Peroxisome biogenesis disorder 8B (PBD8B, OMIM 614877) is the non-classic ("B") end of the PEX16-related Zellweger spectrum. PEX16 defines complementation group D (group 9 in the US series) of the peroxisome biogenesis disorders and encodes an integral peroxisomal membrane peroxin that acts in membrane assembly rather than in matrix protein import. That places PBD8B at a different point in the pathway from every other non-classic Zellweger-spectrum entry curated here. PBD1B, PBD2B and PBD4B are defects of the matrix import machinery - a receptor, or the module that recycles it - and their peroxisomes are present but cannot take up cargo. A complete PEX16 defect is upstream of all of that: it removes the organelle itself. The founding PEX16 patients had no peroxisomal remnants at all, which is what made PEX16 the gene that demonstrated peroxisomes can be built without a pre-existing peroxisome. PBD8B is what happens when that lesion is incomplete, and the resulting cellular picture is genuinely counterintuitive. Fibroblasts from these patients do not show a milder version of "no peroxisomes". They show peroxisomes that are fewer in number but enlarged, and competent to import matrix protein - so the assay that establishes a classic peroxisome biogenesis disorder can read close to normal here. Residual PEX16 protein is detectable on immunoblot in atypical patients and absent in a patient with the severe presentation, which is the molecular counterpart of that morphology. Clinically it does not look like a Zellweger-spectrum disease either. Presentation is in the preschool years with progressive spastic paraparesis and ataxia, a leucodystrophy-plus-atrophy pattern on MRI, and later cataracts and peripheral neuropathy; dystonia and tremor are reported; cognition is often preserved and survival is prolonged. The sensory loss and amelogenesis imperfecta that characterise the rest of the spectrum can be entirely absent. Plasma very-long-chain fatty acids may be only subtly raised or frankly normal. The practical consequence, which the source reports make themselves, is that these individuals are reached by sequencing rather than by biochemical screening, and are more likely to be worked up as hereditary spastic paraplegia or an undiagnosed leukodystrophy than as a peroxisomal disease.
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Conditions with similar clinical presentations that must be differentiated from Peroxisome Biogenesis Disorder 8B:
name: Peroxisome Biogenesis Disorder 8B
creation_date: "2026-09-16T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: peroxisome biogenesis disorder 8B
term:
id: MONDO:0013943
label: peroxisome biogenesis disorder 8B
description: >-
Peroxisome biogenesis disorder 8B (PBD8B, OMIM 614877) is the non-classic
("B") end of the PEX16-related Zellweger spectrum. PEX16 defines
complementation group D (group 9 in the US series) of the peroxisome
biogenesis disorders and encodes an integral peroxisomal membrane peroxin that
acts in membrane assembly rather than in matrix protein import.
That places PBD8B at a different point in the pathway from every other
non-classic Zellweger-spectrum entry curated here. PBD1B, PBD2B and PBD4B are
defects of the matrix import machinery - a receptor, or the module that
recycles it - and their peroxisomes are present but cannot take up cargo. A
complete PEX16 defect is upstream of all of that: it removes the organelle
itself. The founding PEX16 patients had no peroxisomal remnants at all, which
is what made PEX16 the gene that demonstrated peroxisomes can be built without
a pre-existing peroxisome.
PBD8B is what happens when that lesion is incomplete, and the resulting
cellular picture is genuinely counterintuitive. Fibroblasts from these
patients do not show a milder version of "no peroxisomes". They show
peroxisomes that are fewer in number but enlarged, and competent to import
matrix protein - so the assay that establishes a classic peroxisome biogenesis
disorder can read close to normal here. Residual PEX16 protein is detectable
on immunoblot in atypical patients and absent in a patient with the severe
presentation, which is the molecular counterpart of that morphology.
Clinically it does not look like a Zellweger-spectrum disease either.
Presentation is in the preschool years with progressive spastic paraparesis
and ataxia, a leucodystrophy-plus-atrophy pattern on MRI, and later cataracts
and peripheral neuropathy; dystonia and tremor are reported; cognition is
often preserved and survival is prolonged. The sensory loss and amelogenesis
imperfecta that characterise the rest of the spectrum can be entirely absent.
Plasma very-long-chain fatty acids may be only subtly raised or frankly
normal. The practical consequence, which the source reports make themselves,
is that these individuals are reached by sequencing rather than by biochemical
screening, and are more likely to be worked up as hereditary spastic
paraplegia or an undiagnosed leukodystrophy than as a peroxisomal disease.
parents:
- Zellweger Spectrum Disorders
- peroxisome biogenesis disorder
- inborn errors of metabolism
synonyms:
- PBD8B
- peroxisome biogenesis disorder type 8B
- PEX16-related atypical Zellweger spectrum disorder
- atypical PEX16 peroxisome biogenesis disorder
- variant peroxisome biogenesis disorder due to PEX16 mutations
- peroxisome biogenesis disorder, complementation group D, non-classic
notes: >-
CURATION LEVEL, AND WHY THIS IS A STANDALONE ENTRY. Claim issue #11974 asked
whether PBD8B should be an entry, a subtype, or out of scope. It is curated as
a distinct entry, following Peroxisome Biogenesis Disorder 1B (PEX1), 2B
(PEX5) and 4B (PEX6), on the same reasoning those entries record: the A/B
split inside a PEX complementation group is a mechanistic statement about how
much peroxin function survives, not a bare severity label, and the causal gene
differs between groups. Three repository facts back that up rather than a
preference. `Peroxisome_Biogenesis_Disorder.yaml` carries no `has_subtypes`
block at all, so there is no subtype list for this concept to join. MONDO
places MONDO:0013943 under MONDO:0100269 (peroxisome biogenesis disorder due
to PEX16 defect), a gene-level parent that is itself uncurated, not under a
curated disease. And PBD8B has its own primary literature - six patients in
the founding report, seven in a later case series, three in a consanguineous
kindred and one by whole-genome sequencing - which a subtype row could not
carry.
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 and is deliberately not duplicated here.
What this entry carries is what is PEX16- and non-classic-specific: a membrane
assembly lesion rather than a matrix import lesion, and a residual-function
phenotype that presents as enlarged import-competent peroxisomes rather than
as absent ones.
WHERE THE GENE CAME FROM. The stub records no causal gene. PEX16 was resolved
from the MONDO parent chain (MONDO:0100269, "peroxisome biogenesis disorder
due to PEX16 defect") and independently confirmed against NCBI
`mim2gene_medgen`, which maps OMIM:614877 to GeneID 9409 with a GeneMap
source. The HGNC REST API returns HGNC:8857, symbol PEX16, "peroxisomal
biogenesis factor 16", 11p11.2, OMIM gene 603360. `kb/` was then re-checked
for PEX16 rather than for the disease label: the only hit is a `genetic:` row
on `Peroxisome_Biogenesis_Disorder.yaml`, which cites the same ClinGen
assertion used here and curates no PEX16-specific mechanism, so nothing was
already covering this entity under another name.
PBD8A IS NOT CURATED HERE AND IS NOT IMPLIED. Classic PEX16 Zellweger syndrome
(PBD8A, OMIM 614876) has no entry in this knowledge base. It appears in this
entry only as the contrast that defines "8B" - the total absence of
peroxisomal remnants, and the absence of PEX16 protein on immunoblot, against
which the residual-function claim is made. Creating the PBD8A entry is a
reasonable follow-on. Evidence items that describe PBD8A cells are marked
`directness: INDIRECT` where they are cited in support of a PBD8B claim,
because they establish the severe pole rather than this entity.
FREQUENCY BANDS ARE NOT ASSERTED. No phenotype in this entry carries a
`frequency` band. The reason is specific, not a default. Two of the four
clinical sources are single-patient or three-patient reports. The seven-patient
case series (PMID:35106698) gives per-feature counts for some features
("all patients had hypertonia", "Five patients were noted to have dystonia")
and those numerators are recorded in the phenotype `notes`, but the series is
explicitly a selected atypical-phenotype cohort rather than a consecutive
PEX16 series, so a band computed from it would describe the selection and not
the disease. The founding six-patient report (PMID:20647552) describes its
cohort's features collectively in its abstract without per-feature counts.
THE NEGATIVE FINDINGS ARE LOAD-BEARING AND ARE CURATED AS SUCH. Two of the
most useful facts about this entity are absences: classic PBD sensory deficits
and amelogenesis imperfecta were absent in all seven patients of the case
series, and plasma very-long-chain fatty acids were normal in the
whole-genome-sequencing patient. Both are curated - the first in the
Zellweger-spectrum differential, the second on the VLCFA biochemical marker -
rather than left out because they are negative. Do not read either as a claim
that those features never occur in PEX16 disease; they are cohort-level
observations in selected atypical patients.
