Age distribution skews to neonates/infants for the severe form.
Biochemical testing (first-line). Elevated plasma VLCFA — C26:0, C26:0/C22:0 and C24:0/C22:0 ratios; elevated pipecolic, phytanic/pristanic acids; abnormal C27 bile-acid intermediates (DHCA/THCA); reduced erythrocyte plasmalogens (PMID: 34625341).
Dried-blood-spot marker. C26:0-lysophosphatidylcholine (C26:0-lysoPC) is sensitive: "Elevated C26:0-lysoPC levels (>72 nmol/L) were found in 86/91 ZSD DBS (n=33/37 patients) corresponding to a sensitivity of 89.2%" (median 567 nmol/L), whereas C26:0-carnitine is less sensitive (55.2%) — "C26:0-lysoPC in DBS is a sensitive and useful marker for VLCFA accumulation in patients with a ZSD" (PMID: 28677031). This is the analyte used in tandem-MS newborn screening (implemented primarily for X-ALD/ABCD1), which incidentally detects ZSD (PMID: 36256460).
Genetic testing (confirmatory). Sequencing the ~13 PEX genes — whole-exome sequencing or targeted PBD/peroxisomal gene panels; single-gene PEX10 testing where a founder allele is known. Classic functional confirmation is complementation analysis in cultured fibroblasts. Note that milder alleles may yield near-normal fibroblast studies, making molecular analysis essential at the mild end (PMID: 19127411).
Imaging. Brain MRI is highly informative: "cMRI pathology in ZSS consists of abnormal gyration pattern including polymicrogyria and pachygyria, leukencephalopathy, germinolytic cysts and heterotopias" (PMID: 18415699); polymicrogyria/pachygyria predominate in severe disease, leukoencephalopathy in longer survivors (PMID: 14872027).
Differential diagnosis. Other PEX-gene ZSDs (PEX1/PEX6/PEX2/PEX12/PEX26); single peroxisomal enzyme defects that are "Zellweger-like" — notably D-bifunctional protein (HSD17B4) deficiency ("Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures, retinopathy, hearing loss, dysmorphic features," PMID: 32904102) and acyl-CoA oxidase deficiency; rhizomelic chondrodysplasia punctata; Heimler syndrome (mild PEX1/PEX6, PMID: 26387595); and non-peroxisomal causes of neonatal hypotonia/renal cysts/epiphyseal stippling such as Smith-Lemli-Opitz and warfarin embryopathy (PMID: 40995270, PMID: 39359950).
Screening. Cascade carrier testing in families; prenatal diagnosis on CVS/amniocytes (VLCFA/DHAPAT enzyme assay or molecular testing); newborn C26:0-LPC screening detects ZSD as a secondary finding.
Survival. Severity-dependent. Classic (severe) Zellweger — the cerebro-hepato-renal syndrome — "is characterized by the presence of dysmorphias and polymalformative syndrome, severe neurologic abnormalities including neurosensory defects and hepato-intestinal dysfunction with failure to thrive and usually early death," typically before 1 year (PMID: 12069541). Intermediate/mild patients survive into childhood or adulthood (PMID: 26287655).
Prognostic biomarker. Serum VLCFA, particularly C26:0, correlates with severity: "The best predictive value for estimating the projected disease severity and survival time is a concentration of C26:0" (PMID: 32946460).
Morbidity / function. Severe global disability — cortical blindness, deafness, no developmental milestones, seizures, hepatic and renal failure. Complications: coagulopathy, adrenal crisis, fractures, feeding failure, and vulnerability to overwhelming neonatal sepsis (PMID: 33213396).
Recovery potential. None for the severe form; care is palliative/supportive. Milder spectrum patients may stabilize for years (PMID: 26287655).
