Peroxisome biogenesis disorder 2B (PBD2B, OMIM 202370) is the non-classic ("B", milder) end of the PEX5-related Zellweger spectrum, corresponding to the historical entities neonatal adrenoleukodystrophy and infantile Refsum disease. PEX5 defines complementation group 2 of the peroxisome biogenesis disorders and encodes the cytosolic receptor that recognises the type-1 peroxisomal targeting signal (PTS1) on matrix enzymes and delivers them to the organelle. What distinguishes PBD2B from classic Zellweger syndrome (PBD2A) is not a different pathway but a different degree - and, unusually for this spectrum, a different *kind* - of residual function. The three PEX5 patients characterised together in 1999 make the point cleanly, because their phenotypes track their import defects: the nonsense allele R390X gave Zellweger syndrome and lost both PTS1 and PTS2 import; the missense allele N489K gave neonatal adrenoleukodystrophy with a severe PTS1 defect but preserved PTS2 import; and the missense allele S563W gave infantile Refsum disease, the mildest phenotype, with residual function on both arms. The S563W receptor is the informative one, because its residual function is *cargo-selective* rather than simply reduced. It still handles the canonical -SKL signal of acyl-CoA oxidase but has little or no function for the weaker PTS1 variants -AKL (D-bifunctional protein, sterol carrier protein 2) and -KANL (catalase). So a mildly damaged PTS1 receptor does not import less of everything; it imports a subset, chosen by how good a match each cargo's targeting signal is. That is a mechanism for graded severity that has no equivalent in the receptor-export-module disorders PBD1B and PBD4B, where the gradient is set by how much peroxin protein survives. PEX5 is also the gene of rhizomelic chondrodysplasia punctata type 5, an entirely different disease produced by an allele that removes only the long isoform and so knocks out the PTS2 arm while sparing PTS1. RCDP5 is curated separately in this knowledge base. One gene, two diseases, decided by which isoform and which cargo arm an allele hits - and PBD2B is the Zellweger-side half of that split.
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Conditions with similar clinical presentations that must be differentiated from Peroxisome Biogenesis Disorder 2B:
name: Peroxisome Biogenesis Disorder 2B
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: peroxisome biogenesis disorder 2B
term:
id: MONDO:0008736
label: peroxisome biogenesis disorder 2B
description: >-
Peroxisome biogenesis disorder 2B (PBD2B, OMIM 202370) is the non-classic
("B", milder) end of the PEX5-related Zellweger spectrum, corresponding to the
historical entities neonatal adrenoleukodystrophy and infantile Refsum
disease. PEX5 defines complementation group 2 of the peroxisome biogenesis
disorders and encodes the cytosolic receptor that recognises the type-1
peroxisomal targeting signal (PTS1) on matrix enzymes and delivers them to the
organelle.
What distinguishes PBD2B from classic Zellweger syndrome (PBD2A) is not a
different pathway but a different degree - and, unusually for this spectrum, a
different *kind* - of residual function. The three PEX5 patients characterised
together in 1999 make the point cleanly, because their phenotypes track their
import defects: the nonsense allele R390X gave Zellweger syndrome and lost
both PTS1 and PTS2 import; the missense allele N489K gave neonatal
adrenoleukodystrophy with a severe PTS1 defect but preserved PTS2 import; and
the missense allele S563W gave infantile Refsum disease, the mildest
phenotype, with residual function on both arms.
The S563W receptor is the informative one, because its residual function is
*cargo-selective* rather than simply reduced. It still handles the canonical
-SKL signal of acyl-CoA oxidase but has little or no function for the weaker
PTS1 variants -AKL (D-bifunctional protein, sterol carrier protein 2) and
-KANL (catalase). So a mildly damaged PTS1 receptor does not import less of
everything; it imports a subset, chosen by how good a match each cargo's
targeting signal is. That is a mechanism for graded severity that has no
equivalent in the receptor-export-module disorders PBD1B and PBD4B, where the
gradient is set by how much peroxin protein survives.
PEX5 is also the gene of rhizomelic chondrodysplasia punctata type 5, an
entirely different disease produced by an allele that removes only the long
isoform and so knocks out the PTS2 arm while sparing PTS1. RCDP5 is curated
separately in this knowledge base. One gene, two diseases, decided by which
isoform and which cargo arm an allele hits - and PBD2B is the Zellweger-side
half of that split.
parents:
- Zellweger Spectrum Disorders
- peroxisome biogenesis disorder
- inborn errors of metabolism
synonyms:
- PBD2B
- peroxisome biogenesis disorder type 2B
- Neonatal adrenoleukodystrophy, PEX5-related
- Infantile Refsum disease, PEX5-related
- PEX5-related non-classic Zellweger spectrum disorder
- Peroxisome biogenesis disorder, complementation group 2, non-classic
notes: >-
Curation level. PBD2B is curated as a distinct entry rather than folded into
Zellweger Spectrum Disorders, in parallel with Peroxisome Biogenesis Disorder
1B (PEX1) and 4B (PEX6), because the "A"/"B" split within a PEX
complementation group is a mechanistic statement about residual peroxin
function rather than a bare severity label, and because the causal gene
differs. The gene-agnostic downstream cascade shared by the whole spectrum -
loss of peroxisomal beta-oxidation, ether-lipid synthesis and bile acid
side-chain shortening, and the resulting multisystem disease - is curated once
on the Zellweger Spectrum Disorders entry rather than duplicated here. This
entry carries what is PEX5- and non-classic-specific: the receptor rather than
the export module as the lesion, and the cargo-selectivity of the residual
function.
Where the phenotype block comes from, stated plainly because it matters. There
is no PEX5-specific clinical series. The three PEX5 patients whose import
defects define this entity are labelled with their clinical diagnoses and
nothing more; the only PEX5 case in a recent 14-patient Iranian peroxisomal
cohort is one row in a table. So the phenotypes here are curated at the level
of *intermediate/milder Zellweger spectrum disorder*, from GeneReviews and
from a 31-patient prolonged-survival cohort, and every one of them carries
`directness: INDIRECT` for that reason.
That import is licensed by the sources themselves rather than assumed:
GeneReviews states that the term ZSD now refers to all individuals with a
defect in one of the ZSD-PEX genes *regardless of phenotype*, and the
prolonged-survival cohort states that clinical distinctions between ZS, NALD
and IRD are not sharply defined. The nosology is deliberately gene-agnostic on
the clinical side. But note the countervailing fact and do not lose it: 21 of
the 31 patients in that cohort had PEX1 mutations, so the cohort describes the
non-classic ZSD phenotype as PEX1 disease mostly draws it. Nothing here
establishes that a PEX5 patient's phenotype is identical to a PEX1 patient's,
and if a PEX5-specific series is ever published these annotations should be
re-derived from it rather than left in place.
Rhizomelic chondrodysplasia punctata type 5 is the same gene and is
intentionally not modelled as a subtype of this entry. It has separate
OMIM/MONDO identity, an isoform-specific allele, and a PTS2-selective import
defect that is the mirror image of the PTS1-selective lesion here. It is
curated as its own entry and referenced below as a differential.
PBD2A - classic PEX5 Zellweger syndrome - has no entry in this knowledge base
at the time of writing. It is referenced here as the severe counterpart, and
the R390X patient who anchors that end appears in this entry's evidence,
because the contrast between the two is what defines "2B". Creating the PBD2A
entry is a reasonable follow-on.
No `datasets:` block. A review round asked for one on the ground that the
siblings `Peroxisome_Biogenesis_Disorder_1B` and `_4B` carry one; they carry
`datasets: []`, an empty list, so there is no sibling dataset record to
follow. No PEX5-specific omics dataset was identified, and the standing
warning about dataset relevance applies with unusual force here - a PEX5 gene
search would surface Zellweger-spectrum and peroxisome-biology series that
are about PEX1 disease or about peroxisomes in general, which resolve
perfectly and are not about this entity. An empty list would record no more
than this paragraph does.
On the deep-research report committed with this entry. A falcon report was run
with a disambiguating query naming PEX5, the OMIM number and the
complementation group. `just preflight-dr` returned SKIP rather than PASS,
because MONDO records no causal gene for MONDO:0008736 and so its
gene-identity check has nothing to discriminate on - SKIP means unchecked, not
passed. The manual fallback settles it: the report mentions PEX5 120 times
against 21 for PEX1 and 9 for PEX2, states in its own scope paragraph that it
concerns PEX5-related complementation group 2 and not PEX1- or PEX2-related
disease, and carries OMIM 202370, which matches MONDO's cross-reference. It is
about the right entity.
It independently reached the same framing as this entry - hypomorphic PEX5
alleles with residual import, a severity continuum rather than discrete NALD
and IRD entities, and clinical expectations drawn from general ZSD because
PEX5-isolated data do not exist. It also carries leads this entry does not
curate, recorded here so the next curator does not have to re-derive them: an
early review reporting only two US complementation-group-2 patients, which
corroborates the rarity claim above from a second direction; a 2025 homozygous
PEX5 stop-loss allele that remained an ACMG variant of uncertain significance
for want of functional validation; and Pex5-null mouse and pex5 zebrafish
models that reproduce absent matrix import but resemble severe Zellweger
syndrome rather than this entity - which is why no `animal_models:` block is
curated here. None of these is curated as evidence, because a deep-research
report is a lead.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
PBD2B results from biallelic PEX5 pathogenic variants, with at least one
allele retaining partial receptor function. PEX5 is nuclear-encoded and
autosomal, so the recurrence risk is 25 percent per sibship.
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
ZSD is typically inherited in an autosomal recessive manner
explanation: >-
GeneReviews states the autosomal recessive inheritance of Zellweger
spectrum disorders, of which PBD2B is the PEX5 non-classic end.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
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 figure this block's description states. Previously
asserted in prose without a citation.
- reference: PMID:7719337
reference_title: "Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
The peroxisome biogenesis disorders (PBDs) are lethal recessive diseases
caused by defects in peroxisome assembly.
explanation: >-
The paper that assigned PEX5 to complementation group 2 states the
recessive inheritance of the disorder class. Indirect: a class-level
statement in the paper that defines this entity's gene, not a segregation
analysis in a PBD2B pedigree.
- reference: CGGV:assertion_b49d9cfd-0e51-4219-84bb-76b4c9b99fa9-2020-01-17T170000.000Z
reference_title: "PEX5 / peroxisome biogenesis disorder (Definitive)"
supports: SUPPORT
evidence_source: OTHER
directness: DIRECT
snippet: "PEX5 | HGNC:9719 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
explanation: >-
ClinGen classifies the PEX5-peroxisome biogenesis disorder relationship as
definitive with autosomal recessive inheritance.
pathophysiology:
- name: Hypomorphic PEX5 Variants with Residual PTS1 Receptor Function
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: ESTABLISHED
description: >-
The initiating lesion, and the point at which PBD2B separates from classic
PEX5 Zellweger syndrome. PEX5 mutations define complementation group 2 of
the peroxisome biogenesis disorders, and expressing wild-type PEX5 rescues
the PTS1 import defect in patient fibroblasts - which is what makes the
variants causal rather than incidental.
The three PEX5 patients analysed together in 1999 span the group's whole
severity range and correlate it with allele type: a nonsense allele (R390X)
in the Zellweger patient, and missense alleles in the two non-classic
patients (N489K in neonatal adrenoleukodystrophy, S563W in infantile Refsum
disease). PBD2B is the missense, residual-function half of that picture.
genes:
- preferred_term: PEX5
term:
id: hgnc:9719
label: PEX5
genetic_context:
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
variant_origin: GERMLINE
description: >-
Curated as partial rather than complete loss of function on the strength
of the measured import phenotypes: the non-classic alleles retain
demonstrable PTS1 or PTS2 receptor activity in patient fibroblasts, where
the nonsense allele associated with classic Zellweger syndrome does not.
This is the slot's intended use - the claim is about the consequence of a
variant, not about the activity level of a pathway.
evidence:
- reference: PMID:7719337
reference_title: "Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Mutations in PXR1 define complementation group 2 of PBDs and expression of
PXR1 rescues the PTS1 import defect of fibroblasts from these patients.
explanation: >-
Assigns PEX5 (then PXR1) to complementation group 2 and establishes
causality by complementation in patient cells. Graded IN_VITRO because the
quoted finding is a rescue experiment in cultured fibroblasts, and the
same sentence is graded that way wherever it is cited in this file.
- reference: PMID:10462504
reference_title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
The patients 2-01 (Zellweger syndrome) and 2-05 (neonatal
adrenoleukodystrophy) have the reported mutations, R390X and N489K, and
patient 2-03 (infantile Refsum disease) has a newly identified mutation,
S563W.
explanation: >-
Gives the alleles and the clinical diagnosis of each PEX5 patient,
including the two non-classic patients this entry is about.
downstream:
- target: Cargo-Selective Failure of PTS1 Recognition
causal_link_type: DIRECT
- target: Partial Loss of the PEX5L-Dependent PTS2 Arm
causal_link_type: DIRECT
description: >-
Drawn as a separate edge because the two import arms are separably
affected in this disorder - which is the observation that makes the PEX5
gradient interpretable at all.