WHAT IS KNOWINGLY ABSENT. No prevalence rate: none has been estimated, so only
a literature case count is recorded. The Drosophila humanisation study is
curated as an `animal_models:` entry that MEASURES the residual-function node
rather than as a disease model: the flies carry a Pex16 null with human
alleles expressed on top, so they model the allele series, and the study's
own framing is a severity spectrum across PEX2 and PEX16. No `datasets:` block: no PEX16-specific omics
dataset was identified, and a gene search for PEX16 would surface
Zellweger-spectrum and peroxisome-biology series that resolve perfectly and
are not about this entity. No disease-modifying treatment exists; everything
curated is supportive, and the one intervention with a reported response
(levodopa/carbidopa for dystonia) is an uncontrolled treatment trial within a
case series and is curated with that caveat stated in its own description.
DEEP RESEARCH. One falcon run was performed and is committed at
`research/Peroxisome_Biogenesis_Disorder_8B-deep-research-falcon.md`. It was
treated as leads only: every PMID, snippet and ontology term in this entry was
fetched and verified against the local cache independently of it, and nothing
was bound from the report.
The query was disambiguated by temporarily setting this entry's `name:` to
"PEX16 deficiency (peroxisome biogenesis disorder 8B, the mild non-Zellweger
end of the PEX16 spectrum)" for the duration of the run, because the recipe
derives the query from that field and "Peroxisome Biogenesis Disorder 8B"
alone is the kind of numbered label a provider substitutes for something else.
`just preflight-dr` returned SKIP, not PASS, because MONDO records no causal
gene for MONDO:0013943, so its gene-identity check has nothing to discriminate
on; SKIP means unchecked. The manual fallback settles it: the report mentions
PEX16 101 times and no other PEX gene even once, carries OMIM 614877 (which
matches MONDO's cross-reference) alongside 614876 for the severe allelic
disorder and 603360 for the gene, and states in its own scope section that
PBD8B is the mild end of the PEX16 continuum. It is about the right entity.
Its own validators flagged four term problems, recorded here because they are
the reason nothing was bound from it: one invented identifier (`HP:000`), one
obsolete term (`HP:0040083`), and two identifiers named as something else -
`HP:0032312` is "Decreased circulating globulin concentration" and the report
calls it "abnormal very-long-chain fatty-acid level". Its reference validator
resolved all twelve extracted references.
It independently reached the same framing as this entry - residual PEX16
function, a severity position on a continuum rather than a separate
biochemical mechanism, and clinical expectations that cannot be quantified
because no PEX16 cohort supports them. It also carries leads this entry does
not curate, recorded so the next curator does not re-derive them: a
hepatocyte-specific Pex16-knockout mouse with absent hepatic peroxisomes and
altered serum lipids and bile acids; locomotor, bang-sensitivity and
lifespan phenotypes in Pex16-null Drosophila beyond the allele-rescue result
cited here; ocular findings across PEX16 disease including optic atrophy and
abnormal retinal pigmentation; and a second registered study, NCT06190626, on
Zellweger-spectrum retinopathy. None 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: >-
PBD8B requires biallelic PEX16 variants, with at least one allele retaining
partial peroxin function. Reported genotypes include apparent homozygosity
in consanguineous families and compound heterozygosity. PEX16 is autosomal,
so the recurrence risk is 25 percent per sibship.
evidence:
- reference: CGGV:assertion_7506d938-efb4-416c-aafd-221251d00e6e-2020-01-13T170000.000Z
reference_title: "PEX16 / peroxisome biogenesis disorder (Definitive)"
supports: SUPPORT
evidence_source: OTHER
directness: DIRECT
snippet: "PEX16 | HGNC:8857 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
explanation: >-
ClinGen's Peroxisomal Disorders Gene Curation Expert Panel classifies the
PEX16-peroxisome biogenesis disorder relationship as definitive with
autosomal recessive inheritance.
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Subsequent sequencing of all known PEX genes revealed five novel apparent
homozygous mutations in the PEX16 gene.
explanation: >-
Apparent homozygosity in the founding PBD8B cohort, consistent with
recessive inheritance.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
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 states. Indirect: gene-agnostic
across the thirteen ZSD-PEX genes rather than a PEX16 segregation
analysis.
pathophysiology:
- name: Hypomorphic PEX16 Variants with Residual Peroxin Function
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: ESTABLISHED
description: >-
The initiating lesion, and the point at which PBD8B separates from classic
PEX16 Zellweger syndrome. PEX16 mutations define complementation group D of
the peroxisome biogenesis disorders, established by the observation that
expressing wild-type PEX16 restores peroxisome biogenesis in CG-D fibroblasts
and in no other group. What distinguishes the non-classic end is that the
variant protein survives: residual PEX16 is detectable by immunoblot in
fibroblasts from atypical patients and is absent in a patient with the severe
presentation. The allele series has been tested directly in a humanised
Drosophila model, where alleles from mild disease partially rescued a Pex16
null and alleles from atypical ataxia rescued it fully - a graded residual
function that is specific to the allele rather than an all-or-nothing loss.
genes:
- preferred_term: PEX16
term:
id: hgnc:8857
label: PEX16
genetic_context:
variant_origin: GERMLINE
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
evidence:
- reference: PMID:9837814
reference_title: Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
HsPEX16 expression morphologically and biochemically restored peroxisome
biogenesis only in fibroblasts from a CG-D patient with ZS in Japan
explanation: >-
The complementation experiment that assigns PEX16 to this group. Indirect:
the patient complemented was a Zellweger syndrome (PBD8A) patient, so this
establishes the gene for the group and not the residual-function allele
class of PBD8B.
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
We demonstrated residual PEX16 protein amounts by immunoblotting in
fibroblasts available from 5 patients with this atypical PEX16 disease (3
from this series, 2 previously reported), in contrast to the absence of
PEX16 protein in fibroblasts from a patient with the severe ZSD
presentation.
explanation: >-
The direct molecular demonstration that the non-classic end retains PEX16
protein and the severe end does not. This is the evidence the whole
residual-function framing of this entry rests on.
- reference: PMID:40621817
reference_title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
Alleles linked to mild PBD showed partial rescue, while variants
associated with atypical ataxia could fully rescue.
explanation: >-
Human PEX16 alleles graded by how far they rescue a Drosophila Pex16 null,
so the residual function is allele-specific and continuous. Indirect: a
humanised fly assay of the allele series, not an observation in patients.
downstream:
- target: Partially Preserved Peroxisomal Membrane Assembly
description: >-
Residual PEX16 protein leaves the membrane assembly step it serves
partially functional, rather than abolished as in classic PEX16 Zellweger
syndrome.
- name: Partially Preserved Peroxisomal Membrane Assembly
biological_scale: MOLECULAR
role: central_effector
mechanism_confidence: ESTABLISHED
description: >-
PEX16 is an integral peroxisomal membrane protein that functions in membrane
assembly, upstream of Pex3p, and is required for peroxisome formation in the
absence of a pre-existing peroxisome: the cell line in which PEX16 was
identified could not import peroxisomal membrane proteins at all, and
expressing PEX16 restored the formation of new peroxisomes. In current
models, PEX16 arrives on endoplasmic-reticulum-derived vesicles that fuse
with Pex3- and Pex14-bearing pre-peroxisomal structures to confer full import
competence. This is the step PBD8B leaves partly intact and classic PEX16
disease does not, and it is why the lesion here is upstream of the matrix
import machinery affected in PBD1B, PBD2B and PBD4B.
biological_processes:
- preferred_term: peroxisome membrane biogenesis
term:
id: GO:0016557
label: peroxisome membrane biogenesis
modifier: DECREASED
- preferred_term: protein import into peroxisome membrane
term:
id: GO:0045046
label: protein import into peroxisome membrane
modifier: DECREASED
evidence:
- reference: PMID:9922452
reference_title: Peroxisome synthesis in the absence of preexisting peroxisomes.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
we report here a Zellweger syndrome patient (PBD061) with an unusual
cellular phenotype, an inability to import peroxisomal membrane proteins.
We also identified human PEX16, a novel integral peroxisomal membrane
protein, and found that PBD061 had inactivating mutations in the PEX16
gene.
explanation: >-
Establishes that PEX16 acts on peroxisomal membrane protein import rather
than matrix import. Indirect: the cell line carries inactivating
mutations, so it defines the complete-loss pole against which the partial
preservation in PBD8B is described.
- reference: PMID:12223482
reference_title: "The membrane biogenesis peroxin Pex16p. Topogenesis and functional roles in peroxisomal membrane assembly."
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
These results imply that Pex16p functions in peroxisome membrane assembly,
more likely upstream of Pex3p.
explanation: >-
Places PEX16 upstream of PEX3 in membrane assembly, which is what makes
this lesion upstream of the matrix-import defects of the other non-classic
Zellweger-spectrum entries. Indirect: a cell-biological mapping of the
peroxin, not an observation in PBD8B cells.
- reference: PMID:28146471
reference_title: Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
Maturation of pre-peroxisomes containing Pex3 and Pex14 requires fusion
with endoplasmic reticulum-derived vesicles carrying Pex16, thereby
providing full import competence.
explanation: >-
The step at which PEX16 acts, and the reason a partial PEX16 defect yields
peroxisomes that exist but are fewer. Indirect: worked out in
peroxisome-lacking patient fibroblasts and not in PBD8B cells.
downstream:
- target: Reduced Peroxisome Number with Compensatory Enlargement
description: >-
Partial membrane assembly yields a peroxisome population that forms, but
at reduced numerical density.