Pharmacotherapy. Oral cholic acid (Cholbam®) — the only FDA-approved therapy (March 2015), an adjunctive treatment for ZSDs and single-enzyme bile-acid-synthesis disorders. "Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders" (PMID: 34521419). It suppresses endogenous bile-acid synthesis, lowering toxic C27 intermediates and improving liver chemistries. In a Phase-3 continuation study (53 patients, 12 with ZSD), "statistically significant improvements in urinary bile acids (P = 0.003), height (P < 0.001), and body weight (P < 0.001) were observed" (PMID: 31899729); extension studies confirm sustained suppression (PMID: 30793331, PMID: 30519152). NCIT: C29076 (cholic acid).
Adjunct / experimental medical therapies. DHA, Lorenzo's oil, batyl alcohol, and fat-soluble-vitamin supplementation have partial/anecdotal support: "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" (PMID: 34625341).
Advanced therapeutics (preclinical). In vivo adenine base editing (AAV9-ABE8e) corrected up to 60% of the pathogenic allele in liver of a Pex1-G844D ZSD mouse; "base editing eliminated bulk accumulation of very long-chain and branched-chain fatty acids, and toxic C27-bile acid intermediates," and normalized liver histology/transcriptomes (PMID: 41981313). AAV8 gene therapy is in development for the retinal phenotype (PMID: 42182139). Hepatocyte transplantation has been explored in models (PMID: 33396635).
Supportive / rehabilitative. Anti-epileptic drugs; nutritional support/gastrostomy for feeding failure; hearing amplification (improves outcomes, PMID: 34534157); low-vision support; adrenal replacement; management of coagulopathy and liver disease; physical/occupational/speech therapy. Care is multidisciplinary and largely palliative in the severe form.
No primary prevention exists for this congenital, autosomal-recessive genetic disorder with no environmental/infectious cause. "As it is fatal in early life, genetic counseling and prenatal diagnosis are thus crucial" (PMID: 23327810). Preventive mainstays:
No immunization or public-health/environmental interventions are applicable.
Model species with orthologs. PEX10 orthologs are conserved across eukaryotes — mouse (Mus musculus, NCBI Taxon 10090), zebrafish (Danio rerio, 7955), Arabidopsis thaliana (3702), and yeasts (Hansenula/Pichia, Saccharomyces). In Arabidopsis, PEX10 dysfunction is embryo-lethal: "dysfunction of a homologous gene in Arabidopsis leads to lethality at the heart stage of embryogenesis, impairing the biogenesis of peroxisomes, lipid bodies, and protein bodies" (PMID: 12883010), underscoring deep evolutionary conservation of the peroxisome-import machinery.
Natural disease in companion/wildlife species. No well-characterized naturally occurring PEX10-Zellweger equivalent is documented in the reviewed literature (OMIA searches were not resolved in this investigation). Not zoonotic — this is a Mendelian metabolic disorder, not transmissible.
| Model | Type | Key features / recapitulation | Reference |
|---|---|---|---|
| PEX1-p.Gly844Asp (G844D) mouse | Mammalian knock-in | Models the common human PEX1-p.Gly843Asp allele; reproduces retinal & RPE degeneration with subretinal inflammation, liver pathology, metabolic dysfunction | PMID: 40058592, PMID: 41981313 |
| Brain-restricted PEX13-deficient mouse | Mammalian conditional KO | Reduced plasmalogens, impaired cerebellar development, defective granule-cell migration, astro-/microgliosis, ↑ROS/MnSOD, neuronal apoptosis — mechanistic Zellweger brain model | PMID: 20959636 |
| Pex11α-KO mouse | Mammalian KO | Serum/liver/heart lipidomic, metabolomic, proteomic dysregulation | PMID: 35083512 |
| Zebrafish pex mutants (e.g., PEX13) | Vertebrate | Established peroxisome/pexophagy models | PMID: 36541703 |
| Arabidopsis AthPEX10 T-DNA mutant | Plant | Embryo-lethal; absent peroxisomes/oil bodies — proves conserved essentiality | PMID: 12883010 |
| Yeast (Pichia/Hansenula) | Fungal | Defined importomer/Pex20 ubiquitination biochemistry | PMID: 23344950 |
Applications & limitations. Models faithfully reproduce the biochemical lesion (VLCFA/plasmalogen/bile-acid abnormalities) and organ pathology (retina, liver, cerebellum), and have enabled proof-of-concept base-editing and AAV gene therapy (PMID: 41981313, PMID: 42182139). Limitations: most established models use PEX1, not PEX10; complete null models are often perinatally lethal, limiting study of later neurodegeneration; and no single model captures the full human multisystem severity spectrum.