- target: Temperature-Sensitive Residual Peroxisome Function
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cargo-Selective Failure of PTS1 Recognition
biological_scale: MOLECULAR
role: central_effector
mechanism_confidence: ESTABLISHED
description: >-
The mechanism that is specific to this entity rather than borrowed from the
spectrum. PEX5 recognises matrix enzymes by their C-terminal PTS1 tripeptide,
but real PTS1 signals are not equally good matches. The canonical -SKL of
acyl-CoA oxidase is a strong signal; -AKL (D-bifunctional protein, sterol
carrier protein 2) and -KANL (catalase) are weaker variants.
A mildly damaged receptor therefore fails asymmetrically. In the infantile
Refsum patient's fibroblasts the S563W receptor still imported the -SKL
cargo and had little or no function for -AKL and -KANL. The authors draw the
general conclusion: the poorer PTS1 variants are the ones most susceptible
to a receptor mutation.
Two consequences worth holding on to. First, this predicts that the
biochemical profile of a PBD2B patient should be uneven across peroxisomal
pathways rather than uniformly depressed, because which enzymes reach the
organelle depends on their targeting signals. Second, it means "residual
receptor function" in this disorder is not a single number - two patients
with the same residual import of one reporter could differ in which enzymes
they actually import.
biological_processes:
- preferred_term: protein targeting to peroxisome
modifier: DECREASED
term:
id: GO:0006625
label: protein targeting to peroxisome
evidence:
- reference: PMID:10462504
reference_title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
The PTS1 receptor in 2-03 is functional for only the C-terminal -SKL
sequence (acyl-CoA oxidase) and had little or no function for C-terminal
-AKL (D-bifunctional protein and sterol carrier protein 2) and -KANL
(catalase) sequences, respectively.
explanation: >-
The cargo-selectivity measurement itself, in fibroblasts from the mildest
of the three PEX5 patients.
- reference: PMID:10462504
reference_title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
It seems apparent that -AKL and -KANL are poorer variants of PTS1 and are
likely to be more susceptible to effects of mutation of its receptor,
Pex5p.
explanation: >-
The authors' generalisation, which is what turns a single-patient
observation into a mechanism for graded severity in PEX5 disease.
downstream:
- target: Partial Peroxisomal Matrix Protein Import Failure
causal_link_type: DIRECT
- name: Partial Loss of the PEX5L-Dependent PTS2 Arm
biological_scale: MOLECULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
PEX5 is transcribed as two isoforms. The long one, PEX5L, carries an extra
internal exon and additionally acts as the co-receptor through which PEX7
delivers PTS2-tagged cargo; the short one does PTS1 import only.
Transfection experiments separate the two arms cleanly: PEX5S restores PTS1
import but not PTS2 import, PEX5L restores both.
That architecture is why a PEX5 patient's PTS2 arm may or may not be
involved, and the involvement tracks severity. The Zellweger patient's
nonsense allele lost both arms; the neonatal adrenoleukodystrophy patient's
N489K receptor was severely defective in PTS1 import with PTS2 import
preserved; the infantile Refsum patient retained function on both. So in
PBD2B the PTS2 arm is *relatively* spared, and that sparing is part of why
the disease is milder.
A caution against over-reading this. It rests on three patients, one per
phenotype, and the alleles differ in kind as well as in position - so the
correlation between "how many arms fail" and "how severe the disease" is a
pattern across three points, not a demonstrated dose-response.
biological_processes:
- preferred_term: protein import into peroxisome matrix
modifier: DECREASED
term:
id: GO:0016558
label: protein import into peroxisome matrix
evidence:
- reference: PMID:9668159
reference_title: "An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes."
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Transfection of PBD005 cells with PEX5S cDNA restores PTS1 but not PTS2
import; transfection with PXR5L cDNA restores both PTS1 and PTS2 protein
import.
explanation: >-
The isoform-swap experiment that assigns the PTS2 arm specifically to
PEX5L.
- reference: PMID:9668159
reference_title: "An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes."
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Taken together, these data provide an explanation for the different
protein import defects in CG2 patients and show that the long isoform of
the Pex5 protein is required for peroxisomal import of PTS2 proteins.
explanation: >-
States the point exactly: the isoform architecture is what explains why
complementation group 2 patients differ in which arms fail.
- reference: PMID:10462504
reference_title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Fibroblasts from 2-03 (S563W) were detected in both PTS1 and PTS2 imports
despite the PEX5 defect, findings in contrast with fibroblasts from 2-05
(N489K) severely defective in PTS1 import and those from 2-01 (R390X)
severely defective in both PTS1 and PTS2.
explanation: >-
The per-patient import phenotypes, which is what lets the two non-classic
patients be distinguished from the Zellweger one at the cellular level.
downstream:
- target: Partial Peroxisomal Matrix Protein Import Failure
causal_link_type: DIRECT
- name: Temperature-Sensitive Residual Peroxisome Function
biological_scale: CELLULAR
role: modulator
mechanism_confidence: PROVISIONAL
description: >-
A property of the mild end of the peroxisome biogenesis disorders generally,
recorded here because it is the clearest available demonstration that a
non-classic phenotype reflects a conformationally marginal peroxin rather
than a missing one: in cells from patients with mild phenotypes, peroxisomal
biogenesis and metabolic function are restored by culturing at 30 degrees C.
Marked PROVISIONAL, and the reason is specific rather than generic. The
source states the phenomenon for PBD mild phenotypes as a class, and this
knowledge base's PEX1 entry carries the equivalent observation for the
G843D allele directly. Nothing cited here shows temperature rescue in a
PEX5 patient's cells. The node is curated because it is the mechanistic
basis on which "residual function" is claimed for non-classic alleles across
this spectrum, and because it is a directly testable prediction for PBD2B
fibroblasts, not because it has been tested in them.
evidence:
- reference: PMID:11405337
reference_title: "Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
Temperature-sensitivity, whereby peroxisomal biogenesis and metabolic
dysfunctions are restored at 30 degrees C in cells from mild phenotypes,
is a useful event for predicting the clinical severity and for elucidation
of peroxisome biogenesis.
explanation: >-
Establishes temperature-sensitive residual function as the cellular
signature of the mild PBD phenotypes. Indirect: a statement about the PBD
class, with no PEX5 cell line named.
downstream:
- target: Partial Peroxisomal Matrix Protein Import Failure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A modulating rather than a causal edge: residual thermolabile function is
what leaves the import defect partial instead of complete.
- name: Partial Peroxisomal Matrix Protein Import Failure
biological_scale: CELLULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The cellular endpoint of the receptor lesion: peroxisomes are present but
incompletely loaded, because a subset of matrix enzymes never reaches them.
This is the step at which PBD2B rejoins the rest of the Zellweger spectrum -
PBD1B and PBD4B arrive at the same place by failing to recycle the receptor
rather than by failing to recognise the cargo.
Its partial character is what the entry turns on. Complementation restores
the import defect, which fixes causality; the residual import that remains
in the untreated cells is what separates a non-classic phenotype from
classic Zellweger syndrome.
biological_processes:
- preferred_term: protein import into peroxisome matrix
modifier: DECREASED
term:
id: GO:0016558
label: protein import into peroxisome matrix
evidence:
- reference: PMID:7719337
reference_title: "Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Mutations in PXR1 define complementation group 2 of PBDs and expression of
PXR1 rescues the PTS1 import defect of fibroblasts from these patients.
explanation: >-
Documents the import defect in patient fibroblasts and its correction by
the wild-type receptor.
- reference: PMID:7719337
reference_title: "Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
PXR1, like PAS8, encodes a receptor for proteins with the type-1
peroxisomal targeting signal (PTS1).
explanation: >-
Establishes what the gene product does, which is what makes an import
failure the expected consequence of losing it. Indirect: it states the
normal function rather than the disease state.
downstream:
- target: Attenuated Peroxisomal Metabolic Block
causal_link_type: DIRECT
- name: Attenuated Peroxisomal Metabolic Block
biological_scale: ORGANISM
role: effector
mechanism_confidence: PROVISIONAL
description: >-
Peroxisomes are essential for beta-oxidation of fatty acids, for ether-lipid
(plasmalogen) synthesis and for redox homeostasis, so incompletely loaded
peroxisomes produce a metabolic block across all of these. In the
non-classic phenotypes that block is attenuated rather than complete, which
is why the disease is degenerative over years instead of lethal in infancy.
Marked PROVISIONAL for this entity specifically. The metabolic consequences
of peroxisomal import failure are not in doubt, and they are curated in
detail on the Zellweger Spectrum Disorders entry; what is not established
here is the *quantitative* profile in a PEX5 non-classic patient. The
cargo-selectivity result upstream predicts that the profile should be
uneven - catalase and D-bifunctional protein import failing before acyl-CoA
oxidase import does - and no one has measured that in a PBD2B patient.
biological_processes:
- preferred_term: fatty acid beta-oxidation
modifier: DECREASED
term:
id: GO:0006635
label: fatty acid beta-oxidation
- preferred_term: ether lipid biosynthetic process
modifier: DECREASED
term:
id: GO:0008611
label: ether lipid biosynthetic process
evidence:
- reference: PMID:35917894
reference_title: Molecular insights into peroxisome homeostasis and peroxisome biogenesis disorders.
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: >-
Peroxisomes are single-membrane organelles essential for cell metabolism
including the β-oxidation of fatty acids, synthesis of etherlipid
plasmalogens, and redox homeostasis.
explanation: >-
States the metabolic functions lost when matrix enzymes fail to reach the
organelle. Indirect: a statement of normal peroxisome biology, not a
measurement in a PBD2B patient.
downstream:
- target: Progressive Degenerative Multisystem Disease
causal_link_type: DIRECT
- name: Progressive Degenerative Multisystem Disease
biological_scale: ORGANISM
role: effector
mechanism_confidence: PROVISIONAL
description: >-
The clinical endpoint, and the node at which this entry is at its most
borrowed. The non-classic Zellweger spectrum phenotype is degenerative
rather than malformative: these patients do not have the congenital
malformations of classic Zellweger syndrome, and instead accumulate sensory
loss, neurological involvement, liver dysfunction, adrenal insufficiency and
renal oxalate stones over years.
PROVISIONAL because the evidence for it is gene-agnostic. GeneReviews
describes intermediate/milder ZSD across all thirteen ZSD-PEX genes, and the
prolonged-survival cohort that supplies the "common to all patients"
findings was 21/31 PEX1. No PEX5-specific clinical series exists. The
phenotypes below inherit that limitation and each is marked INDIRECT.
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Individuals with intermediate/milder ZSD do not have congenital
malformations, but rather progressive peroxisome dysfunction variably
manifest as sensory loss (secondary to retinal dystrophy and sensorineural
hearing loss), neurologic involvement (ataxia, polyneuropathy, and
leukodystrophy), liver dysfunction, adrenal insufficiency, and renal
oxalate stones.
explanation: >-
The non-classic ZSD phenotype in one sentence. Indirect for PBD2B: it
describes the intermediate/milder end of the spectrum across all ZSD-PEX
genes, not PEX5 patients specifically.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
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: >-
The sources' own licence for describing this entity's clinical picture at
spectrum level: the clinical nosology is deliberately gene-agnostic. It
justifies the import; it does not make it PEX5-specific.
downstream:
- target: Hypotonia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Global Developmental Delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Retinal Dystrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Sensorineural Hearing Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Ataxia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Polyneuropathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Leukodystrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Hepatic Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Adrenal Insufficiency
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Hyperoxaluria
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Amelogenesis Imperfecta
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Osteopenia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Postnatal Growth Failure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Hypotonia
category: Neurologic
description: >-
Typical across the Zellweger spectrum including the non-classic end, and
usually the presenting sign. No frequency band: the source is a qualitative
class-level statement, not a counted series, and there is no PEX5-specific
denominator to compute one from.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
While hypotonia and developmental delays are typical, intellect can be
normal.
explanation: >-
Hypotonia in intermediate/milder ZSD. Indirect: gene-agnostic across the
thirteen ZSD-PEX genes.
- name: Global Developmental Delay
category: Neurologic
description: >-
Typical, but explicitly not universal in outcome: the same GeneReviews
sentence that reports developmental delay adds that intellect can be normal,
and the prolonged-survival cohort found speech ranging from non-verbal to
grammatical speech and comprehensive reading. Both facts belong in a
counselling conversation, and quoting only the first would misrepresent the
range.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
While hypotonia and developmental delays are typical, intellect can be
normal.
explanation: >-
Developmental delay in intermediate/milder ZSD, together with the caveat
that cognitive outcome varies. Indirect: gene-agnostic.
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Common to all patients were cognitive and motor dysfunction, retinopathy,
sensorineural hearing impairment, and hepatic involvement.
explanation: >-
Cognitive dysfunction in every patient of a prolonged-survival PBD cohort.
Indirect: 21 of the 31 patients had PEX1 mutations, so this describes the
non-classic phenotype as PEX1 disease mostly draws it.