- name: Reduced Peroxisome Number with Compensatory Enlargement
biological_scale: CELLULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The cellular signature of PBD8B, and the finding that makes it hard to
diagnose. Fibroblasts from the founding cohort contained peroxisomes that
were import-competent and increased in size but reduced in number - the
opposite of the absent peroxisomal remnants reported for severe PEX16
disease. The same morphology was reproduced by quantitative imaging in
olfactory-neurosphere-derived neural stem cells from an independent patient,
and fewer catalase- and PMP70-containing particles were seen in a third
kindred. Why the surviving peroxisomes are enlarged is not established; the
source reporting the quantification says the mechanism is unclear, and this
entry does not assert one.
biological_processes:
- preferred_term: peroxisome organization
term:
id: GO:0007031
label: peroxisome organization
modifier: DECREASED
cellular_components:
- preferred_term: peroxisome
term:
id: GO:0005777
label: peroxisome
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Immunofluorescence microscopy revealed the presence of import-competent
peroxisomes, which were increased in size but reduced in number.
explanation: >-
The defining cellular observation in the six founding PBD8B patients.
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
PEX16-defective patients have been reported to have a severe clinical
presentation. Fibroblasts from these patients displayed a defect in the
import of peroxisomal matrix and membrane proteins, resulting in a total
absence of peroxisomal remnants.
explanation: >-
The contrast that makes the finding above surprising. Indirect: this
sentence describes previously reported severe PEX16 patients (PBD8A), not
this entity, and is quoted from the paper's background.
quote_role: BACKGROUND
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Using olfactory-neurosphere derived cells, a population of neural stem
cells, we showed patient cells had reduced peroxisome density and
increased peroxisome size, replicating previously reported findings in
PEX16 cell lines.
explanation: >-
Independent quantitative replication of the morphology, in a neural cell
type rather than in fibroblasts.
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Immunocytochemical investigations on fibroblasts revealed fewer catalase
and PMP70-containing particles indicating aberrant peroxisomal assembly.
explanation: >-
A third, independent kindred showing reduced peroxisome number by a
different pair of markers.
downstream:
- target: Attenuated Peroxisomal Metabolic Block
description: >-
Fewer peroxisomes per cell give a partial rather than complete loss of
peroxisomal metabolic capacity.
- target: Reduced Peroxisomal Catalase Activity
description: >-
Fewer peroxisomes carry less catalase, which is the one peroxisomal
enzyme activity measured directly in PBD8B patient cells.
- name: Reduced Peroxisomal Catalase Activity
biological_scale: CELLULAR
role: effector
mechanism_confidence: PROVISIONAL
description: >-
Catalase activity was lower in patient-derived neural stem cells than in
controls, and the reporting authors attribute it to the reduced peroxisome
number rather than to a separate lesion. The oxidative-stress consequence did
not follow: challenged with hydrogen peroxide, patient cells showed lower
rather than higher signal on an oxidative-stress indicator, which the authors
read as compensation by non-catalase peroxide-metabolising enzymes. Marked
PROVISIONAL deliberately. It rests on one patient cell line; the authors
themselves note that total cellular catalase deficiency does not prove
peroxisomal catalase was mistargeted, and that particulate catalase was not
measured. No link from this node to the white-matter phenotype has been
demonstrated in PEX16 disease, and none is asserted below beyond a
PROVISIONAL edge.
molecular_functions:
- preferred_term: catalase activity
term:
id: GO:0004096
label: catalase activity
modifier: DECREASED
biological_processes:
- preferred_term: hydrogen peroxide catabolic process
term:
id: GO:0042744
label: hydrogen peroxide catabolic process
modifier: DECREASED
evidence:
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Along with alterations in peroxisome morphology, patient cells also had
impaired peroxisome function with reduced catalase activity.
explanation: >-
The measurement this node records, in patient-derived neural stem cells.
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Furthermore, patient cells had reduced oxidative stress levels after
exposure to hydrogen-peroxide (H2O2), which may be a result of
compensation by H2O2 metabolising enzymes other than catalase to preserve
peroxisome-related cell functions.
explanation: >-
The counterintuitive downstream result, recorded here so the node is not
read as establishing oxidative stress in this disease. The authors offer
compensation as a hypothesis, which is why this node is PROVISIONAL.
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Although total cellular catalase was mildly deficient in the patient's
cultured cells, this does not prove that peroxisomal catalase was
mistargeted.
explanation: >-
The authors' own limitation on the measurement above, and the reason this
node carries PROVISIONAL confidence rather than ESTABLISHED.
downstream:
- target: Progressive Central White Matter and Long Tract Degeneration
description: >-
A plausible but undemonstrated contribution. No study has linked reduced
catalase activity to the white-matter lesion in PEX16 disease, and the
compensation result above argues that whole-cell peroxide handling is not
simply impaired. Carried as a PROVISIONAL edge rather than dropped, so the
open question stays visible; see the knowledge-gap discussion.
- name: Attenuated Peroxisomal Metabolic Block
biological_scale: ORGANISM
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The whole-organism metabolic consequence, and it is attenuated to the point
of being unreliable as a diagnostic signal. Plasma analysis in the founding
cohort showed abnormalities suggesting a peroxisomal disorder, but
biochemical variables in the same patients' fibroblasts were only mildly
abnormal or within the normal range. A later kindred had only subtle
elevations of C26 and the C26/C22 ratio, and the whole-genome-sequencing
patient had frankly normal plasma very-long-chain fatty acids. The specific
peroxisomal functions curated on the Zellweger Spectrum Disorders entry -
beta-oxidation of very-long-chain fatty acids and ether-lipid synthesis -
are the ones at issue, and the point here is the degree of block rather than
a different set of pathways.
biological_processes:
- preferred_term: very long-chain fatty acid catabolic process
term:
id: GO:0042760
label: very long-chain fatty acid catabolic process
modifier: DECREASED
- preferred_term: ether lipid biosynthetic process
term:
id: GO:0008611
label: ether lipid biosynthetic process
modifier: DECREASED
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal
disorder. Biochemical variables in fibroblasts were only mildly abnormal or
within the normal range.
explanation: >-
Both halves of the attenuation in the founding cohort: a detectable plasma
abnormality alongside near-normal cellular biochemistry.
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Very-long-chain fatty acids analysis showed subtle elevations in C26 and
C26/C22.
explanation: >-
Quantifies how small the beta-oxidation block can be at this end of the
spectrum.
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Although plasmalogen levels are low in severely affected cases of Zellweger
spectrum disorder it can be completely normal in milder patients
explanation: >-
The ether-lipid arm is attenuated in the same way as the beta-oxidation
arm, so a normal plasmalogen result does not exclude this disorder.
quote_role: BACKGROUND
downstream:
- target: Progressive Central White Matter and Long Tract Degeneration
description: >-
The partial metabolic block is the accepted route to the degenerative CNS
disease, in common with the rest of the Zellweger spectrum.
- target: Cataract
description: >-
A late non-neurological manifestation in the founding cohort, attributed
here to the systemic peroxisomal deficit rather than to the white-matter
lesion.
- target: Peripheral Neuropathy
description: >-
Also late, and peripheral rather than central, so it is drawn from the
systemic metabolic node rather than from the central white-matter node.
- name: Progressive Central White Matter and Long Tract Degeneration
biological_scale: TISSUE
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The tissue lesion that produces the clinical picture. Imaging in the founding
cohort showed a characteristic pattern of progressive leucodystrophy with
brain atrophy, and the later case series localised the T2/FLAIR change to the
brainstem, the superior and middle cerebellar peduncles, the corticospinal
tracts and the splenium of the corpus callosum - which is the anatomical
explanation for a syndrome dominated by spasticity and cerebellar signs with
cognition relatively spared. Magnetic resonance spectroscopy in one patient
showed a raised myo-inositol peak, interpreted by the reporting authors as a
non-specific marker of glial proliferation; this entry records that
interpretation rather than asserting astrocytosis.
locations:
- preferred_term: white matter
term:
id: UBERON:0002316
label: white matter
cell_types:
- preferred_term: oligodendrocyte
term:
id: CL:0000128
label: oligodendrocyte
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients presented in the preschool years with progressive spastic
paraparesis and ataxia (with a characteristic pattern of progressive
leucodystrophy and brain atrophy on MRI scan) and later developed cataracts
and peripheral neuropathy.
explanation: >-
The imaging lesion and its clinical correlate in the founding cohort, and
the source for the temporal ordering used across this entry's phenotypes.