PEX10 biallelic LoF (C3HC4 RING-finger mutation)
│ abolishes E3-ubiquitin-ligase activity
▼
Importomer failure → PEX5 receptor not ubiquitinated/recycled
│
▼
Collapse of peroxisomal matrix-protein import → "ghost" peroxisomes
│
├──► ↓ β-/α-oxidation ─────► VLCFA ↑ (C26:0), phytanic/pristanic ↑
├──► defective bile-acid synth ─► toxic C27 intermediates (DHCA/THCA) ↑
├──► ↓ ether-lipid synth ──────► plasmalogen ↓, DHA ↓
│
▼ (convergence)
Mitochondria-mediated OXIDATIVE STRESS (↑ROS, ↑SOD2) + lipotoxicity
│
┌────┴───────────────┬──────────────┬───────────────┬─────────────┐
▼ ▼ ▼ ▼ ▼
BRAIN LIVER KIDNEY EYE/EAR ADRENAL/BONE
migration defects cholestasis cortical cysts retinopathy insufficiency
(PMG/pachygyria), fibrosis, hyperoxaluria SNHL chondrodysplasia
germinolytic cysts, coagulopathy punctata
apoptosis, gliosis
│
▼
Classic Zellweger phenotype → death usually < 1 year
The unifying interpretation is that a single upstream molecular lesion (RING-E3 failure) produces a broad metabolic derangement because peroxisomes host many non-redundant pathways. Severity tracks with residual PEX10 function: null/severe alleles → Zellweger; hypomorphic alleles → NALD/ataxic form with survival into adulthood. C26:0 is both the diagnostic and prognostic readout of this pathway, and correcting the pathway (base editing) reverses the biochemistry in models — validating the causal chain.
| PMID | Contribution | Role |
|---|---|---|
| 32069232 | PEX10 among 13 PEX genes; genotype–phenotype correlation | Supports etiology (F001) |
| 28320181 | PEX10 import function; severity spectrum; RING p.C307Y | Supports gene function/variants (F001) |
| 20679226 | PEX10/PEX2/PEX12 zinc-RING E3 ligases | Supports mechanism (F012) |
| 23344950 | RING peroxins ubiquitinate PTS receptors | Supports mechanism |
| 34625341 | VLCFA/bile-acid metabolic failure; adjunct therapies | Supports mechanism/treatment (F002, F003) |
| 28784167 | Classic Zellweger neonatal phenotype | Supports phenotype (F002) |
| 35741019 | Severity-graded clinical findings (meta-analysis) | Supports phenotypes (F004) |
| 37541626 | Near-universal retinal degeneration | Supports phenotype (F004) |
| 34534157 | Sensorineural hearing-loss characterization | Supports phenotype (F004) |
| 20959636 | Oxidative-stress neurodegeneration (PEX13 brain model) | Supports mechanism (F007) |
| 28677031 | C26:0-lysoPC DBS marker (89.2% sensitivity) | Supports diagnostics (F008) |
| 36256460 | ZSD detected as secondary finding of C26:0-LPC NBS | Supports diagnostics (F008) |
| 32946460 | C26:0 best predictor of severity/survival | Supports prognosis (F009) |
| 18415699 | MRI: polymicrogyria/pachygyria, germinolytic cysts | Supports diagnostics (F009) |
| 12069541 | Historical CHRS synonym; early-death course | Supports identity/prognosis (F009, F010) |
| 23327810 | Fatal AR disorder; counseling/prenatal prevention | Supports identity/prevention (F010) |
| 30846882 | Incidence ~1/90,000 (NBS) | Supports epidemiology (F006) |
| 22894767 | PEX6 founder effect Quebec (1/12,191; carrier 1/55) | Supports epidemiology (F006) |
| 12794690 | PEX10 founder 2-bp deletion, Japan | Supports epidemiology (F006) |
| 34521419 | Cholic acid sole FDA-approved therapy | Supports treatment (F003) |
| 31899729 | Phase-3 cholic-acid efficacy (urinary BA P=0.003) | Supports treatment (F003) |
| 41981313 | In vivo base editing rescues ZSD mouse | Supports treatment/models (F005) |