- name: Retinal Dystrophy
category: Ophthalmologic
description: >-
Progressive retinal dystrophy is one of the two sensory manifestations that
define the non-classic Zellweger spectrum phenotype, and it was present in
every patient of the prolonged-survival cohort.
phenotype_term:
preferred_term: Retinal dystrophy
term:
id: HP:0000556
label: Retinal dystrophy
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
progressive peroxisome dysfunction variably manifest as sensory loss
(secondary to retinal dystrophy and sensorineural hearing loss)
explanation: >-
Attributes sensory loss in intermediate/milder ZSD to retinal dystrophy.
Indirect: gene-agnostic.
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Common to all patients were cognitive and motor dysfunction, retinopathy,
sensorineural hearing impairment, and hepatic involvement.
explanation: >-
Retinopathy in all 31 patients of a prolonged-survival cohort. Indirect:
PEX1-dominated.
- name: Sensorineural Hearing Loss
category: Auditory
description: >-
The second defining sensory manifestation of the non-classic phenotype, and
likewise universal in the prolonged-survival cohort.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Common to all patients were cognitive and motor dysfunction, retinopathy,
sensorineural hearing impairment, and hepatic involvement.
explanation: >-
Sensorineural hearing impairment in all 31 patients. Indirect:
PEX1-dominated cohort.
- name: Ataxia
category: Neurologic
description: >-
One of the three neurological manifestations GeneReviews names for
intermediate/milder ZSD, alongside polyneuropathy and leukodystrophy.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Individuals with intermediate/milder ZSD do not have congenital
malformations, but rather progressive peroxisome dysfunction variably
manifest as sensory loss (secondary to retinal dystrophy and sensorineural
hearing loss), neurologic involvement (ataxia, polyneuropathy, and
leukodystrophy), liver dysfunction, adrenal insufficiency, and renal
oxalate stones.
explanation: >-
Ataxia among the neurologic features of intermediate/milder ZSD.
Indirect: gene-agnostic.
- name: Polyneuropathy
category: Neurologic
description: >-
Peripheral nerve involvement in the non-classic phenotype, named by
GeneReviews alongside ataxia and leukodystrophy.
phenotype_term:
preferred_term: Polyneuropathy
term:
id: HP:0001271
label: Polyneuropathy
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Individuals with intermediate/milder ZSD do not have congenital
malformations, but rather progressive peroxisome dysfunction variably
manifest as sensory loss (secondary to retinal dystrophy and sensorineural
hearing loss), neurologic involvement (ataxia, polyneuropathy, and
leukodystrophy), liver dysfunction, adrenal insufficiency, and renal
oxalate stones.
explanation: >-
Polyneuropathy among the neurologic features of intermediate/milder ZSD.
Indirect: gene-agnostic.
- name: Leukodystrophy
category: Neurologic
description: >-
White-matter disease is the feature that gave neonatal adrenoleukodystrophy
- the historical name for this entity's severe half - its name. It is one of
the neurologic manifestations of intermediate/milder ZSD, and in the
prolonged-survival cohort it was one of the recognised outcome profiles
rather than a universal finding.
phenotype_term:
preferred_term: Leukodystrophy
term:
id: HP:0002415
label: Leukodystrophy
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Individuals with intermediate/milder ZSD do not have congenital
malformations, but rather progressive peroxisome dysfunction variably
manifest as sensory loss (secondary to retinal dystrophy and sensorineural
hearing loss), neurologic involvement (ataxia, polyneuropathy, and
leukodystrophy), liver dysfunction, adrenal insufficiency, and renal
oxalate stones.
explanation: >-
Leukodystrophy among the neurologic features of intermediate/milder ZSD.
Indirect: gene-agnostic.
- name: Hepatic Dysfunction
category: Hepatic
description: >-
Liver involvement was present in every patient of the prolonged-survival
cohort and is named by GeneReviews as part of the non-classic phenotype.
phenotype_term:
preferred_term: Decreased liver function
term:
id: HP:0001410
label: Decreased liver function
evidence:
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Common to all patients were cognitive and motor dysfunction, retinopathy,
sensorineural hearing impairment, and hepatic involvement.
explanation: >-
Hepatic involvement in all 31 patients. Indirect: PEX1-dominated cohort.
- name: Adrenal Insufficiency
category: Endocrine
description: >-
Adrenal failure is part of the non-classic ZSD picture and is the reason the
historical name for this phenotype carried "adrenoleukodystrophy". It is
treatable, which is why it is worth surveillance rather than merely
recording.
phenotype_term:
preferred_term: Adrenal insufficiency
term:
id: HP:0000846
label: Adrenal insufficiency
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Individuals with intermediate/milder ZSD do not have congenital
malformations, but rather progressive peroxisome dysfunction variably
manifest as sensory loss (secondary to retinal dystrophy and sensorineural
hearing loss), neurologic involvement (ataxia, polyneuropathy, and
leukodystrophy), liver dysfunction, adrenal insufficiency, and renal
oxalate stones.
explanation: >-
Adrenal insufficiency among the features of intermediate/milder ZSD.
Indirect: gene-agnostic.
- name: Hyperoxaluria
category: Renal
description: >-
Peroxisomal alanine-glyoxylate aminotransferase is a PTS1 cargo, so a PTS1
receptor defect is a mechanistically apt cause of hyperoxaluria - but note
that connection is stated here as reasoning, not as something the cited
sources measured in a PBD2B patient. What they report is the association:
renal oxalate stones in intermediate/milder ZSD, and hyperoxaluria in 10 of
31 prolonged-survival patients, 4 of whom had stones.
phenotype_term:
preferred_term: Hyperoxaluria
term:
id: HP:0003159
label: Hyperoxaluria
evidence:
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Many patients showed postnatal growth failure, 10 patients displayed
hyperoxaluria of whom 4 had renal stones.
explanation: >-
Counted hyperoxaluria in a prolonged-survival PBD cohort. Indirect:
PEX1-dominated, so the 10/31 is not a PBD2B frequency and no band is
recorded from it.
sequelae:
- target: Nephrolithiasis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Stone formation is downstream of the oxalate load rather than a parallel
manifestation: the intermediates - urinary calcium oxalate supersaturation
and crystal nucleation - are known renal physiology, and are omitted from
the graph rather than unknown. The cited cohort reports the stones inside
the hyperoxaluric subgroup, and GeneReviews names them oxalate stones.
- name: Amelogenesis Imperfecta
category: Dental
description: >-
Defective enamel in the secondary teeth is near-universal in the non-classic
phenotype and is one of the few features distinctive enough to raise the
diagnosis in an older child who has been carried as "cerebral palsy" or
"syndromic hearing loss".
phenotype_term:
preferred_term: Amelogenesis imperfecta
term:
id: HP:0000705
label: Amelogenesis imperfecta
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
almost all have ameleogenesis imperfecta in the secondary teeth
explanation: >-
Near-universal amelogenesis imperfecta in intermediate/milder ZSD.
Indirect: gene-agnostic. The source's spelling of the term is retained in
the quote.
- name: Osteopenia
category: Skeletal
description: >-
Reduced bone density occurs in part of the non-classic Zellweger spectrum
population - GeneReviews says "some", without a proportion, so no frequency
band is recorded. It is curated because it is one of the manifestations
GeneReviews attaches a specific management recommendation to, and because
it sits in the same sentence as the amelogenesis imperfecta this entry
already curates.
The mechanism is not established here. Reduced mobility, fat-soluble
vitamin malabsorption from bile-acid deficiency, and chronic liver disease
are all plausible contributors in this population, and none of the cited
sources attributes the bone loss to any of them, so the edge from the
clinical node is left as unknown intermediates.
phenotype_term:
preferred_term: Osteopenia
term:
id: HP:0000938
label: Osteopenia
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Some have osteopenia; almost all have ameleogenesis imperfecta in the
secondary teeth.
explanation: >-
Osteopenia in part of the intermediate/milder ZSD population. Indirect:
gene-agnostic, describing the whole ZSD-PEX spectrum rather than PEX5
patients.
- name: Postnatal Growth Failure
category: Growth
description: >-
Growth deficiency emerging after birth, reported in many patients in the
prolonged-survival cohort. It matters clinically because it is the
manifestation gastrostomy feeding addresses, and because - unlike the
congenital growth deficiency of classic Zellweger syndrome - it is
consistent with the postnatal, degenerative character of this end of the
spectrum.
No frequency band: the source says "many" without a count, and the cohort
is PEX1-dominated.
notes: >-
Bound to HP:0008897 (Postnatal growth retardation) rather than to
HP:0001508 (Failure to thrive), which the sibling entry
Peroxisome_Biogenesis_Disorder_1B uses for the same source sentence.
HP:0008897 is the literal match for what the source says - growth
deficiency apparent after birth - whereas failure to thrive carries a
weight-gain and feeding connotation the cited sentence does not make. The
divergence from the sibling is deliberate and recorded here rather than
silently introduced.
phenotype_term:
preferred_term: Postnatal growth failure
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Many patients showed postnatal growth failure, 10 patients displayed
hyperoxaluria of whom 4 had renal stones.
explanation: >-
Postnatal growth failure in the prolonged-survival PBD cohort. Indirect:
21 of the 31 patients had PEX1 mutations, so this is not a PBD2B
observation and no band is recorded from it.
- name: Nephrolithiasis
category: Renal
description: >-
Renal oxalate stones, the clinical consequence of the hyperoxaluria curated
above. In the prolonged-survival cohort 4 of the 10 hyperoxaluric patients
had stones; GeneReviews lists renal oxalate stones among the
intermediate/milder ZSD manifestations, and attaches both a surveillance
schedule and a supportive treatment to them. Curated separately from
hyperoxaluria because the two need different clinical actions - a urine
ratio for one, hydration and lithotripsy for the other.
phenotype_term:
preferred_term: Nephrolithiasis
term:
id: HP:0000787
label: Nephrolithiasis
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
liver dysfunction, adrenal insufficiency, and renal oxalate stones
explanation: >-
Renal oxalate stones among the intermediate/milder ZSD manifestations.
Indirect: gene-agnostic across the ZSD-PEX genes.
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Many patients showed postnatal growth failure, 10 patients displayed
hyperoxaluria of whom 4 had renal stones.
explanation: >-
Stones in 4 of the 10 hyperoxaluric patients in the prolonged-survival
cohort. Indirect: PEX1-dominated, and 4/31 is not a PBD2B frequency.
genetic:
- name: PEX5
gene_term:
preferred_term: PEX5
term:
id: hgnc:9719
label: PEX5
relationship_type: CAUSATIVE
variant_origin: GERMLINE
presence: PRESENT
notes: >-
PEX5 encodes the cytosolic PTS1 receptor and defines complementation group 2
of the peroxisome biogenesis disorders. ClinGen classifies the gene-disease
relationship as definitive with autosomal recessive inheritance.
Three alleles anchor the severity range and are quoted on the evidence items
in this entry: R390X (nonsense) in classic Zellweger syndrome, N489K
(missense) in neonatal adrenoleukodystrophy, and S563W (missense) in
infantile Refsum disease. The two missense alleles are the PBD2B end.
Two things a curator adding PEX5 variants here needs to know. First, the
isoform matters: an allele in the long-isoform-specific exon 9 does not give
Zellweger spectrum disease at all - it gives rhizomelic chondrodysplasia
punctata type 5, curated separately, by knocking out the PTS2 arm while
sparing PTS1. Second, residue numbering in the PEX5 literature is reported
against both isoforms, and the older Chinese hamster work states its
positions in both (for example Gly485Glu of the short isoform is G522E of
the long one). Check which isoform a paper is numbering against before
matching an allele.
PEX5 is a rare cause within the peroxisome biogenesis disorders. In a
14-patient Iranian series, PEX1 accounted for five patients and PEX5 for
one - a proportion consistent with the older complementation-group data, in
which group 1 (PEX1) dominates.
evidence:
- reference: CGGV:assertion_b49d9cfd-0e51-4219-84bb-76b4c9b99fa9-2020-01-17T170000.000Z
reference_title: "PEX5 / peroxisome biogenesis disorder (Definitive)"
supports: SUPPORT
evidence_source: OTHER
directness: DIRECT
snippet: "PEX5 | HGNC:9719 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
explanation: >-
ClinGen's definitive gene-disease validity assertion for PEX5.
- reference: PMID:9668159
reference_title: "An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Mutations in the peroxisome targeting signal (PTS) 1 receptor gene, PEX5 ,
are responsible for complementation group (CG) 2 of the peroxisome
biogenesis disorders (PBD).
explanation: >-
States the gene-to-complementation-group assignment that this entry's
identity rests on.
- reference: PMID:40205409
reference_title: "Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the Iranian population: a case series study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
PEX1 variants were detected in five patients. PEX2, PEX5, PEX6 and PEX7
variants were detected in three, one, one, and two cases, respectively.
explanation: >-
Shows PEX5 as an uncommon cause relative to PEX1 in a contemporary
peroxisomal-disorder series. Indirect: a 14-patient single-country series
spanning the whole Zellweger spectrum, not a PBD2B denominator.
biochemical:
- name: Peroxisomal Matrix Protein Import in Patient Fibroblasts
notes: >-
The assay that defines this entity at the cellular level, and the one that
distinguishes PBD2B from PBD2A. Import of PTS1 and PTS2 reporters is scored
separately in cultured fibroblasts, and complementation with wild-type PEX5
is what establishes that a candidate variant is causal.