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Brain MRI studies commonly showed T2/FLAIR hyperintensities in the
brainstem, superior and middle cerebellar peduncles, corticospinal tracts,
and splenium of the corpus callosum.
explanation: >-
Localises the lesion to the tracts whose involvement the clinical syndrome
predicts.
downstream:
- target: Progressive Spastic Paraparesis
- target: Cerebellar Ataxia
- target: Leukodystrophy
- target: Cerebral Atrophy
- target: Dystonia
- target: Tremor
- target: Dysarthria
phenotypes:
- name: Progressive Spastic Paraparesis
category: Neurologic
description: >-
Usually the presenting problem, in the preschool years, and progressive
thereafter. It is the feature that most often routes these individuals to a
hereditary spastic paraplegia workup rather than to a peroxisomal one.
phenotype_term:
preferred_term: Progressive spastic paraplegia
term:
id: HP:0007020
label: Progressive spastic paraplegia
clinical_course: PROGRESSIVE
notes: >-
No frequency band. The case series reports hypertonia in all seven of its
patients, but that cohort was selected for the atypical phenotype, so the
numerator describes the selection. The founding report describes its six
patients collectively without per-feature counts.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients presented in the preschool years with progressive spastic
paraparesis and ataxia (with a characteristic pattern of progressive
leucodystrophy and brain atrophy on MRI scan) and later developed cataracts
and peripheral neuropathy.
explanation: >-
Spastic paraparesis as the presenting feature in the six founding
patients, with its age of onset.
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Classic PBD features such as sensory deficits and amelogenesis imperfecta
were absent in all 7 patients, while all patients had hypertonia.
explanation: >-
Hypertonia in all seven patients of the case series. The same sentence
carries the negative findings used in the Zellweger-spectrum differential.
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Despite normal development in the first year, regression and progressive
spastic diplegia, poor coordination and dysarthria occurred thereafter.
explanation: >-
An independent kindred, and the clearest statement of the pattern: normal
early development followed by regression.
- name: Cerebellar Ataxia
category: Neurologic
description: >-
Present with the spasticity from the outset in the founding cohort, and
reported as cerebellar dysfunction in the later case series. The imaging
correlate is involvement of the superior and middle cerebellar peduncles.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
notes: >-
No frequency band, for the reasons given in the entry notes. Bound to the
general HP term for ataxia rather than to a cerebellar-specific child,
because the cited sentences say "ataxia" and "cerebellar dysfunction"
without localising the deficit clinically; the peduncular imaging finding is
curated on the tissue node instead.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients presented in the preschool years with progressive spastic
paraparesis and ataxia (with a characteristic pattern of progressive
leucodystrophy and brain atrophy on MRI scan) and later developed cataracts
and peripheral neuropathy.
explanation: >-
Ataxia alongside the spasticity at presentation in the founding cohort.
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Compared to other PEX-related disorders, some PEX16 defects are associated
with an atypical phenotype consisting of spasticity, cerebellar
dysfunction, preserved cognition, and prolonged survival.
explanation: >-
Cerebellar dysfunction as one of the four features that define the
atypical PEX16 phenotype.
- name: Leukodystrophy
category: Neurologic
description: >-
Progressive white-matter disease is the constant imaging finding and, with
the spasticity, the reason these patients are investigated as an
undiagnosed leukodystrophy.
phenotype_term:
preferred_term: Leukodystrophy
term:
id: HP:0002415
label: Leukodystrophy
clinical_course: PROGRESSIVE
notes: >-
No frequency band; see entry notes.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients presented in the preschool years with progressive spastic
paraparesis and ataxia (with a characteristic pattern of progressive
leucodystrophy and brain atrophy on MRI scan) and later developed cataracts
and peripheral neuropathy.
explanation: >-
Progressive leucodystrophy as a characteristic MRI pattern in the founding
cohort.
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
in an individual with leukodystrophy, spastic paraplegia, cerebellar
ataxia, and craniocervical dystonia with normal plasma very long chain
fatty acids
explanation: >-
Leukodystrophy in an independent patient, reached by whole-genome
sequencing despite normal plasma very-long-chain fatty acids. The
variant list that opens this sentence is trimmed out of the quote because
the reference validator strips bracketed spans; the two alleles are
recorded in the `genetic:` block instead.
- name: Cerebral Atrophy
category: Neurologic
description: >-
Brain atrophy accompanies the white-matter change on MRI and progresses with
it.
phenotype_term:
preferred_term: Cerebral atrophy
term:
id: HP:0002059
label: Cerebral atrophy
notes: >-
No frequency band; see entry notes.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients presented in the preschool years with progressive spastic
paraparesis and ataxia (with a characteristic pattern of progressive
leucodystrophy and brain atrophy on MRI scan) and later developed cataracts
and peripheral neuropathy.
explanation: >-
Brain atrophy as part of the characteristic MRI pattern in the founding
cohort.
- name: Dystonia
category: Neurologic
description: >-
Reported in five of the seven patients of the case series, and the feature
that the whole-genome-sequencing report added to the PEX16 spectrum. It is
also the only feature in this entry with a reported treatment response.
phenotype_term:
preferred_term: Dystonia
term:
id: HP:0001332
label: Dystonia
notes: >-
Five of seven in the case series (PMID:35106698). Not converted to a
frequency band: that cohort was assembled for the atypical phenotype, so the
denominator is a selected series rather than a consecutive PEX16 population.
evidence:
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Five patients were noted to have dystonia and received a treatment trial of
levodopa/carbidopa.
explanation: >-
The numerator recorded in this phenotype's notes.
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
To our knowledge, dystonia is a newly associated manifestation that adds to
the phenotypic spectrum of PEX16-related disorders.
explanation: >-
The report that first added dystonia to the PEX16 phenotype, in a patient
with craniocervical dystonia.
- name: Tremor
category: Neurologic
description: >-
Reported alongside the dystonia in the case series, and improved with it
under the levodopa/carbidopa trial.
phenotype_term:
preferred_term: Tremor
term:
id: HP:0001337
label: Tremor
notes: >-
No frequency band. Tremor is named only in the treatment-response sentence
of the case series, which counts treated patients rather than patients with
tremor, so no numerator for the phenotype itself is available.
evidence:
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Four treated patients had partial but significant improvements in their
dystonia and tremors, and 1 patient had only minimal response.
explanation: >-
Establishes tremor as present in treated patients. It is reported only
through the treatment response, which is why no separate prevalence is
recorded.
- name: Dysarthria
category: Neurologic
description: >-
Part of the progressive bulbar and cerebellar involvement, described in the
consanguineous kindred and consistent with the brainstem imaging findings.
phenotype_term:
preferred_term: Dysarthria
term:
id: HP:0001260
label: Dysarthria
notes: >-
No frequency band; reported in a three-patient kindred.
evidence:
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Despite normal development in the first year, regression and progressive
spastic diplegia, poor coordination and dysarthria occurred thereafter.
explanation: >-
Dysarthria in the proband of the consanguineous kindred, in the context of
post-infancy regression.
- name: Cataract
category: Ophthalmologic
description: >-
A late feature, developing after the neurological presentation rather than
with it. Cataract removal is one of the supportive interventions
GeneReviews lists for the Zellweger spectrum generally.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
notes: >-
No frequency band; the founding report describes it as a later development
in its cohort without a count.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients presented in the preschool years with progressive spastic
paraparesis and ataxia (with a characteristic pattern of progressive
leucodystrophy and brain atrophy on MRI scan) and later developed cataracts
and peripheral neuropathy.
explanation: >-
Cataract as a later development in the founding cohort.
- name: Peripheral Neuropathy
category: Neurologic
description: >-
Also late. Note that it is not universal even among reported patients: nerve
conduction studies and needle electromyography were within normal range in
the whole-genome-sequencing patient, whose disease was otherwise advanced.
phenotype_term:
preferred_term: Peripheral neuropathy
term:
id: HP:0009830
label: Peripheral neuropathy
notes: >-
No frequency band. The founding cohort reports it as a later development
without a count, and an independent patient had normal nerve conduction
studies, so the feature is variable.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patients presented in the preschool years with progressive spastic
paraparesis and ataxia (with a characteristic pattern of progressive
leucodystrophy and brain atrophy on MRI scan) and later developed cataracts
and peripheral neuropathy.
explanation: >-
Peripheral neuropathy as a later development in the founding cohort.
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Nerve conduction studies and needle electromyography were within normal
range.
explanation: >-
A patient with established PEX16 disease and no electrophysiological
neuropathy. Recorded as REFUTE against the claim that peripheral
neuropathy is a constant feature, which is what keeps this phenotype
correctly variable rather than expected.
genetic:
- name: PEX16
gene_term:
preferred_term: PEX16
term:
id: hgnc:8857
label: PEX16
relationship_type: CAUSATIVE
variant_origin: GERMLINE
presence: Biallelic pathogenic or likely pathogenic variants
notes: >-
PEX16 (HGNC:8857, OMIM 603360) is at 11p11.2 and encodes a 336-amino-acid
integral peroxisomal membrane peroxin, Pex16p. Reported PBD8B genotypes are
private and scattered: five novel apparent homozygous mutations across the
six founding patients, a homozygous c.859C>T in a consanguineous kindred,
compound heterozygous c.658G>A p.(Ala220Thr) and c.830G>A p.(Arg277Gln) in a
whole-genome-sequencing patient, and four further novel alleles in the case
series. No recurrent founder allele is described, and no genotype-phenotype
rule is asserted here - the humanised Drosophila work grades alleles by
rescue rather than by clinical prediction. The severe-end allele that
anchors the contrast is the nonsense R176X of the original complementation
group D patient.
evidence:
- reference: CGGV:assertion_7506d938-efb4-416c-aafd-221251d00e6e-2020-01-13T170000.000Z
reference_title: "PEX16 / peroxisome biogenesis disorder (Definitive)"
supports: SUPPORT
evidence_source: OTHER
directness: DIRECT
snippet: "PEX16 | HGNC:8857 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
explanation: >-
ClinGen's definitive gene-disease validity classification for PEX16.