| 40058592 | PEX1-G844D mouse retinal/RPE phenotype | Supports models (F005) |
| 32904102 | DBP deficiency = Zellweger-like DDx | Supports diagnostics (F012) |
| 26387595 | Heimler = mild PBD (PEX1/PEX6) | Supports DDx/spectrum |
| 33213396 | Peroxisomes in immunity; neonatal sepsis | Supports anatomy/immune (F011) |
| 37144748 | Craniofacial/neonatal presentation (PEX6 severe) | Supports anatomy (F011) |
| 12883010 | Arabidopsis PEX10 embryo-lethal; conservation | Supports models (F012) |
| 39359950 | Lists related PBD phenotypes (differential spectrum) | Supports DDx |
Report compiled from a 5-iteration autonomous investigation: 12 confirmed findings, 55 papers reviewed. Evidence sources span human clinical cohorts, model-organism (mouse/zebrafish/plant/yeast) studies, in vitro biochemistry, and computational/population-genetic estimates.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 42 |
| Resolved | 42 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 17 |
| Quoted claims found in source | 16 |
| Quoted claims not found in source | 1 |
| References weighed for topical relevance | 42 |
| On topic | 31 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:20959636 (abstract only): "impaired cerebellar fissure/cortical layer formation, defective granule cell migration and Purkinje cell layer development"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 38 |
| Resolved | 37 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 30 |
| Terms named correctly | 16 |
| Terms named as a different term | 8 |
| Terms whose name is worth a second look | 6 |
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:
HP:0001250 (1 mention) - the report calls it "Clinical sign"; HP calls it SeizureHP:0000546 (1 mention) - the report calls it "Lab/clinical"; HP calls it Retinal degenerationHP:0000407 (1 mention) - the report calls it "Clinical"; HP calls it Sensorineural hearing impairmentHP:0000107 (1 mention) - the report calls it "Imaging/lab"; HP calls it Renal cystHP:0000846 (1 mention) - the report calls it "Lab"; HP calls it Adrenal insufficiencyHP:0000943 (1 mention) - the report calls it "Imaging"; HP calls it Dysostosis multiplexCHEBI:76724 (1 mention) - the report calls it "very-long-chain fatty acid"; CHEBI calls it 2-hydroxyoctadecanoateCHEBI:36021 (1 mention) - the report calls it "plasmalogen"; CHEBI calls it octadec-9-enoic acidThe 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:
MONDO:0013936 (2 mentions) - the report calls it "PBD6A"; MONDO calls it peroxisome biogenesis disorder 6A (Zellweger), and lists "PBD6A" among its other namesHP:0001263 (1 mention) - the report calls it "Behavioral/developmental"; HP calls it Global developmental delay, and lists "Retarded development" among its other namesGO:0006635 (1 mention) - the report calls it "fatty-acid β-oxidation"; GO calls it fatty acid beta-oxidationGO:0008203 (1 mention) - the report calls it "cholesterol/bile-acid metabolism"; GO calls it cholesterol metabolic process, and lists "cholesterol metabolism" among its other namesCL:0000573 (1 mention) - the report calls it "retinal photoreceptor"; CL calls it retinal cone cellUBERON:0001846 (1 mention) - the report calls it "inner ear"; UBERON calls it internal ear, and lists "inner ear" among its other namesTerms 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.