Two refinements specific to PEX5 disease. First, the PTS1 arm should not be
scored with a single reporter: the cargo-selectivity result means a receptor
can import a -SKL protein normally while failing -AKL and -KANL proteins, so
a normal acyl-CoA oxidase import does not exclude the disorder. Second, PTS2
import status is informative rather than redundant - in the three
characterised patients it separated the Zellweger allele, which lost both
arms, from the non-classic alleles.
Temperature is the third variable. Culturing mild-phenotype PBD fibroblasts
at 30 degrees C restores peroxisomal biogenesis and metabolic function,
which is both a severity predictor and a way of demonstrating that residual
peroxin function exists. It has not been reported in a PEX5 patient's cells;
see the pathophysiology node of that name.
evidence:
- reference: PMID:10462504
reference_title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
we analyzed peroxisome matrix protein import in fibroblasts from three
patients with peroxisome biogenesis disorders, all with different
mutations in the PEX5 gene
explanation: >-
Describes the assay and the material - patient fibroblasts - on which this
entity's cellular characterisation rests.
- name: Very-long-chain fatty acids
presence: Increased
context: >-
Plasma C26:0 and the C26:0/C22:0 ratio are the first-line biochemical screen
that brings a child with a suggestive phenotype to ZSD-PEX sequencing. The
caveat matters more at this end of the spectrum than at the classic end: in
the mildest individuals the elevation can be modest, so a borderline result
does not exclude the diagnosis.
biomarker_term:
preferred_term: very long-chain fatty acid
term:
id: CHEBI:27283
label: very long-chain fatty acid
readouts:
- target: Attenuated Peroxisomal Metabolic Block
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Accumulating very-long-chain fatty acids report the residual peroxisomal
beta-oxidation block - the "attenuated" part of that node is what makes
the elevation modest rather than absent.
evidence:
- reference: PMID:28677031
reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
C26:0-lysoPC in DBS is a sensitive and useful marker for VLCFA
accumulation in patients with a ZSD.
explanation: >-
Establishes the measured analyte as a readout of very-long-chain fatty
acid accumulation from the peroxisomal block. Indirect for PBD2B: the
cohort is Zellweger spectrum at large, not PEX5 patients.
evidence:
- reference: PMID:28677031
reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Zellweger spectrum disorders (ZSD) are a group of genetic metabolic
disorders caused by a defect in peroxisome biogenesis. This results in
multiple metabolic abnormalities, including elevated very long-chain fatty
acid (VLCFA) levels.
explanation: >-
Very-long-chain fatty acid elevation as the metabolic consequence of the
peroxisome biogenesis defect. Indirect: stated for the spectrum, not for
PEX5 disease specifically.
- name: C26:0-lysophosphatidylcholine
presence: Increased
context: >-
C26:0-lysoPC in dried blood spots is the sensitive VLCFA marker, at 89
percent sensitivity across 91 ZSD blood spots, and is the assay that makes
newborn screening for Zellweger spectrum disease technically plausible.
Whether it would catch this end of the spectrum is a separate question the
cited study does not answer: sensitivity was measured across ZSD as a whole,
and five of the 91 spots were not elevated.
readouts:
- target: Attenuated Peroxisomal Metabolic Block
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Elevated dried-blood-spot C26:0-lysoPC reports the peroxisomal
beta-oxidation block.
evidence:
- reference: PMID:28677031
reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Elevated C26:0-lysoPC levels (>72 nmol/L) were found in 86/91 ZSD DBS
explanation: >-
Quantifies the performance of this readout against the block it
reports. Indirect: a spectrum-wide cohort.
evidence:
- reference: PMID:28677031
reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Implementation of C26:0-lysoPC measurement in the diagnostic work-up when
suspecting a ZSD is advised.
explanation: >-
The authors' recommendation placing this analyte in the diagnostic
work-up. Indirect: spectrum-level, not PEX5-specific.
diagnosis:
- name: Biochemical Screening Followed by ZSD-PEX Gene Sequencing
description: >-
The diagnosis is established by biallelic pathogenic variants in one of the
thirteen ZSD-PEX genes in a proband with suggestive clinical and biochemical
findings. In practice a raised very-long-chain fatty acid profile brings the
patient to genetic testing, and a panel or exome then identifies the gene;
PEX5 is one of the rarer answers, so it is found by broad sequencing rather
than by being suspected.
The non-classic phenotype is the one that gets missed. These children have
no congenital malformations, so a child with progressive hearing and vision
loss, ataxia and abnormal enamel may be carried for years under another
label before a peroxisomal screen is sent.
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
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' diagnostic criterion, which applies to PBD2B as a ZSD-PEX
gene disorder.
- reference: PMID:28677031
reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Implementation of C26:0-lysoPC measurement in the diagnostic work-up when
suspecting a ZSD is advised.
explanation: >-
Backs the first half of this entry's diagnostic route - that a
very-long-chain fatty acid abnormality is what brings the patient to
ZSD-PEX sequencing - which was previously asserted in the description
without a citation. Indirect: the recommendation is for ZSD as a whole.
- name: Import-Arm Phenotyping to Interpret a Novel PEX5 Variant
description: >-
Because so few pathogenic PEX5 alleles have been reported, a new PEX5
variant found in a patient with a peroxisomal phenotype will usually be one
of uncertain significance. Fibroblast import phenotyping is the assay with
the most PEX5-specific precedent: scoring PTS1 and PTS2 import separately,
and scoring PTS1 import with more than one cargo, distinguishes the classic
from the non-classic pattern and would separate a Zellweger-spectrum allele
from an RCDP5-type isoform allele.
evidence:
- reference: PMID:10462504
reference_title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Fibroblasts from 2-03 (S563W) were detected in both PTS1 and PTS2 imports
despite the PEX5 defect, findings in contrast with fibroblasts from 2-05
(N489K) severely defective in PTS1 import and those from 2-01 (R390X)
severely defective in both PTS1 and PTS2.
explanation: >-
The worked example of import-arm phenotyping separating three PEX5
genotypes.
treatments:
- name: Symptomatic and Supportive Management
description: >-
There is no treatment that restores peroxisomal import. Management of the
non-classic Zellweger spectrum is symptomatic and organ-directed, and
several of its components matter because the manifestations they address are
themselves treatable: hearing aids, cataract removal and refractive
correction, fat-soluble vitamin supplementation, cholic acid, gastrostomy
for caloric intake, adrenal replacement, vitamin D with consideration of
bisphosphonates for osteopenia, dental care for the amelogenesis
imperfecta, and hydration, lithotripsy or surgery for renal oxalate
stones.
Curated as one treatment rather than split into a dozen, because the source
presents it as one management approach and splitting it would create
treatment entries with no evidence of their own.
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: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
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 recommendation for Zellweger spectrum disorder.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
vitamin D supplementation and consideration of bisphosphonates for
osteopenia
explanation: >-
The bone arm of the same management recommendation, which is why
osteopenia is curated as a phenotype here rather than left out.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Supportive treatment for renal oxalate stones has included hydration,
lithotripsy, and surgical intervention.
explanation: >-
The renal-stone arm of the same management recommendation.
target_mechanisms:
- target: Progressive Degenerative Multisystem Disease
description: >-
Supportive management acts on the clinical consequences and not on any
step upstream of them. The edge is drawn to the clinical node deliberately:
nothing in this treatment touches the import defect, and drawing it to a
molecular node would assert a disease-modifying effect that does not exist.
- name: Scheduled Multisystem Surveillance
action_category: MONITORING
description: >-
GeneReviews gives surveillance its own labelled sub-section, separate from
treatment of manifestations, and the distinction is worth keeping: the
manifestations that most reward early detection here - adrenal
insufficiency, hyperoxaluria, hearing and vision loss - are the ones with
treatments that work, and they are progressive rather than present at
diagnosis. So the schedule is what converts a treatable complication into a
treated one.
Annual audiology and ophthalmology; annual liver function, coagulation
factors and hepatic imaging; ACTH and cortisol by age one year and annually
thereafter; annual urine oxalate-to-creatinine ratio with kidney imaging
taken alongside liver imaging; six-monthly dental examination; growth and
nutrition at every visit; and head MRI when cognitive or motor ability
changes.
treatment_term:
preferred_term: scheduled multisystem disease surveillance
notes: >-
No `term:` on the treatment_term. NCIT has no clinical-action term for
scheduled disease surveillance reachable from NCIT:C25218 (Clinical
Intervention or Procedure) - NCIT:C61256 Monitoring is not in that subtree -
so this follows the documented free-text fallback, with the MONITORING
`action_category` carrying the machine-queryable intent. The same
disposition is recorded on the surveillance entry in
MPI-Congenital_Disorder_of_Glycosylation.
No `target_mechanisms:` and no `target_phenotypes:`, because surveillance
detects rather than modifies, and the schema's MONITORING category says
those slots should not be used.
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Annual audiology and ophthalmologic evaluations; annual monitoring of
liver function and coagulation factors, and ultrasound and/or fibroscan to
evaluate liver architecture
explanation: >-
The sensory and hepatic surveillance schedule, covering four of this
entry's curated phenotypes.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
ACTH and cortisol levels by age one year and annually thereafter.
explanation: >-
The adrenal surveillance schedule, for a curated phenotype whose
replacement therapy is effective and whose crisis is avoidable.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Annual urine oxalate-to-creatinine ratio with consideration of kidney
imaging when performing liver imaging.
explanation: >-
The renal surveillance schedule, which is the monitoring arm of the
hyperoxaluria-to-nephrolithiasis edge curated in the phenotypes.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Dental examinations every six months.
explanation: >-
The dental surveillance schedule, for the near-universal amelogenesis
imperfecta.
prevalence:
- population: Reported patients
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
PEX5 is one of the rarest causes of Zellweger spectrum disease. The
complementation-group literature describes group 2 with a handful of
patients, three of whom carry the characterised alleles cited in this entry,
and a contemporary 14-patient Iranian peroxisomal series found one PEX5
patient against five with PEX1.
No population estimate exists for PBD2B, and none should be constructed from
those numbers: both are ascertainment series, not denominators, and neither
separates the "A" from the "B" end. Zellweger spectrum disorder as a whole
is the denominator a reader will want, and it is curated on that entry.
evidence:
- reference: PMID:40205409
reference_title: "Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the Iranian population: a case series study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
PEX1 variants were detected in five patients. PEX2, PEX5, PEX6 and PEX7
variants were detected in three, one, one, and two cases, respectively.
explanation: >-
The relative rarity of PEX5 within a peroxisomal-disorder series.
Indirect: 14 patients in one country, spanning the whole spectrum.
differential_diagnoses:
- name: Peroxisome biogenesis disorder 2A (classic PEX5 Zellweger syndrome)
description: >-
The same gene and the severe end of the same allelic series. The distinction
is not clinical in the first instance but developmental: classic Zellweger
syndrome has congenital malformations - neuronal migration defects, renal
cysts, bony stippling - and death usually in the first year, whereas the
non-classic phenotype has none of those and is degenerative over years. At
the cellular level the R390X Zellweger allele lost both import arms while
the non-classic alleles did not.
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Infants with severe ZSD are significantly impaired and typically die
during the first year of life, usually having made no developmental
progress.
explanation: >-
The severe-end outcome that separates PBD2A from PBD2B.
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
There is clinical, biochemical, and genetic overlap among the three
phenotypes, also known as Zellweger spectrum disorders. Clinical
distinctions between the phenotypes are not sharply defined.
explanation: >-
The caution that goes with this differential: the A/B boundary is a
convention on a continuum, not a sharp line.
- name: Rhizomelic chondrodysplasia punctata type 5
description: >-
The other PEX5 disease, and the reason a PEX5 variant cannot be interpreted
without knowing which isoform it hits. RCDP5 is caused by an allele in the
long-isoform-specific exon, which removes the PTS2 co-receptor function
while leaving PTS1 import intact - the mirror image of the lesion in this
entry. It is curated separately in this knowledge base and presents as
rhizomelic chondrodysplasia punctata, not as Zellweger spectrum disease.
evidence:
- reference: PMID:9668159
reference_title: "An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes."
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
Taken together, these data provide an explanation for the different
protein import defects in CG2 patients and show that the long isoform of
the Pex5 protein is required for peroxisomal import of PTS2 proteins.
explanation: >-
Establishes the isoform architecture that makes an isolated PTS2 defect
possible from a PEX5 allele. Indirect for the differential itself: this
paper predates RCDP5 and is cited for the mechanism, not the entity.
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in
PEX5.
explanation: >-
The paper that establishes RCDP5 as a separate PEX5 entity, which is what
makes this a differential rather than a subtype of the present entry.
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
we show that the c.722dupA mutation, located in the PEX5L-specific exon 9,
results in loss of PEX5L only
explanation: >-
The isoform-selectivity result that makes the RCDP5 lesion the mirror
image of this entry's: PEX5L lost, PEX5S and therefore PTS1 import
retained.