- reference: PMID:9837814
reference_title: Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
These results demonstrate that mutation in PEX16 is the genetic cause of
CG-D PBDs.
explanation: >-
Assigns PEX16 to complementation group D. Indirect for PBD8B: the patient
characterised had Zellweger syndrome, so this establishes the gene for the
group rather than the non-classic allele class.
- reference: PMID:9837814
reference_title: Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
One patient (PBDD-01) possessed a homozygous, inactivating nonsense
mutation, C-->T at position 526 in a codon (CGA) for 176Arg, that resulted
in a termination codon (TGA).
explanation: >-
The severe-end nonsense allele named in this block's notes. Indirect: a
PBD8A genotype, cited to anchor the contrast with the hypomorphic alleles
of this entity.
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
WES revealed a novel homozygous variant in PEX16 (c.859C>T).
explanation: >-
One of the PBD8B genotypes listed in this block's notes.
biochemical:
- 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
for a peroxisomal disorder, and at this end of the spectrum they are an
unreliable gate rather than a reliable one. Elevations may be subtle, and at
least one genetically confirmed patient had frankly normal values. A normal
result does not exclude PBD8B.
biomarker_term:
preferred_term: very long-chain fatty acid
term:
id: CHEBI:27283
label: very long-chain fatty acid
evidence:
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Very-long-chain fatty acids analysis showed subtle elevations in C26 and
C26/C22.
explanation: >-
The magnitude of the abnormality in a genetically confirmed kindred:
subtle, not diagnostic on its own.
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Plasma very long chain fatty acids (VLCFA) and lysosomal enzymes were
normal
explanation: >-
A genetically confirmed PEX16 patient with normal plasma VLCFA. Recorded
as REFUTE against the claim that this marker is reliably elevated in this
disorder, which is the practical point a curator or clinician needs from
this row.
- name: Peroxisome number and size in patient cells
notes: >-
The cellular assay that actually identifies this entity, and the one whose
result is counterintuitive. Immunofluorescence for a peroxisomal marker
shows peroxisomes that are import-competent, larger, and fewer - not absent
as in severe PEX16 disease, and not import-incompetent as in the matrix
import disorders. Reported with PEX14 and with catalase/PMP70 as markers,
and quantified as density and size by automated image analysis in one study.
A laboratory scoring only matrix protein import can therefore call these
cells normal.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Although PEX16 is involved in peroxisomal membrane assembly, PEX16 defects
can present with enlarged import-competent peroxisomes in fibroblasts. This
is important for future diagnostics of patients with a peroxisomal
disorder.
explanation: >-
The authors' own diagnostic conclusion: the cellular phenotype is not what
a laboratory expects from a membrane-assembly peroxin.
- name: Catalase activity
presence: Decreased
context: >-
Measured in patient-derived olfactory-neurosphere neural stem cells against
three control lines, and lower in the patient cells. Not a validated
diagnostic assay for this disorder - it is a single research measurement in
one patient line, and the same report cautions that it does not establish
catalase mistargeting.
biomarker_term:
preferred_term: catalase
term:
id: NCIT:C61062
label: Catalase
evidence:
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Compared to control cells, patient cells had lower catalase activity
explanation: >-
The measurement itself.
animal_models:
- name: Humanised Pex16-null Drosophila
species: Drosophila melanogaster
genotype: Pex16 KozakGAL4 null (Pex16KZ) expressing human PEX16 reference or variant alleles
category: Loss-of-function with cross-species allele rescue
genes:
- preferred_term: PEX16
term:
id: hgnc:8857
label: PEX16
publication: PMID:40621817
description: >-
The fly Pex16 coding sequence is replaced by a GAL4 driver, which both
removes the fly gene and drives expression of a human PEX16 transgene. The
null flies have severe behavioural phenotypes; the human reference allele
rescues them, and patient alleles rescue to different degrees. It is a
readout of how much function each human allele retains, not a model of the
leukodystrophy or spastic ataxia of PBD8B.
associated_phenotypes:
- Severe behavioural phenotypes in Pex16-null flies
- Rescue by the human PEX16 reference allele
- Partial rescue by alleles from mild PBD and full rescue by alleles from atypical ataxia
modeled_mechanisms:
- target: Hypomorphic PEX16 Variants with Residual Peroxin Function
relationship: MEASURES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
Grades the residual function of human PEX16 alleles by how far each
rescues the fly null, which is the allele-specific, continuous residual
function this node describes.
limitations: >-
The human alleles are expressed from a GAL4-driven transgene on a fly
null background rather than at the endogenous locus, so expression level
is not physiological, and the readouts are organismal behaviour and
lifespan rather than white-matter or long-tract degeneration.
readouts:
- name: Rescue of Pex16-null phenotypes by human PEX16 alleles
target: Hypomorphic PEX16 Variants with Residual Peroxin Function
direction: RESTORED
interpretation: >-
Full rescue by alleles from atypical ataxia and partial rescue by alleles
from mild PBD place the atypical alleles at the high-residual-function end
of the series.
evidence:
- reference: PMID:40621817
reference_title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Alleles linked to mild PBD showed partial rescue, while variants associated with atypical ataxia could fully rescue."
explanation: >-
The allele-graded rescue result that this readout records.
evidence:
- reference: PMID:40621817
reference_title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We identified a severity spectrum for PEX2 and PEX16 alleles, with some missense mutations exhibiting severity comparable to truncations."
explanation: >-
The model resolves a severity spectrum across PEX16 alleles, which is
why it is informative for the residual-function node.
evidence:
- reference: PMID:40621817
reference_title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We performed rescue with human reference, variant PEX2 and PEX16 alleles, and phenotypic rescue was observed when human PEX2Ref or PEX16Ref were expressed in Pex2KZ or Pex16KZ flies, respectively."
explanation: >-
Establishes that the human reference protein functions in the fly, which
is what licenses reading the variant rescues as a measure of residual
human PEX16 function.
diagnosis:
- name: Genomic sequencing as the primary route to diagnosis
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
description: >-
Unlike classic Zellweger-spectrum disease, PBD8B is usually reached by
sequencing rather than by biochemistry. Of the four clinical reports behind
this entry, one identified the gene only after sequencing all known PEX
genes, one by whole-exome sequencing, and one by whole-genome sequencing in a
patient whose plasma very-long-chain fatty acids were normal and who had
already had targeted hereditary-spastic-paraplegia and leukodystrophy genes
excluded. The practical rule is that PEX16 should be on the gene list for
unexplained childhood-onset spastic ataxia with leukodystrophy, whatever the
peroxisomal biochemistry shows.
evidence:
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
This paper highlights the diagnostic challenge of PEX16 patients due to the
widely variable clinical and biochemical phenotypes.
explanation: >-
States the diagnostic problem this block exists to record.
- reference: PMID:30078639
reference_title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
It also emphasizes the important roles of combined biochemical assays with
next generation sequencing techniques in reaching diagnosis in the context
of atypical clinical presentations, subtle biomarker abnormalities and
consanguinity.
explanation: >-
The authors' own recommendation to combine sequencing with biochemistry
rather than gating on biochemistry.
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Subsequent sequencing of all known PEX genes revealed five novel apparent
homozygous mutations in the PEX16 gene.
explanation: >-
Even in the founding cohort the gene was reached by sequencing the whole
PEX panel, after the cellular assays had failed to point at PEX16.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
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: >-
The GeneReviews confirmatory criterion: biallelic pathogenic variants in a
ZSD-PEX gene, of which PEX16 is one. INDIRECT because the sentence covers
all thirteen genes rather than PEX16, and GeneReviews frames it as
following suggestive biochemistry, which in PBD8B may be mild or absent,
as the entries above record.
- name: Peroxisome morphology in cultured patient cells
diagnosis_term:
preferred_term: clinical laboratory procedure
term:
id: NCIT:C25294
label: Laboratory Procedure
description: >-
Immunofluorescence for peroxisomal markers in fibroblasts or another
patient-derived line, scored for peroxisome number and size rather than only
for matrix protein import. This is the assay that can be misread in PBD8B:
the peroxisomes are import-competent, so an import-only readout looks normal
while the density and size are abnormal.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Immunofluorescence microscopy revealed the presence of import-competent
peroxisomes, which were increased in size but reduced in number.
explanation: >-
What the assay shows, and the two parameters that must be scored for it to
be informative here.
- name: Brain MRI
diagnosis_term:
preferred_term: brain magnetic resonance imaging
term:
id: NCIT:C16809
label: Magnetic Resonance Imaging
description: >-
Brain MRI shows a recurring pattern of T2/FLAIR hyperintensity in the
brainstem, the superior and middle cerebellar peduncles, the corticospinal
tracts and the splenium of the corpus callosum. It does not establish the
diagnosis, but in a child with spastic ataxia it points towards a
peroxisomal leukodystrophy and so towards sequencing that includes PEX16.
Repeat imaging is also how white-matter progression is followed.
evidence:
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Brain MRI studies commonly showed T2/FLAIR hyperintensities in the
brainstem, superior and middle cerebellar peduncles, corticospinal tracts,
and splenium of the corpus callosum.
explanation: >-
The imaging pattern across a case series of patients with this PEX16
presentation.
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
head MRI to evaluate for white matter changes that may explain changes in
cognitive and/or motor ability
explanation: >-
GeneReviews surveillance for the Zellweger spectrum includes repeat head
MRI for white-matter change. INDIRECT because it is stated for the
spectrum as a whole.
treatments:
- name: Levodopa/Carbidopa for Dystonia
therapeutic_modality: SMALL_MOLECULE
description: >-
The only intervention in this entry with a reported response. Five patients
with dystonia in the case series were given a levodopa/carbidopa trial; four
had partial but significant improvement in dystonia and tremor and one had
only a minimal response. Read this as a reported, uncontrolled treatment
trial inside a seven-patient case series, not as an established therapy: no
control arm, no blinding, no dose-response and no replication. The reporting
authors present it as a proposed treatment for the dystonia rather than as a
validated one.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: levodopa
term:
id: CHEBI:15765
label: L-dopa
- preferred_term: carbidopa
term:
id: CHEBI:3395
label: carbidopa
target_mechanisms:
- target: Dystonia
description: >-
Symptomatic: the drug is directed at the dystonic phenotype, not at the
peroxisomal lesion. Nothing in the report claims an effect on peroxisome
number, biochemistry, or the white-matter disease.
evidence:
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Four treated patients had partial but significant improvements in their
dystonia and tremors, and 1 patient had only minimal response.
explanation: >-
The reported response, including the patient who did not respond.
evidence:
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Five patients were noted to have dystonia and received a treatment trial of
levodopa/carbidopa.
explanation: >-
Establishes the intervention and the number of patients exposed to it.
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
This study further characterizes the phenotype of PEX16 defects by
highlighting novel and distinctive clinical, neuroradiological, and
molecular features of the disease and proposes a potential treatment for
the dystonia.
explanation: >-
The authors' own framing - a proposed potential treatment - which is the
strength of claim this entry records.
- name: Symptomatic and Supportive Management
therapeutic_modality: OTHER
description: >-
No disease-modifying treatment exists for any peroxisome biogenesis
disorder. Management is symptomatic and is drawn from the Zellweger-spectrum
guidance: cataract removal, glasses for refractive error, fat-soluble vitamin
supplementation, and early intervention for developmental needs. Which
elements apply to an individual with PBD8B depends on which manifestations
they have, and several items on the ZSD list - hearing aids, adrenal
replacement, dental management of amelogenesis imperfecta - address features
that were absent in every patient of the PEX16 case series.
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: INDIRECT
snippet: >-
Treatment of manifestations: The focus is on symptomatic therapy and may
include gastrostomy to provide adequate calories, hearing aids, cataract
removal, glasses to correct refractive errors, supplementation of
fat-soluble vitamins, and cholic acid supplementation
explanation: >-
The supportive package for the Zellweger spectrum. Indirect: gene-agnostic
guidance covering the thirteen ZSD-PEX genes, and written mostly around
phenotypes that this entity may not have.
- name: Genetic Counseling
therapeutic_modality: BEHAVIORAL
description: >-
Recessive inheritance with a 25 percent sibling recurrence risk, and carrier
and prenatal testing available once both familial variants are known.
Consanguinity is prominent in the reported families, which makes carrier
testing of at-risk relatives particularly relevant here.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:20301621
reference_title: Zellweger Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Carrier testing for at-risk relatives is possible if the pathogenic
variants have been identified in an affected family member.
explanation: >-
The counselling options available once the genotype is known. Indirect:
gene-agnostic ZSD guidance.
clinical_trials:
- name: NCT01668186
phase: NOT_APPLICABLE
status: UNKNOWN
description: >-
A longitudinal natural history study of peroxisome biogenesis disorders, not
an interventional trial. It is recorded here because the seven-patient
atypical PEX16 case series that supplies most of this entry's clinical
evidence, including the levodopa/carbidopa observation, was registered under
it. Status is recorded as UNKNOWN because the cached registry summary does
not state a current recruitment status.
evidence:
- reference: clinicaltrials:NCT01668186
reference_title: Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: >-
The Peroxisome Biogenesis Disorders (PBD) are a group of inherited
disorders due to defects in peroxisome assembly causing complex
developmental and metabolic sequelae.
explanation: >-
The registry record establishing the study's scope. Indirect: a
registration document covering peroxisome biogenesis disorders as a class,
not a PEX16-specific protocol.
prevalence:
- population: Global
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Roughly seventeen individuals are reported across the four clinical sources
used here: six in the founding cohort (PMID:20647552), seven in the case
series (PMID:35106698, two of whom were previously reported and so may
overlap the founding six), three in a consanguineous kindred (PMID:30078639)
and one by whole-genome sequencing (PMID:30094183). The overlap is not
resolvable from the cached abstracts, so this is an upper bound on distinct
individuals rather than a count. No population prevalence or incidence has
been estimated for PBD8B, and none is recorded.
evidence:
- reference: PMID:20647552
reference_title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
To report on six patients with an unexpected mild variant peroxisome
biogenesis disorder due to mutations in the PEX16 gene.
explanation: >-
The founding cohort size.
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
In this case series, medical records and brain MRIs from 7 patients with
this PEX16 presentation were reviewed to further characterize this
phenotype.
explanation: >-
The case-series size, and the second largest published group.
differential_diagnoses:
- name: Peroxisome biogenesis disorder 8A (classic PEX16 Zellweger syndrome)
description: >-
The same gene at the severe pole. PBD8A presents in the newborn period with
the full Zellweger picture and has no peroxisomal remnants in fibroblasts and
no detectable PEX16 protein on immunoblot. It has no entry in this knowledge
base yet.
distinguishing_features:
- >-
Severity and age of onset - PBD8A presents as neonatal Zellweger syndrome,
PBD8B in the preschool years with spastic paraparesis and ataxia.
- >-
Cellular phenotype is the discriminator that actually works - total absence
of peroxisomal remnants in PBD8A against enlarged, import-competent
peroxisomes in PBD8B.
- Residual PEX16 protein is detectable on immunoblot in the atypical presentation
and absent in the severe one.
evidence:
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
We demonstrated residual PEX16 protein amounts by immunoblotting in
fibroblasts available from 5 patients with this atypical PEX16 disease (3
from this series, 2 previously reported), in contrast to the absence of
PEX16 protein in fibroblasts from a patient with the severe ZSD
presentation.
explanation: >-
The molecular distinction between the two ends of the PEX16 spectrum.
- name: Intermediate and milder Zellweger spectrum disorder of other complementation groups
disease_term:
preferred_term: Zellweger spectrum disorder
term:
id: MONDO:0019234
label: peroxisome biogenesis disorder
description: >-
The non-classic ends of the other PEX genes - PEX1 (PBD1B), PEX5 (PBD2B),
PEX6 (PBD4B) and others - share the biochemical screen and are distinguished
only by sequencing. The PEX16 presentation is nonetheless atypical for the
group, and the differences are usable at the bedside.
distinguishing_features:
- Sensory loss from retinal dystrophy and sensorineural hearing loss, and amelogenesis
imperfecta in the secondary teeth, are characteristic of intermediate/milder ZSD
generally but were absent in all seven patients of the PEX16 case series.
- Cognition is often preserved in PEX16 disease and survival is prolonged, where
hypotonia and developmental delay are the typical ZSD picture.
- The cellular lesion is membrane assembly rather than matrix protein import, so
an import-scored fibroblast assay may read normal in PEX16 disease and abnormal
in the others.
evidence:
- reference: PMID:35106698
reference_title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Classic PBD features such as sensory deficits and amelogenesis imperfecta
were absent in all 7 patients, while all patients had hypertonia.
explanation: >-
The negative findings that separate the PEX16 presentation from the rest
of the spectrum.
- 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 intermediate/milder ZSD phenotype that the PEX16 presentation departs
from. Indirect: gene-agnostic across the thirteen ZSD-PEX genes.
- name: Hereditary spastic paraplegia
description: >-
The label these patients most often carry before sequencing. Childhood-onset
progressive spastic paraparesis with white-matter change and preserved
cognition is an HSP presentation until a PEX gene is found, and at least one
reported patient had HSP genes specifically excluded first.
distinguishing_features:
- Cerebellar signs, cataract, and later peripheral neuropathy alongside the spasticity
point away from uncomplicated HSP.
- A leucodystrophy-plus-atrophy MRI pattern with brainstem and cerebellar peduncle
involvement is not typical of common HSP genotypes.