- name: Peroxisome biogenesis disorders of other complementation groups
description: >-
PBD2B cannot be separated from PBD1B, PBD4B or the other non-classic PEX
disorders on clinical or biochemical grounds - only by genotype. This
matters more than it usually does, because the largest natural-history
cohort available for the non-classic phenotype is PEX1-dominated, so the
clinical expectations attached to this entry are in substance PEX1-derived.
evidence:
- reference: PMID:15098231
reference_title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
At the molecular level, 21 patients had mutations in the PEX1 gene.
explanation: >-
Quantifies the PEX1 dominance of the cohort that supplies most of the
non-classic natural-history data.
discussions:
- discussion_id: pbd2b_no_pex5_specific_phenotype_series
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does PEX5 non-classic disease differ clinically from PEX1 non-classic
disease, or is the Zellweger spectrum phenotype genuinely gene-independent
at the mild end?
attaches_to:
- "pathophysiology#Progressive Degenerative Multisystem Disease"
- "phenotypes#"
rationale: >-
Every phenotype in this entry is imported from gene-agnostic sources, and
each is marked INDIRECT for that reason. The nosology invites this -
GeneReviews says the term ZSD now covers any ZSD-PEX gene defect regardless
of phenotype - but "the clinical categories do not track genes" is a claim
that was made when almost all the genotyped patients were PEX1, and it has
not been re-tested gene by gene.
There is a specific reason to think PEX5 might differ, and it comes from
this entry's own mechanism. In the export-module disorders PBD1B and PBD4B
the residual function is a reduced *amount* of peroxin, so every cargo is
imported less. In PEX5 disease the residual function is *cargo-selective*:
a mildly damaged receptor imports strong-PTS1 enzymes and not weak-PTS1
ones. Those two lesions should produce different biochemical profiles even
at matched severity, and a different biochemical profile is a plausible
route to a different clinical emphasis.
The gap is narrow and cheap to close: it needs the PEX5 patients in existing
peroxisomal-disease registries pulled out and described together.
proposed_experiments:
- experiment_id: exp_pbd2b_pex5_case_series
name: Assemble a PEX5-specific Zellweger spectrum case series
description: >-
Query peroxisomal-disease registries and diagnostic laboratories for
patients with biallelic PEX5 variants, and describe their phenotypes,
biochemistry and survival alongside genotype, separating the classic from
the non-classic end. Compare against the PEX1 non-classic phenotype from
the existing cohorts.
- experiment_id: exp_pbd2b_cargo_resolved_biochemistry
name: Cargo-resolved peroxisomal biochemistry in PEX5 versus PEX1 patients
description: >-
Measure import and activity of enzymes carrying strong (-SKL) and weak
(-AKL, -KANL) PTS1 signals side by side in fibroblasts from non-classic
PEX5 and non-classic PEX1 patients matched for overall severity. The
prediction from the cargo-selectivity result is an uneven profile in the
PEX5 cells and a uniform one in the PEX1 cells.
- discussion_id: pbd2b_temperature_sensitivity_untested_in_pex5
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Do PEX5 non-classic patient fibroblasts show the temperature-sensitive
rescue that defines residual peroxin function at the mild end of the other
complementation groups?
attaches_to:
- "pathophysiology#Temperature-Sensitive Residual Peroxisome Function"
rationale: >-
Curated as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the
evidence is not absent - it is good evidence from a system whose applicability
to PEX5 is untested. Temperature-sensitive restoration of peroxisomal
biogenesis at 30 degrees C is established for mild-phenotype PBD cells, and
this knowledge base's PEX1 entry carries it for the G843D allele directly.
No source cited here shows it in a PEX5 patient's cells.
It is not a foregone conclusion either way, and that is the point. Thermal
rescue is a folding-stability phenomenon; the PEX5 non-classic lesion, as
characterised, is a *recognition* defect at the cargo interface. A receptor
that misreads a weak targeting signal need not be rescued by lowering the
temperature, so a negative result here would be informative rather than
merely absent.
proposed_experiments:
- experiment_id: exp_pbd2b_thermal_rescue
name: Test 30-degree rescue in PEX5 non-classic fibroblasts
description: >-
Culture fibroblasts carrying the N489K and S563W PEX5 alleles at 30 versus
37 degrees C and score PTS1 import with strong- and weak-signal cargoes,
PTS2 import, and peroxisomal metabolite profiles. Compare against a PEX1
G843D line as the positive control for thermal rescue.
references:
- reference: PMID:7719337
title: "Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders."
- reference: PMID:10462504
title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
- reference: PMID:9668159
title: "An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes."
- reference: PMID:11405337
title: "Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders."
- reference: PMID:20301621
title: Zellweger Spectrum Disorder.
tags:
- GeneReviews
- reference: PMID:15098231
title: "Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients."
- reference: PMID:40205409
title: "Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the Iranian population: a case series study."
- reference: PMID:35917894
title: Molecular insights into peroxisome homeostasis and peroxisome biogenesis disorders.
- reference: PMID:28677031
title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders.
- reference: PMID:26220973
title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
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
Curation level. PBD2B is curated as a distinct entry rather than folded into Zellweger Spectrum Disorders, in parallel with Peroxisome Biogenesis Disorder 1B (PEX1) and 4B (PEX6), because the "A"/"B" split within a PEX complementation group is a mechanistic statement about residual peroxin function rather than a bare severity label, and because the causal gene differs. The gene-agnostic downstream cascade shared by the whole spectrum - loss of peroxisomal beta-oxidation, ether-lipid synthesis and bile acid side-chain shortening, and the resulting multisystem disease - is curated once on the Zellweger Spectrum Disorders entry rather than duplicated here. This entry carries what is PEX5- and non-classic-specific: the receptor rather than the export module as the lesion, and the cargo-selectivity of the residual function. Where the phenotype block comes from, stated plainly because it matters. There is no PEX5-specific clinical series. The three PEX5 patients whose import defects define this entity are labelled with their clinical diagnoses and nothing more; the only PEX5 case in a recent 14-patient Iranian peroxisomal cohort is one row in a table. So the phenotypes here are curated at the level of *intermediate/milder Zellweger spectrum disorder*, from GeneReviews and from a 31-patient prolonged-survival cohort, and every one of them carries `directness: INDIRECT` for that reason. That import is licensed by the sources themselves rather than assumed: GeneReviews states that the term ZSD now refers to all individuals with a defect in one of the ZSD-PEX genes *regardless of phenotype*, and the prolonged-survival cohort states that clinical distinctions between ZS, NALD and IRD are not sharply defined. The nosology is deliberately gene-agnostic on the clinical side. But note the countervailing fact and do not lose it: 21 of the 31 patients in that cohort had PEX1 mutations, so the cohort describes the non-classic ZSD phenotype as PEX1 disease mostly draws it. Nothing here establishes that a PEX5 patient's phenotype is identical to a PEX1 patient's, and if a PEX5-specific series is ever published these annotations should be re-derived from it rather than left in place. Rhizomelic chondrodysplasia punctata type 5 is the same gene and is intentionally not modelled as a subtype of this entry. It has separate OMIM/MONDO identity, an isoform-specific allele, and a PTS2-selective import defect that is the mirror image of the PTS1-selective lesion here. It is curated as its own entry and referenced below as a differential. PBD2A - classic PEX5 Zellweger syndrome - has no entry in this knowledge base at the time of writing. It is referenced here as the severe counterpart, and the R390X patient who anchors that end appears in this entry's evidence, because the contrast between the two is what defines "2B". Creating the PBD2A entry is a reasonable follow-on. No `datasets:` block. A review round asked for one on the ground that the siblings `Peroxisome_Biogenesis_Disorder_1B` and `_4B` carry one; they carry `datasets: []`, an empty list, so there is no sibling dataset record to follow. No PEX5-specific omics dataset was identified, and the standing warning about dataset relevance applies with unusual force here - a PEX5 gene search would surface Zellweger-spectrum and peroxisome-biology series that are about PEX1 disease or about peroxisomes in general, which resolve perfectly and are not about this entity. An empty list would record no more than this paragraph does. On the deep-research report committed with this entry. A falcon report was run with a disambiguating query naming PEX5, the OMIM number and the complementation group. `just preflight-dr` returned SKIP rather than PASS, because MONDO records no causal gene for MONDO:0008736 and so its gene-identity check has nothing to discriminate on - SKIP means unchecked, not passed. The manual fallback settles it: the report mentions PEX5 120 times against 21 for PEX1 and 9 for PEX2, states in its own scope paragraph that it concerns PEX5-related complementation group 2 and not PEX1- or PEX2-related disease, and carries OMIM 202370, which matches MONDO's cross-reference. It is about the right entity. It independently reached the same framing as this entry - hypomorphic PEX5 alleles with residual import, a severity continuum rather than discrete NALD and IRD entities, and clinical expectations drawn from general ZSD because PEX5-isolated data do not exist. It also carries leads this entry does not curate, recorded here so the next curator does not have to re-derive them: an early review reporting only two US complementation-group-2 patients, which corroborates the rarity claim above from a second direction; a 2025 homozygous PEX5 stop-loss allele that remained an ACMG variant of uncertain significance for want of functional validation; and Pex5-null mouse and pex5 zebrafish models that reproduce absent matrix import but resemble severe Zellweger syndrome rather than this entity - which is why no `animal_models:` block is curated here. None of these is curated as evidence, because a deep-research report is a lead.
Create: Peroxisome Biogenesis Disorder 2B (MONDO:0008736, PEX5) · 2026-09-04T21:30:32Z · View source
New standalone Disease entry for PBD2B (OMIM 202370), the non-classic end of the PEX5-related Zellweger spectrum. entry_type decision: DISEASE, not SUBTYPE. The claim issue flagged this as a likely SUBTYPE of kb/disorders/Peroxisome_Biogenesis_Disorder.yaml. That was reasonable a priori and is superseded by what is actually on main: dismech already curates the per-complementation-group non-classic entries as standalone files - Peroxisome_Biogenesis_Disorder_1B (PEX1), 4B (PEX6) and 11B (PEX13) all exist, and 1B's own notes state the reasoning explicitly, that the A/B split within a PEX group is a mechanistic statement about residual peroxin function rather than a severity label, and that the causal gene differs. PBD2B is the direct PEX5 analogue. The general Peroxisome_Biogenesis_Disorder.yaml entry is the gene-agnostic spectrum entry and lists PEX5 in its genetic block; it has no has_subtypes block at all, so there was no subtype slot to fill. MONDO:0008736 is bound as the entry's disease_term, so the stub is deleted. What is PEX5-specific in this entry, as opposed to inherited from the spectrum. The mechanism is: PEX5's residual function in the non-classic alleles is cargo-selective rather than merely reduced. The S563W receptor still imports the canonical -SKL cargo and fails the weaker -AKL and -KANL signals (PMID:10462504). That has no counterpart in PBD1B/PBD4B, where the gradient is set by how much peroxin protein survives, and it generates a testable prediction of an uneven biochemical profile that nobody has measured. The PTS2 arm is modelled separately because PEX5L is the PEX7 co-receptor and the three characterised patients separate on which arms fail. What is borrowed, and marked as such. There is no PEX5-specific clinical series. Every phenotype is curated at the level of intermediate/milder Zellweger spectrum disorder from GeneReviews (PMID:20301621) and a 31-patient prolonged-survival cohort (PMID:15098231), and every one carries directness: INDIRECT. The import is licensed by the sources themselves - GeneReviews states the ZSD term now covers any ZSD-PEX gene defect regardless of phenotype - but the countervailing fact is recorded in notes and in a differential: 21 of the 31 cohort patients had PEX1 mutations, so the clinical expectations attached to this entry are in substance PEX1-derived. A knowledge gap discussion proposes assembling a PEX5-specific series. Evidence: 41/41 snippets verified. No DOI-prefixed citations, so nothing was skipped by prefix. Sources: PMID:7719337 (the 1995 paper assigning PEX5/PXR1 to complementation group 2), PMID:10462504 (the three-patient cargo-selectivity study that is the mechanistic core), PMID:9668159 (PEX5L/PTS2 isoform architecture), PMID:11405337 (temperature sensitivity in mild PBD phenotypes), PMID:20301621 (GeneReviews), PMID:15098231 (prolonged-survival cohort), PMID:40205409 (2025 Iranian series, for PEX5's rarity relative to PEX1), PMID:35917894 (peroxisome functions), and the ClinGen PEX5 definitive assertion. One gate finding fixed during curation: check-snippet-grading caught the PMID:7719337 complementation sentence graded HUMAN_CLINICAL on one node and IN_VITRO on another. It is a rescue experiment in cultured fibroblasts, so both are now IN_VITRO and the explanation says so. Deep research: falcon, disambiguated query naming PEX5, OMIM 202370 and complementation group 2. preflight-dr returned SKIP, not PASS - MONDO records no causal gene for MONDO:0008736 so the gene-identity check cannot discriminate. Manual fallback per the SKIP guidance: PEX5 mentioned 120 times against PEX1 21 and PEX2 9; the report's own scope paragraph states it concerns PEX5 complementation group 2 and not PEX1 or PEX2; report OMIM 202370 matches MONDO. Right entity. The report independently reached the same framing and its extra leads are recorded in notes as uncited leads, including why no animal_models block is curated (Pex5-null mouse and zebrafish models resemble severe Zellweger syndrome, not this entity). Validation: just validate, validate-terms, count-verified-snippets, validate-disorders, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-stubs all pass; whole-KB check-title-snippets, check-snippet-length and check-snippet-grading pass. Pathograph orphan audit: no orphan downstream or target_mechanisms targets, no unwired phenotypes, no isolated nodes.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Peroxisome biogenesis disorder 2B, PBD2B, OMIM 202370 — the non-classic, milder end of the PEX5-related Zellweger spectrum, historically called neonatal adrenoleukodystrophy or infantile Refsum disease. Caused by biallelic hypomorphic variants in PEX5, which encodes the cytosolic PTS1 peroxisomal matrix protein import receptor. This is complementation group 2, gene PEX5 - not PEX1, not PEX2. covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
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This report concerns biallelic PEX5-related, non-classic Zellweger spectrum disorder (ZSD), complementation group 2—not PEX1- or PEX2-related disease. The historical labels neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) describe intermediate and milder portions of a continuous phenotype and are no longer regarded as cleanly separable diseases. A major limitation is that PEX5 disease is exceptionally rare: most modern natural-history studies combine all ZSD genes or predominantly study PEX1. Accordingly, claims below are labeled PEX5-specific human, general ZSD, or model/in-vitro inference.
The following table summarizes the principal conclusions.
| Domain | PEX5/PBD2B-specific conclusion | Evidence scope/caveat |
|---|---|---|
| Identity | Peroxisome biogenesis disorder 2B (PBD2B; OMIM 202370) denotes the non-classic, milder end of PEX5-related Zellweger spectrum disorder (ZSD); historical labels include neonatal adrenoleukodystrophy and infantile Refsum disease. It belongs to complementation group 2 (Japanese group F), not PEX1- or PEX2-related disease. (moser1998moleculargeneticsof pages 2-4, rosewich2015clinicalutilitygene pages 1-2) | Historical phenotype labels overlap and are now generally treated as a severity continuum rather than discrete disorders. A dedicated MONDO term for PBD2B was not verified; broader ZSD is MONDO:0019609. (OpenTargets Search: Zellweger spectrum disorder-PEX5) |
| Gene/protein | PEX5 (12p13.31; OMIM *600414; ENSG00000139197) encodes the cytosolic receptor/chaperone for proteins bearing a C-terminal peroxisomal targeting signal type 1 (PTS1). PEX5L also supports PTS2 import through PEX7. (OpenTargets Search: Zellweger spectrum disorder-PEX5, rosewich2015clinicalutilitygene pages 1-2, argyriou2016peroxisomebiogenesisdisorders pages 5-7) | This is specifically a PEX5 disorder; PEX1 and PEX2 encode different components of peroxisome biogenesis. |
| Inheritance | Autosomal recessive: disease results from biallelic germline PEX5 variants; PBD2B is expected to reflect hypomorphic alleles retaining partial receptor/import activity. (moser1998moleculargeneticsof pages 2-4, rosewich2015clinicalutilitygene pages 1-2) | Penetrance is expected to be high for pathogenic biallelic genotypes, but PEX5-specific estimates, modifier genes, founder effects, and carrier frequencies are unavailable. A reported 2025 homozygous stop-loss/frameshift allele remained an ACMG VUS without functional validation. (bernalbonilla2025detectionofa pages 2-4) |
| Core mechanism | Reduced PEX5 function impairs PTS1-cargo recognition, docking at PEX13/PEX14, matrix translocation, or receptor recycling after Cys11 monoubiquitination and PEX1–PEX6–PEX26-mediated extraction; this reduces peroxisomal matrix-enzyme activity and perturbs lipid and redox metabolism. (constantin2024theroleof pages 10-16, fujiki2020recentinsightsinto pages 2-3, argyriou2016peroxisomebiogenesisdisorders pages 5-7, pandey2024molecularinteractionsof pages 16-20) | Import failure is well established; the relative contribution of individual metabolites, mitochondrial dysfunction, oxidative stress, inflammation, and pexophagy to each human phenotype remains partly inferred from cells and models. |
| Biochemical signature | Expected ZSD profile: elevated plasma C26:0/C26:1 and C24:0/C22:0 or C26:0/C22:0 ratios, phytanic/pristanic acids, pipecolic acid, and C27 bile-acid intermediates (DHCA/THCA), with reduced erythrocyte plasmalogens; fibroblasts show impaired matrix-protein import. (rosewich2015clinicalutilitygene pages 1-2, braverman2016peroxisomebiogenesisdisorders pages 3-4, klouwer2015zellwegerspectrumdisorders pages 8-9) | Results vary with age, diet, residual function, and tissue; mild disease may yield borderline or normal plasma results. These are general ZSD biomarkers, not validated PEX5-specific prognostic surrogates. |
| Mild-spectrum phenotypes | Typical features include infantile/childhood hypotonia and developmental delay, sensorineural hearing loss, progressive retinal dystrophy or visual loss, liver dysfunction, enamel hypoplasia, ataxia, peripheral neuropathy, spasticity, and stable or progressive leukodystrophy; renal stones/hyperoxaluria and adrenal insufficiency may emerge. (rosewich2015clinicalutilitygene pages 1-2, klouwer2015zellwegerspectrumdisorders pages 8-9, argyriou2016peroxisomebiogenesisdisorders pages 9-10) | PEX5-isolated frequencies are unavailable. General ZSD ophthalmic cohorts found abnormal ERGs in about 93%, macular cysts/schisis in 16/21 milder patients, and slow visual-acuity decline of approximately 0.01 LogMAR/year, but these cohorts were not PEX5-specific. (yergeau2022peroxisomebiogenesisdisorders pages 1-4) |
| Diagnosis | Confirm a compatible phenotype with a multianalyte peroxisomal biochemical profile, followed by a PEX/ZSD gene panel, exome, or genome sequencing demonstrating two clinically significant PEX5 alleles in trans. Use fibroblast PTS1-import/localization and metabolic assays when biochemical or variant findings are equivocal. (rosewich2015clinicalutilitygene pages 1-2, braverman2016peroxisomebiogenesisdisorders pages 3-4) | Single-marker VLCFA testing can miss mild PEX disorders. CMA, karyotyping, FISH, mitochondrial-DNA, and repeat-expansion testing are not first-line unless another diagnosis is suspected. |
| Treatment | No approved curative or PEX5-targeted disease-modifying therapy exists. Management is multidisciplinary and supportive: nutrition/gastrostomy when needed, antiseizure medication, hearing aids or cochlear implants, visual aids, physical/occupational/speech therapy, fat-soluble vitamins when deficient, adrenal replacement, vitamin K for coagulopathy, and renal-stone prevention. (klouwer2015zellwegerspectrumdisorders pages 8-9, braverman2016peroxisomebiogenesisdisorders pages 20-20) | Evidence is based mainly on expert guidance and general ZSD practice; controlled PEX5-specific response rates and pharmacogenomic guidance are absent. |
| Prognosis | Hypomorphic PEX5 disease is expected to permit survival through childhood and potentially adulthood, with chronic sensory, neurologic, hepatic, and renal morbidity; leukodystrophy may remain stable or progress. (yergeau2022peroxisomebiogenesisdisorders pages 1-4, argyriou2016peroxisomebiogenesisdisorders pages 9-10) | No PEX5/PBD2B survival curve, median life expectancy, or validated prognostic biomarker exists. Severe-ZSD mortality within 1–2 years should not be directly applied to PBD2B. |
| Epidemiology | PBD2B is ultra-rare; no reliable PEX5-specific incidence, prevalence, sex ratio, ethnic distribution, or carrier-frequency estimate was identified. Both sexes should be affected equally under autosomal-recessive inheritance. | Published ZSD-wide or PEX1-specific estimates cannot be assigned to PEX5. Historical evidence identified only very small numbers of complementation-group-2 patients. (moser1998moleculargeneticsof pages 2-4, malone2025estimationofpex1mediated pages 1-2) |
| Models/trials | Pex5-null and conditional mice reproduce absent matrix import, mitochondrial/ER abnormalities, neuronal-migration delay, dysmyelination, axonal degeneration, neuroinflammation, motor/cognitive impairment, and early death; CRISPR pex5 zebrafish show reduced import, hepatic lipid accumulation, demyelination, edema, impaired movement, and reduced survival. (jiang2025modellingperoxisomaldisorders pages 8-9) | Null models resemble severe ZSD more than hypomorphic PBD2B. General ZSD studies include natural-history and retinal cohorts, while betaine and hydroxychloroquine trials targeted PEX1 or PEX1/PEX6/PEX26—not PEX5—and have not established disease-modifying efficacy. (NCT01668186 chunk 1, NCT01838941 chunk 1, NCT06190626 chunk 1, NCT03856866 chunk 1) |
Table: Compact evidence summary distinguishing PEX5-specific conclusions from broader Zellweger-spectrum extrapolation. It highlights the scarcity of PEX5-isolated quantitative data and absence of a PEX5-targeted disease-modifying therapy.
PBD2B is an autosomal-recessive Mendelian disorder caused by biallelic, usually hypomorphic, variants in PEX5, encoding the cytosolic receptor for peroxisomal targeting signal type 1 (PTS1)-bearing matrix proteins. Residual PEX5-dependent import distinguishes the non-classic phenotype from severe PEX5-related Zellweger syndrome, although the boundary is biological rather than categorical. Historical complementation analysis assigned PEX5 deficiency to US complementation group 2; an early review reported only two group-2 patients, illustrating the evidence scarcity. ZS, NALD, and IRD were already recognized as a severity continuum, with IRD least severe and NALD intermediate. (moser1998moleculargeneticsof pages 2-4, rosewich2015clinicalutilitygene pages 1-2)
The evidence is principally aggregated disease-level literature, small case series, cultured fibroblasts, and model organisms—not EHR-derived individual-level population data.
The necessary cause is biallelic germline PEX5 dysfunction. Hypomorphic alleles retain enough PTS1 import to produce the milder PBD2B phenotype; two severe loss-of-function alleles would be expected to move the phenotype toward classic neonatal Zellweger syndrome. This is a receptor/import defect, not an isolated enzyme deficiency. PEX5’s causal association with ZSD is supported by human genetic evidence and curated disease-target resources. (OpenTargets Search: Zellweger spectrum disorder-PEX5, rosewich2015clinicalutilitygene pages 1-2)
Risk is highest for offspring of two heterozygous carriers: for each conception, the theoretical risks are 25% affected, 50% carrier, and 25% unaffected/non-carrier. Consanguinity or endogamy increases the probability that both parents carry the same rare allele. No validated susceptibility loci, modifier genes, protective alleles, polygenic score, or PEX5-specific founder allele were identified.
A 1999 primary report described functional heterogeneity in PEX5-defective patients and identified p.Asn489Lys (N489K) in an IRD patient (PMID 10462504, published August 1999; DOI: https://doi.org/10.1006/bbrc.1999.1232). The available excerpt did not provide a complete modern transcript-level genotype, population frequency, or ACMG classification; it should therefore not be entered as a fully resolved pathogenic genotype without checking the original sequence table.
A 2025 report identified homozygous NM_001131025.2:c.1897_1900dupACTA, p.(Met634Asnfs*16) in two affected siblings from an endogamous family. Both parents were heterozygous; the variant was absent from reviewed population/literature resources, but remained an ACMG VUS (PM4, PM2, PP1) and lacked a PTS1-import functional assay. It should not be represented as definitively pathogenic. (bernalbonilla2025detectionofa pages 2-4)
No toxin, infection, smoking behavior, alcohol exposure, occupation, sex, or lifestyle factor causes PBD2B. Diet can modify measured phytanic/pristanic acid and may modify metabolite burden, but does not prevent the genetic disorder. Age and diet also influence biochemical test sensitivity. No proven environmental or genetic protective factor prevents disease in a person with a pathogenic biallelic genotype. (braverman2016peroxisomebiogenesisdisorders pages 3-4, klouwer2015zellwegerspectrumdisorders pages 8-9)
Gene–environment interaction: residual import capacity is primary; dietary phytanic-acid exposure and physiologic stress may alter downstream metabolite burden or complications. This is clinically plausible/general ZSD evidence, not a quantified PEX5-specific interaction.