- Peroxisomal biochemistry may be normal, so it cannot be used to exclude the
peroxisomal aetiology.
evidence:
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Previous genetic testing was negative including sequencing and multiplex
ligation depended probe amplification of ATL1 and sequencing of the NIPA1
and EIF2B1 - EIF2B5 genes.
explanation: >-
A reported patient in whom hereditary spastic paraplegia and leukodystrophy
genes were excluded before PEX16 was found, which is the diagnostic path
this differential describes.
discussions:
- discussion_id: pex16_enlarged_peroxisome_mechanism
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why do the peroxisomes that survive a partial PEX16 defect become enlarged
rather than simply fewer?
attaches_to:
- pathophysiology#Reduced Peroxisome Number with Compensatory Enlargement
rationale: >-
Reduced number and increased size have now been observed together in three
independent patient materials - fibroblasts from six founding patients,
olfactory-neurosphere neural stem cells from an unrelated patient, and
fibroblasts from a consanguineous kindred - so the morphology is
reproducible. No mechanism for the enlargement has been established. The
obvious candidate, a shift in the balance between PEX11-mediated division of
existing peroxisomes and PEX16-dependent de novo formation, has not been
tested in PBD8B cells. The authors who quantified the morphology state
explicitly that the mechanism is unclear. This matters beyond curiosity:
whether the enlarged organelles are functionally adequate per unit membrane
determines whether the cellular deficit is one of total peroxisomal capacity
or of peroxisome distribution.
evidence:
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
as well as putative novel features observed in this study including
reduced catalase activity, is currently unclear
explanation: >-
The gap stated by the authors who measured the morphology.
proposed_experiments:
- experiment_id: pex16_division_vs_de_novo
name: Separate division from de novo formation in PBD8B cells
description: >-
In patient-derived cells carrying hypomorphic PEX16 alleles, measure
peroxisome fission and de novo formation independently - PEX11-beta
knockdown and rescue, and pulse labelling of newly formed peroxisomes -
to determine whether the enlargement reflects impaired division of a
reduced founder population or an altered division-to-formation balance.
would_support:
- pathophysiology#Reduced Peroxisome Number with Compensatory Enlargement
- experiment_id: pex16_per_peroxisome_capacity
name: Metabolic capacity per unit peroxisome membrane
description: >-
Normalise beta-oxidation flux and plasmalogen synthesis to total
peroxisomal membrane area rather than to cell number in patient and
control cells, to test whether the enlarged peroxisomes are functionally
equivalent to a larger number of normal ones.
would_support:
- pathophysiology#Attenuated Peroxisomal Metabolic Block
- discussion_id: pex16_catalase_to_white_matter_link
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does reduced peroxisomal catalase activity contribute to the white-matter
lesion in PEX16 disease, or is the metabolic block the whole story?
attaches_to:
- pathophysiology#Reduced Peroxisomal Catalase Activity
- pathophysiology#Progressive Central White Matter and Long Tract Degeneration
rationale: >-
The edge between these two nodes is the weakest in this entry and is marked
PROVISIONAL for a reason. Catalase activity is reduced in one patient cell
line, but the expected oxidative-stress consequence did not appear: on
hydrogen peroxide challenge the patient cells showed less signal on an
oxidative-stress indicator, not more, which the reporting authors attribute
to compensation by other peroxide-metabolising enzymes. The measurement was
also whole-cell rather than particulate, so it does not establish that
peroxisomal catalase specifically was lost. Until the question is settled,
the white-matter lesion in this entry should be read as following from the
attenuated metabolic block, with the catalase branch an open possibility
rather than a second established route.
evidence:
- reference: PMID:30094183
reference_title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
snippet: >-
Furthermore, patient cells had reduced oxidative stress levels after
exposure to hydrogen-peroxide (H2O2), which may be a result of
compensation by H2O2 metabolising enzymes other than catalase to preserve
peroxisome-related cell functions.
explanation: >-
The result that blocks the straightforward reading of reduced catalase as
increased oxidative stress.
proposed_experiments:
- experiment_id: pex16_particulate_catalase
name: Particulate versus cytosolic catalase in PEX16 patient cells
description: >-
Fractionate patient and control cells and measure catalase activity in the
peroxisomal versus the cytosolic fraction, in several genetically
confirmed PEX16 lines, to establish whether catalase is mislocalised or
simply reduced in proportion to peroxisome number.
would_support:
- pathophysiology#Reduced Peroxisomal Catalase Activity
- experiment_id: pex16_oligodendrocyte_model
name: Redox and lipid phenotype in a PEX16 oligodendrocyte model
description: >-
Differentiate patient-derived induced pluripotent stem cells to
oligodendrocytes and measure peroxisome number, catalase activity,
peroxide handling, and myelin lipid composition, to test whether the
cell type that fails in vivo shows the redox phenotype that fibroblasts
and neural stem cells do not.
would_support:
- pathophysiology#Progressive Central White Matter and Long Tract Degeneration
references:
- reference: PMID:20647552
title: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
- reference: PMID:35106698
title: "Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series."
- reference: PMID:30078639
title: Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
- reference: PMID:30094183
title: Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
- reference: PMID:9837814
title: Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D.
- reference: PMID:9922452
title: Peroxisome synthesis in the absence of preexisting peroxisomes.
- reference: PMID:12223482
title: "The membrane biogenesis peroxin Pex16p. Topogenesis and functional roles in peroxisomal membrane assembly."
- reference: PMID:28146471
title: Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes.
- reference: PMID:40621817
title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
- reference: PMID:20301621
title: Zellweger Spectrum Disorder.
tags:
- GeneReviews
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, AND WHY THIS IS A STANDALONE ENTRY. Claim issue #11974 asked whether PBD8B should be an entry, a subtype, or out of scope. It is curated as a distinct entry, following Peroxisome Biogenesis Disorder 1B (PEX1), 2B (PEX5) and 4B (PEX6), on the same reasoning those entries record: the A/B split inside a PEX complementation group is a mechanistic statement about how much peroxin function survives, not a bare severity label, and the causal gene differs between groups. Three repository facts back that up rather than a preference. `Peroxisome_Biogenesis_Disorder.yaml` carries no `has_subtypes` block at all, so there is no subtype list for this concept to join. MONDO places MONDO:0013943 under MONDO:0100269 (peroxisome biogenesis disorder due to PEX16 defect), a gene-level parent that is itself uncurated, not under a curated disease. And PBD8B has its own primary literature - six patients in the founding report, seven in a later case series, three in a consanguineous kindred and one by whole-genome sequencing - which a subtype row could not carry. 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 and is deliberately not duplicated here. What this entry carries is what is PEX16- and non-classic-specific: a membrane assembly lesion rather than a matrix import lesion, and a residual-function phenotype that presents as enlarged import-competent peroxisomes rather than as absent ones. WHERE THE GENE CAME FROM. The stub records no causal gene. PEX16 was resolved from the MONDO parent chain (MONDO:0100269, "peroxisome biogenesis disorder due to PEX16 defect") and independently confirmed against NCBI `mim2gene_medgen`, which maps OMIM:614877 to GeneID 9409 with a GeneMap source. The HGNC REST API returns HGNC:8857, symbol PEX16, "peroxisomal biogenesis factor 16", 11p11.2, OMIM gene 603360. `kb/` was then re-checked for PEX16 rather than for the disease label: the only hit is a `genetic:` row on `Peroxisome_Biogenesis_Disorder.yaml`, which cites the same ClinGen assertion used here and curates no PEX16-specific mechanism, so nothing was already covering this entity under another name. PBD8A IS NOT CURATED HERE AND IS NOT IMPLIED. Classic PEX16 Zellweger syndrome (PBD8A, OMIM 614876) has no entry in this knowledge base. It appears in this entry only as the contrast that defines "8B" - the total absence of peroxisomal remnants, and the absence of PEX16 protein on immunoblot, against which the residual-function claim is made. Creating the PBD8A entry is a reasonable follow-on. Evidence items that describe PBD8A cells are marked `directness: INDIRECT` where they are cited in support of a PBD8B claim, because they establish the severe pole rather than this entity. FREQUENCY BANDS ARE NOT ASSERTED. No phenotype in this entry carries a `frequency` band. The reason is specific, not a default. Two of the four clinical sources are single-patient or three-patient reports. The seven-patient case series (PMID:35106698) gives per-feature counts for some features ("all patients had hypertonia", "Five patients were noted to have dystonia") and those numerators are recorded in the phenotype `notes`, but the series is explicitly a selected atypical-phenotype cohort rather than a consecutive PEX16 series, so a band computed from it would describe the selection and not the disease. The founding six-patient report (PMID:20647552) describes its cohort's features collectively in its abstract without per-feature counts. THE NEGATIVE FINDINGS ARE LOAD-BEARING AND ARE CURATED AS SUCH. Two of the most useful facts about this entity are absences: classic PBD sensory deficits and amelogenesis imperfecta were absent in all seven patients of the case series, and plasma very-long-chain fatty acids were normal in the whole-genome-sequencing patient. Both are curated - the first in the Zellweger-spectrum differential, the second on the VLCFA biochemical marker - rather than left out because they are negative. Do not read either as a claim that those features never occur in PEX16 disease; they are cohort-level observations in selected atypical patients. WHAT IS KNOWINGLY ABSENT. No prevalence rate: none has been estimated, so only a literature case count is recorded. The Drosophila humanisation study is curated as an `animal_models:` entry that MEASURES the residual-function node rather than as a disease model: the flies carry a Pex16 null with human alleles expressed on top, so they model the allele series, and the study's own framing is a severity spectrum across PEX2 and PEX16. No `datasets:` block: no PEX16-specific omics dataset was identified, and a gene search for PEX16 would surface Zellweger-spectrum and peroxisome-biology series that resolve perfectly and are not about this entity. No disease-modifying treatment exists; everything curated is supportive, and the one intervention with a reported response (levodopa/carbidopa for dystonia) is an uncontrolled treatment trial within a case series and is curated with that caveat stated in its own description. DEEP RESEARCH. One falcon run was performed and is committed at `research/Peroxisome_Biogenesis_Disorder_8B-deep-research-falcon.md`. It was treated as leads only: every PMID, snippet and ontology term in this entry was fetched and verified against the local cache independently of it, and nothing was bound from the report. The query was disambiguated by temporarily setting this entry's `name:` to "PEX16 deficiency (peroxisome biogenesis disorder 8B, the mild non-Zellweger end of the PEX16 spectrum)" for the duration of the run, because the recipe derives the query from that field and "Peroxisome Biogenesis Disorder 8B" alone is the kind of numbered label a provider substitutes for something else. `just preflight-dr` returned SKIP, not PASS, because MONDO records no causal gene for MONDO:0013943, so its gene-identity check has nothing to discriminate on; SKIP means unchecked. The manual fallback settles it: the report mentions PEX16 101 times and no other PEX gene even once, carries OMIM 614877 (which matches MONDO's cross-reference) alongside 614876 for the severe allelic disorder and 603360 for the gene, and states in its own scope section that PBD8B is the mild end of the PEX16 continuum. It is about the right entity. Its own validators flagged four term problems, recorded here because they are the reason nothing was bound from it: one invented identifier (`HP:000`), one obsolete term (`HP:0040083`), and two identifiers named as something else - `HP:0032312` is "Decreased circulating globulin concentration" and the report calls it "abnormal very-long-chain fatty-acid level". Its reference validator resolved all twelve extracted references. It independently reached the same framing as this entry - residual PEX16 function, a severity position on a continuum rather than a separate biochemical mechanism, and clinical expectations that cannot be quantified because no PEX16 cohort supports them. It also carries leads this entry does not curate, recorded so the next curator does not re-derive them: a hepatocyte-specific Pex16-knockout mouse with absent hepatic peroxisomes and altered serum lipids and bile acids; locomotor, bang-sensitivity and lifespan phenotypes in Pex16-null Drosophila beyond the allele-rescue result cited here; ocular findings across PEX16 disease including optic atrophy and abnormal retinal pigmentation; and a second registered study, NCT06190626, on Zellweger-spectrum retinopathy. None is curated as evidence, because a deep-research report is a lead.