PEX5-isolated frequencies do not exist. The following phenotype annotations represent the expected non-classic ZSD phenotype, supported by historical PEX5 cases and broader ZSD cohorts.
| Phenotype | Type, onset, course, impact | Suggested HPO term |
|---|---|---|
| Hypotonia | Sign; congenital/infantile; variable, sometimes followed by spasticity; impairs feeding and motor milestones | HP:0001252 |
| Global developmental delay | Sign; infancy/childhood; mild to severe and variably progressive | HP:0001263 |
| Intellectual disability | Neurobehavioral; variable; cognition can be relatively preserved in mild disease | HP:0001249 |
| Seizures/epilepsy | Symptom/sign; neonatal through childhood; episodic, variable severity | HP:0001250 / HP:0001251 |
| Sensorineural hearing loss | Sign; often infancy/early childhood; usually bilateral and slowly progressive/stable | HP:0000407 |
| Retinal dystrophy/retinitis-pigmentosa-like disease | Sign; infancy onward; progressive night blindness, field and acuity loss | HP:0000556 / HP:0000510 |
| Nystagmus/visual impairment | Sign; infancy; persistent | HP:0000639 / HP:0000505 |
| Leukodystrophy/demyelination | MRI/pathology; childhood to adult; stable or progressive/regressive | HP:0002415 |
| Ataxia, spasticity, neuropathy | Neurologic signs; commonly later childhood/adulthood; progressive | HP:0001251, HP:0001257, HP:0009830 |
| Hepatomegaly/liver dysfunction | Sign/laboratory; infancy onward; may improve, persist, or progress to fibrosis/cirrhosis | HP:0002240 / HP:0002910 |
| Failure to thrive/feeding difficulty | Symptom/sign; infancy; variable | HP:0001508 / HP:0011968 |
| Renal cortical cysts, hyperoxaluria/nephrolithiasis | Imaging/laboratory; variable, sometimes later | HP:0000107 / HP:0003073 / HP:0000787 |
| Adrenal insufficiency | Endocrine/laboratory; may emerge progressively | HP:0000824 |
| Enamel hypoplasia | Dental sign; secondary dentition | HP:0006297 |
| Dysmorphic facial features | Physical manifestation; congenital, generally mild in PBD2B | HP:0001999 |
Historical severe-ZSD figures—hypotonia 99%, hearing impairment 100%, hepatomegaly 100%, retinopathy 71%, seizures 80%, renal cysts 93%, and neuronal-migration defects 67%—must not be assigned as PBD2B frequencies; they came from predominantly severe, mixed-gene disease. (moser1998moleculargeneticsof pages 2-4)
More relevant but still non-PEX5-specific intermediate/mild ophthalmic data show mean visual-acuity decline of approximately +0.01 LogMAR/year, legal blindness beginning at mean age 7.8 years, abnormal ERGs in 93%, and macular cysts/schisis in 16/21 milder patients. Another analysis estimated median blindness at 3.8 years in intermediate disease and 7.3 years in mild disease. These data support a substantial effect on mobility, communication, education, and independence, but no PEX5-specific EQ-5D, SF-36, PROMIS, or validated patient-reported outcome has been published. (yergeau2022peroxisomebiogenesisdisorders pages 1-4, yergeau2022peroxisomebiogenesisdisorders pages 22-24)
A 42-patient mixed PBD-ZSD/D-bifunctional-protein cohort, comprising 300 audiograms, found that most hearing loss was moderately severe to severe, usually changed slowly, and improved functionally with amplification; again, it was not a PEX5 subgroup.
PEX5 encodes two principal splice isoforms, PEX5S and PEX5L. The C-terminal tetratricopeptide-repeat domain recognizes the C-terminal PTS1 motif, commonly -Ser-Lys-Leu (-SKL) or a conservative variant. The N-terminal region acts as a cargo chaperone/holdase and contains interaction motifs for the docking and export machinery. PEX5L additionally acts with PEX7 in PTS2 import. (argyriou2016peroxisomebiogenesisdisorders pages 5-7, pandey2024molecularinteractionsof pages 16-20)
Suggested annotations include HGNC HGNC:9719; GO molecular functions peroxisomal targeting sequence binding and protein transporter/chaperone activity; GO biological processes protein import into peroxisome matrix (GO:0016558) and peroxisome organization (GO:0007031).
Disease alleles may be missense, nonsense, frameshift, splice-altering, stop-loss, or larger copy-number variants. PBD2B specifically requires enough residual PEX5 function to avoid complete neonatal disease; therefore, at least one hypomorphic allele is biologically expected, but a validated allele-by-allele PEX5 severity catalogue was not recovered. Variants are germline, not somatic. The mechanism is partial loss of function, not gain of function or dominant negative action.
Population frequencies must be checked in the current gnomAD release by exact transcript/HGVS. No reliable PEX5 carrier-frequency estimate was found. Neither chromosomal rearrangements nor recurrent aneuploidy characterize PBD2B. No disease-specific methylation, histone, or chromatin signature and no validated epigenetic modifier are known.
Environmental toxins, ionizing radiation, pollution, occupational exposure, infectious agents, smoking, and alcohol are not established etiologies or triggers. Nutritional state affects clinical resilience and some biomarker concentrations. Phytanic acid derives largely from dietary ruminant fat/dairy and can be restricted if elevated, but evidence that restriction changes long-term PBD2B neurologic outcome is weak. Infection and fasting can precipitate decompensation in many metabolic diseases, but a PEX5-specific risk estimate is unavailable. There is no zoonotic or transmissible component.
Cargo-bound PEX5 docks at the PEX13/PEX14 translocation module. After cargo release, PEX5 is monoubiquitinated at Cys11 by the PEX2/PEX10/PEX12 RING complex and extracted by the ATP-dependent PEX1–PEX6 AAA complex anchored by PEX26. A 2024 mechanistic study stated: “PEX5, the peroxisomal protein shuttling receptor, binds newly synthesized proteins in the cytosol and transports them to the organelle.” It showed that reversible cysteine ubiquitination prevents inappropriate PEX5 polyubiquitination and translocon obstruction (published March 2024; DOI: https://doi.org/10.1371/journal.pbio.3002567). This clarifies receptor quality control but is not a PBD2B treatment study. (constantin2024theroleof pages 10-16, fujiki2020recentinsightsinto pages 2-3, pandey2024molecularinteractionsof pages 16-20)
A 2024 Nature Communications study showed that PEX13’s SH3 domain dynamically recognizes PEX5 WxxxF/Y motifs, refining the docking mechanism (published April 2024; DOI: https://doi.org/10.1038/s41467-024-47605-w). A 2024 genome-wide CRISPRi study linked RNF146/tankyrase-dependent PARylation at PEX14 to import efficiency and Wnt/β-catenin signaling (published July 2024; DOI: https://doi.org/10.1083/jcb.202312069). These results suggest developmental signaling consequences of peroxisome dysfunction, but a direct causal role in human PEX5-PBD2B remains unproven.
Pexophagy may amplify loss of functional organelles when ubiquitinated PEX5 accumulates. However, this mechanism is strongest for receptor-export defects such as PEX1/PEX6/PEX26, not necessarily primary hypomorphic PEX5 deficiency. A 2023 study found that loss of PEX13 caused ubiquitinated PEX5 and ROS to cooperate in inducing pexophagy (published January 2023; DOI: https://doi.org/10.1080/15548627.2022.2160566). It is mechanistically relevant but should not be treated as direct PEX5 patient evidence.
No PEX5-specific single-cell, spatial-transcriptomic, patient proteomic, or integrated multi-omic disease atlas was identified. Cell-type-specific lipid abnormalities have been demonstrated in mixed-gene ZSD iPSC derivatives, so fibroblast biomarkers cannot be assumed to reflect neural or hepatic metabolism.
Primary systems are nervous, sensory, hepatic, renal, endocrine, skeletal, and dental. Suggested UBERON annotations include brain UBERON:0000955, cerebral cortex UBERON:0000956, cerebral white matter UBERON:0002437, cerebellum UBERON:0002037, retina UBERON:0000966, cochlea UBERON:0001844, liver UBERON:0002107, kidney UBERON:0002113, adrenal gland UBERON:0002369, peripheral nerve UBERON:0001021, and tooth UBERON:0001091. Disease is usually bilateral/systemic rather than lateralized. Asymmetric cortical malformation has been reported in an individual PEX5 family, but it is not a defining pattern. (bernalbonilla2025detectionofa pages 2-4)
At the tissue level, white-matter myelin and axons, cortical developmental zones, photoreceptor/RPE layers, cochlear sensory pathways, hepatocytes, renal tubules, and adrenal cortex are implicated. At the subcellular level, the initiating compartment is the peroxisomal matrix-import apparatus; secondary mitochondrial, ER, lysosomal/autophagic, and cytosolic abnormalities may follow.
Non-classic disease usually begins congenitally or in infancy with hypotonia, feeding/growth difficulty, hearing loss, nystagmus/visual dysfunction, or developmental delay. Ataxia, neuropathy, spasticity, retinal degeneration, leukodystrophy, adrenal insufficiency, and nephrolithiasis may become prominent later. Leukodystrophy can be stable for years or progress at any age. (argyriou2016peroxisomebiogenesisdisorders pages 9-10)
The course is chronic and lifelong, not relapsing-remitting. Residual PEX5 function can permit survival into childhood or adulthood, but no PEX5-specific staging system, progression rate, median survival, remission pattern, or critical therapeutic window has been validated. Developmental periods and the interval before irreversible retinal/white-matter injury are rational intervention windows, but this remains inferential.
Inheritance is autosomal recessive. Both sexes are expected to be affected equally. Penetrance should be high for genuinely pathogenic biallelic genotypes, while expressivity is variable and related largely to residual import. Anticipation is not expected. Germline mosaicism has not been established as a characteristic feature, although a small residual recurrence risk can never be excluded after an apparently de novo event.
No reliable PEX5/PBD2B prevalence, incidence, carrier frequency, geographic distribution, sex ratio, or population-specific variant distribution is available. Historical identification of only two complementation-group-2 patients confirms extreme rarity but is not an epidemiologic denominator. PEX1-specific modeling and general ZSD birth estimates must not be assigned to PEX5. (moser1998moleculargeneticsof pages 2-4, malone2025estimationofpex1mediated pages 1-2)
Interpretive caution: biomarker concentrations may diminish with age and correlate poorly with clinical severity, so they are diagnostic/supportive markers rather than validated prognostic or treatment surrogate endpoints. (klouwer2015zellwegerspectrumdisorders pages 8-9)
Brain MRI may show leukodystrophy, cortical malformation, perisylvian/polymicrogyric change, or cerebellar-region white-matter disease; mild patients may have normal MRI. OCT can detect intraretinal schisis/cysts and atrophy. ERG is commonly abnormal or extinguished, but may be too insensitive to longitudinal functional change; visual acuity, fields, mobility, and functional-vision questionnaires are complementary. EEG is indicated for seizures; nerve-conduction studies for neuropathy; ABR/audiometry for hearing loss. (yergeau2022peroxisomebiogenesisdisorders pages 22-24, yergeau2022peroxisomebiogenesisdisorders pages 4-6)
Important alternatives are severe PEX5-Zellweger syndrome; other PEX-gene ZSDs; D-bifunctional protein deficiency (HSD17B4); acyl-CoA oxidase-1 deficiency (ACOX1); X-linked adrenoleukodystrophy (ABCD1); adult Refsum disease (PHYH/PEX7); rhizomelic chondrodysplasia punctata; isolated hereditary retinal/hearing disorders; mitochondrial disease; and other leukodystrophies. Approximately 10–15% of patients evaluated for elevated VLCFAs may have a single-enzyme defect rather than ZSD. (braverman2016peroxisomebiogenesisdisorders pages 3-4)
CMA may detect an unusual exon/gene deletion but is not first-line for sequence-level PEX5 disease. Karyotype, FISH, mtDNA analysis, and repeat-expansion assays are not routinely indicated. RNA sequencing can clarify suspected splice variants; untargeted metabolomics/proteomics remain adjunct research methods.
Population newborn screening is not uniformly established for ZSD; C26:0-lysophosphatidylcholine-based screening used for X-ALD may identify some ZSD cases but can miss mild disease. Cascade testing of relatives and targeted carrier testing are appropriate after familial variants are known. Prenatal diagnosis and PGT-M are technically available.
PBD2B generally has a better prognosis than classic neonatal Zellweger syndrome, with survival into later childhood and potentially adulthood. Nevertheless, morbidity may be substantial from deafness, progressive retinal degeneration, motor disability, epilepsy, leukodystrophy, neuropathy, liver disease, adrenal insufficiency, and renal stones. Recovery of established neurodevelopmental or retinal injury is unlikely under current supportive care.
No PEX5-specific 5- or 10-year survival rate, median life expectancy, mortality rate, or validated prognostic model exists. Severe-ZSD survival of only 1–2 years should not be applied directly to PBD2B. General mild-ZSD evidence supports slow visual deterioration and possible adult survival, but much of it comes from PEX1 p.Gly843Asp cohorts. (yergeau2022peroxisomebiogenesisdisorders pages 1-4, yergeau2022peroxisomebiogenesisdisorders pages 12-15)
Likely prognostic factors are residual import activity, genotype class, congenital brain malformation, early liver/coagulation disease, feeding/respiratory compromise, and onset/progression of leukodystrophy. Plasma VLCFA concentration alone is not a reliable severity predictor. Quality-of-life burden extends to caregivers: a completed 2018 survey enrolled 92 caregivers and measured symptoms, parental stress, and family quality of life, but no PEX5 subgroup result was available. (klouwer2015zellwegerspectrumdisorders pages 8-9, NCT03440905 chunk 1)
There is no approved curative or PEX5-directed disease-modifying therapy. Real-world management is multidisciplinary and complication-directed:
Suggested NCIt intervention concepts include Supportive Care (C15747), physical therapy, occupational therapy, speech therapy, gastrostomy, hearing aid, cochlear implant, anticonvulsant therapy, glucocorticoid replacement, vitamin supplementation, and genetic counseling. Exact NCIt identifiers should be verified against the current release before database ingestion.
Phytanic-acid restriction may lower substrate exposure when phytanic acid is elevated, but it is not curative and has no demonstrated PEX5-specific neurologic response rate. Cholic acid and other bile-acid strategies have been investigated in ZSD, but effectiveness and hepatotoxicity require specialist oversight; no PEX5-specific efficacy evidence was recovered. Liver transplantation has been reported in only two general-ZSD children with biochemical improvement and uncertain long-term multisystem benefit. (klouwer2015zellwegerspectrumdisorders pages 8-9)
Gene replacement/editing, RNA therapy, and cell therapy remain preclinical concepts. Multisystem expression, developmental onset, and the need to reach brain, retina, liver, and other tissues make delivery difficult. Retinal gene therapy may be the most anatomically tractable application, but no PEX5 clinical efficacy data exist.
Primary lifestyle prevention is impossible because PBD2B is inherited. Effective reproductive prevention options are genetic counseling, partner/carrier testing in an identified family, prenatal diagnosis by chorionic-villus sampling or amniocentesis, and PGT-M. Secondary prevention consists of early biochemical/genetic diagnosis, cascade testing, and prompt surveillance for treatable complications. Tertiary prevention includes seizure control, hearing amplification, low-vision intervention, nutrition support, adrenal-crisis prevention, vitamin/coagulation management, renal-stone prevention, rehabilitation, and vaccination according to routine schedules. No disease-specific vaccine, antimicrobial prophylaxis, or environmental public-health measure applies.
No well-established naturally occurring companion-animal PEX5/PBD2B syndrome, breed predisposition, or veterinary prevalence was identified. PEX5 is evolutionarily conserved across eukaryotes, and orthologous import-cycle function is studied in yeast, flies, fish, and mice. This is inherited cellular disease, not infection; there is no zoonotic transmission or cross-species contagion.
Suggested taxa are Homo sapiens NCBI Taxon 9606, Mus musculus 10090, Danio rerio 7955, Drosophila melanogaster 7227, and Saccharomyces cerevisiae 4932. Current NCBI ortholog Gene IDs and any VBO breed terms should be verified programmatically before ingestion.
Global Pex5-null mice model severe Zellweger syndrome rather than PBD2B: they exhibit absent matrix import, neuronal-migration abnormalities, hepatic disease, secondary mitochondrial changes, hypotonia, and early death. Conditional Nestin-Pex5 deletion isolates neural peroxisome deficiency and produces progressive motor/coordination and cognitive impairment, dysmyelination, axonal degeneration, lipid accumulation, astrogliosis/microgliosis, and death before six months. Neural innate-immune activation occurs early and precedes overt demyelination, supporting inflammation as a downstream amplifier rather than the initiating lesion. These null models overstate the severity expected from hypomorphic PBD2B.
CRISPR/Cas9 pex5 knockout zebrafish show reduced matrix-protein import and peroxisome abundance, altered motor activity, hepatic lipid accumulation, demyelination, edema, deflated swim bladder, small liver, and reduced survival. They are useful for developmental imaging and drug screening but again represent near-complete deficiency, not a validated human PBD2B allele. (jiang2025modellingperoxisomaldisorders pages 8-9)
Patient fibroblasts remain the most directly useful functional system for PTS1 import, catalase localization, VLCFA oxidation, plasmalogen synthesis, complementation, temperature sensitivity, and variant rescue. GFP-PTS1 reporters permit live/high-content screening. ZSD iPSCs differentiated into neurons, neural progenitors, oligodendrocyte precursors, and hepatocyte-like cells demonstrate cell-type-dependent lipid abnormalities and impaired assembly, but retrieved lines carried PEX1, PEX10, PEX12, or PEX26—not PEX5—so their relevance is pathway-level.
Drosophila and yeast are valuable for conserved import machinery and genetic interaction screens, but they incompletely model human brain, retina, hearing, bile-acid metabolism, and chronic multisystem natural history.
Abstract-supported quotations: the 2015 clinical review states, “There is currently no curative therapy, but supportive care is available.” The 2024 peroxisome review describes peroxisomes as organelles with key functions in fatty-acid β-oxidation, myelin-lipid synthesis, and cellular redox balance. These authoritative summaries accurately frame current care and mechanism, but neither supplies PEX5-specific treatment-response statistics.
References
(moser1998moleculargeneticsof pages 2-4): Hugo W. Moser. Molecular genetics of peroxisomal disorders. Frontiers in bioscience : a journal and virtual library, 5:D298-306, Nov 1998. URL: https://doi.org/10.1080/15513819809168801, doi:10.1080/15513819809168801. This article has 52 citations.
(rosewich2015clinicalutilitygene pages 1-2): Hendrik Rosewich, Hans Waterham, Bwee Tien Poll-The, Andreas Ohlenbusch, and Jutta Gärtner. Clinical utility gene card for: zellweger syndrome spectrum. European Journal of Human Genetics, 23(8):1111-1111, Nov 2015. URL: https://doi.org/10.1038/ejhg.2014.250, doi:10.1038/ejhg.2014.250. This article has 10 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: Zellweger spectrum disorder-PEX5): Open Targets Query (Zellweger spectrum disorder-PEX5, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(argyriou2016peroxisomebiogenesisdisorders pages 5-7): Catherine Argyriou, Maria Daniela D’Agostino, and Nancy Braverman. Peroxisome biogenesis disorders. Translational Science of Rare Diseases, 1:111-144, Sep 2016. URL: https://doi.org/10.3233/trd-160003, doi:10.3233/trd-160003. This article has 129 citations.
(bernalbonilla2025detectionofa pages 2-4): Ingrid Bernal-Bonilla, Juan Arias-Florez, Sandra Ximena Ramírez, Bibiana Bayona-Gomez, Lina Castro-Castillo, Valeria Correa-Martinez, Yasmín Sánchez-Gómez, Natalia Santiago-Tovar, C. Gaviria-Sabogal, Nora Constanza Contreras Bravo, R. Cabrera, Adrien Morel, D. Fonseca-Mendoza, and C. Restrepo. Detection of a novel homozygous pex5 stop-loss variant associated with zellweger syndrome in a highly endogamic family. Sep 2025. URL: https://doi.org/10.2147/tacg.s518636, doi:10.2147/tacg.s518636. This article has 1 citations.
(constantin2024theroleof pages 10-16): Constantin Mouzaaber. The role of peroxins 1 and 6 in the retinal pigment epithelium. Text, 2024. URL: https://doi.org/10.7939/r3-v6ev-1s49, doi:10.7939/r3-v6ev-1s49. This article has 0 citations and is from a peer-reviewed journal.
(fujiki2020recentinsightsinto pages 2-3): Yukio Fujiki, Yuichi Abe, Yuuta Imoto, Akemi J. Tanaka, Kanji Okumoto, Masanori Honsho, Shigehiko Tamura, Non Miyata, Toshihide Yamashita, Wendy K. Chung, and Tsuneyoshi Kuroiwa. Recent insights into peroxisome biogenesis and associated diseases. Journal of Cell Science, May 2020. URL: https://doi.org/10.1242/jcs.236943, doi:10.1242/jcs.236943. This article has 95 citations and is from a domain leading peer-reviewed journal.
(pandey2024molecularinteractionsof pages 16-20): Saroj Pandey. Molecular interactions of the human pex1/pex6 aaa+ atpase complex and in vivo mrna editing of the pex1-g843d mutation. May 2024. URL: https://doi.org/10.15496/publikation-94953, doi:10.15496/publikation-94953. This article has 0 citations.
(braverman2016peroxisomebiogenesisdisorders pages 3-4): Nancy E. Braverman, Gerald V. Raymond, William B. Rizzo, Ann B. Moser, Mark E. Wilkinson, Edwin M. Stone, Steven J. Steinberg, Michael F. Wangler, Eric T. Rush, Joseph G. Hacia, and Mousumi Bose. Peroxisome biogenesis disorders in the zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Molecular genetics and metabolism, 117 3:313-21, Mar 2016. URL: https://doi.org/10.1016/j.ymgme.2015.12.009, doi:10.1016/j.ymgme.2015.12.009. This article has 352 citations and is from a peer-reviewed journal.
(klouwer2015zellwegerspectrumdisorders pages 8-9): Femke C. C. Klouwer, Kevin Berendse, Sacha Ferdinandusse, Ronald J. A. Wanders, Marc Engelen, and Bwee Tien Poll-The. Zellweger spectrum disorders: clinical overview and management approach. Orphanet Journal of Rare Diseases, Dec 2015. URL: https://doi.org/10.1186/s13023-015-0368-9, doi:10.1186/s13023-015-0368-9. This article has 300 citations and is from a peer-reviewed journal.
(argyriou2016peroxisomebiogenesisdisorders pages 9-10): Catherine Argyriou, Maria Daniela D’Agostino, and Nancy Braverman. Peroxisome biogenesis disorders. Translational Science of Rare Diseases, 1:111-144, Sep 2016. URL: https://doi.org/10.3233/trd-160003, doi:10.3233/trd-160003. This article has 129 citations.
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(NCT01838941 chunk 1): Nancy Braverman. Betaine and Peroxisome Biogenesis Disorders. McGill University Health Centre/Research Institute of the McGill University Health Centre. 2013. ClinicalTrials.gov Identifier: NCT01838941
(NCT06190626 chunk 1): Nancy Braverman. Longitudinal Prospective Natural History Study of Retinopathy in Zellweger Spectrum Disorder. McGill University Health Centre/Research Institute of the McGill University Health Centre. 2023. ClinicalTrials.gov Identifier: NCT06190626
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(argyriou2016peroxisomebiogenesisdisorders pages 3-5): Catherine Argyriou, Maria Daniela D’Agostino, and Nancy Braverman. Peroxisome biogenesis disorders. Translational Science of Rare Diseases, 1:111-144, Sep 2016. URL: https://doi.org/10.3233/trd-160003, doi:10.3233/trd-160003. This article has 129 citations.
(yergeau2022peroxisomebiogenesisdisorders pages 4-6): Christine Yergeau, Razek Georges Coussa, Fares Antaki, Catherine Argyriou, Robert K. Koenekoop, and Nancy E. Braverman. Peroxisome biogenesis disorders in the zellweger spectrum: ophthalmic findings from a new natural history study cohort and scoping literature review. MedRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.06.22279732, doi:10.1101/2022.11.06.22279732. This article has 2 citations.
(yergeau2022peroxisomebiogenesisdisorders pages 12-15): Christine Yergeau, Razek Georges Coussa, Fares Antaki, Catherine Argyriou, Robert K. Koenekoop, and Nancy E. Braverman. Peroxisome biogenesis disorders in the zellweger spectrum: ophthalmic findings from a new natural history study cohort and scoping literature review. MedRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.06.22279732, doi:10.1101/2022.11.06.22279732. This article has 2 citations.
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Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 17 |
| Resolved | 17 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 17 |
| On topic | 5 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 62 |
| Resolved | 58 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 3 |
| Terms whose name was checked | 9 |
| Terms named correctly | 0 |
| Terms named as a different term | 8 |
| Terms whose name is worth a second look | 1 |
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:0001252 (1 mention) - the report calls it "Sign; congenital/infantile; variable, sometimes followed by spasticity; impairs feeding and motor milestones"; HP calls it HypotoniaHP:0001263 (1 mention) - the report calls it "Sign; infancy/childhood; mild to severe and variably progressive"; HP calls it Global developmental delayHP:0001249 (1 mention) - the report calls it "Neurobehavioral; variable; cognition can be relatively preserved in mild disease"; HP calls it Intellectual disabilityHP:0000407 (1 mention) - the report calls it "Sign; often infancy/early childhood; usually bilateral and slowly progressive/stable"; HP calls it Sensorineural hearing impairmentHP:0002415 (1 mention) - the report calls it "MRI/pathology; childhood to adult; stable or progressive/regressive"; HP calls it LeukodystrophyHP:0000824 (1 mention) - the report calls it "Endocrine/laboratory; may emerge progressively"; HP calls it Decreased response to growth hormone stimulation testHP:0006297 (1 mention) - the report calls it "Dental sign; secondary dentition"; HP calls it Enamel hypoplasiaHP:0001999 (1 mention) - the report calls it "Physical manifestation; congenital, generally mild in PBD2B"; HP calls it Abnormal facial shapeThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0061912 (obsolete selective autophagy) (1 mention)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:
CL:0000540 (1 mention) - the report calls it "Cells: neuron"; CL calls it neuron**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: Orphanet.