Create: Peroxisome Biogenesis Disorder 8B (MONDO:0013943, PEX16) · 2026-09-16T21:50:13Z · View source
Claim issue #11974. Resolved as DISEASE and curated standalone, following the PBD1B/2B/4B precedent: the A/B split inside a PEX complementation group is a mechanistic claim about residual peroxin function rather than a severity label. Three repository facts supported that rather than a preference - Peroxisome_Biogenesis_Disorder.yaml carries no has_subtypes block, MONDO's parent for MONDO:0013943 is the uncurated gene-level term MONDO:0100269, and PBD8B has its own primary literature across four reports. GENE RESOLUTION. The stub records no causal gene. PEX16 was read off the MONDO parent chain (MONDO:0100269, "peroxisome biogenesis disorder due to PEX16 defect") and independently confirmed two ways: NCBI mim2gene_medgen maps OMIM:614877 to GeneID 9409 with a GeneMap source, and the HGNC REST API returns HGNC:8857 PEX16 "peroxisomal biogenesis factor 16", 11p11.2, gene OMIM 603360. kb/ was then re-searched for PEX16 rather than for the disease label; the only hit is a genetic: row on Peroxisome_Biogenesis_Disorder.yaml citing the same ClinGen assertion, which curates no PEX16 mechanism, so nothing was covering this entity under another name. CONTENT. Six pathophysiology nodes from hypomorphic PEX16 alleles with residual protein, through partially preserved ER-derived membrane assembly and a peroxisome population that is fewer-but-enlarged and import-competent, to an attenuated metabolic block and progressive central white-matter and long-tract degeneration. Nine phenotypes, all wired: no orphan phenotype and no unresolved bare-name target (checked by diffing every downstream[].target, sequelae[].target and target_mechanisms[].target against node and phenotype names). One PEX16 genetic row, three biochemical markers, two diagnosis entries, three treatments including the levodopa/carbidopa dystonia trial, one clinical_trials row for the natural-history study the case series ran under, a CASES_IN_LITERATURE prevalence, three differentials, and two knowledge-gap discussions with four proposed experiments. EVIDENCE DISCIPLINE. 62/62 snippets verified against cached references, 0 skipped by prefix (no DOI citations). Two snippets were requoted to avoid bracketed spans the reference validator strips, rather than widening literal_bracket_patterns. Two evidence items carry supports: REFUTE - a genetically confirmed PEX16 patient with normal plasma VLCFA, and the same patient's normal nerve conduction studies - because both are real negative results that keep the VLCFA marker and the peripheral neuropathy phenotype correctly variable rather than expected. Two items carry quote_role: BACKGROUND where the quoted sentence restates prior work. Every item citing PBD8A material (PMID:9837814, PMID:9922452, PMID:12223482, PMID:28146471) is marked directness: INDIRECT, because those establish the severe pole or the cell biology of the peroxin rather than this entity. No phenotype carries a frequency band; the reason is recorded in the entry notes, and per-feature numerators from the seven-patient case series are recorded in phenotype notes instead. ONTOLOGY TERMS. Every CURIE was resolved through OLS at the time of writing and its canonical label copied from the lookup: HP:0007020, HP:0001251, HP:0002415, HP:0002059, HP:0001332, HP:0001337, HP:0001260, HP:0000518, HP:0009830, HP:0000007, GO:0016557, GO:0045046, GO:0007031, GO:0005777, GO:0004096, GO:0042744, GO:0042760, GO:0008611, CL:0000128, UBERON:0002316, CHEBI:27283, CHEBI:15765 (L-dopa), CHEBI:3395, NCIT:C61062, NCIT:C15986, NCIT:C15747, NCIT:C15240, NCIT:C19770, NCIT:C25294, hgnc:8857. A catalase binding was first written as a GO molecular function on the Biochemical class, which has no such slot; it was moved to biomarker_term with NCIT:C61062. A free-text zygosity string was removed from genetic_context rather than forced into the enum, because reported genotypes are both homozygous and compound heterozygous. DEEP RESEARCH. One falcon run, committed. preflight-dr returned SKIP (MONDO records no causal gene for this term, so the gene check cannot discriminate); the manual fallback is decisive - PEX16 101 mentions, zero for any other PEX gene, OMIM 614877 matching MONDO's xref. Nothing was bound from the report; its own term validator flagged one invented identifier, one obsolete term and two mislabelled ones, all recorded in the entry notes. Its leads that this entry does not curate are listed there too. The nine DOI_*.md cache files the report's reference validator wrote are not committed, because this entry cites none of them. A cosmetic frontmatter rewrite of the tracked references_cache/clinicaltrials_NCT01668186.md was reverted. VALIDATION. just validate, validate-terms, validate-disorders (batched), count-verified-snippets, check-entity-refs, check-duplicate-keys, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-title-snippets, check-snippet-length, check-snippet-grading, check-environmental-evidence, check-stubs, validate-history. Stub stubs/Peroxisome_Biogenesis_Disorder_8B.yaml deleted.
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 PEX16 deficiency (peroxisome biogenesis disorder 8B, the mild non-Zellweger end of the PEX16 spectrum) 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.
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For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
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Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.
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For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
PEX16 deficiency is an ultra-rare, autosomal-recessive peroxisome-biogenesis disorder caused by biallelic pathogenic variants in PEX16. The historical label peroxisome biogenesis disorder 8B (PBD8B) denotes the milder, non-classic-Zellweger end of the PEX16 phenotypic continuum. Its best-documented presentation is a childhood-onset, slowly progressive spastic-ataxia/leukodystrophy syndrome that may include dystonia, tremor, dysarthria, neuropathy, hearing or visual disease, while cognition and plasma very-long-chain fatty acids (VLCFAs) can be relatively preserved. This is not a separate biochemical mechanism from PEX16-related Zellweger spectrum disorder (ZSD), but a severity category generally associated with residual PEX16 function. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2, rayana2026polyunsaturatedfattyacid pages 14-15)
The evidence base is unusually small. Many statements below derive either from individual PEX16 patients, patient-derived cells, or aggregate ZSD guidance rather than PBD8B-specific cohorts. Consequently, frequencies, penetrance, incidence, survival, and treatment-response estimates cannot presently be calculated reliably.
| Domain | PEX16-specific finding | Evidence strength/type | Suggested ontology identifiers |
|---|---|---|---|
| Identity | Mild PEX16 deficiency / peroxisome biogenesis disorder 8B (PBD8B) is the non-neonatal, milder end of the PEX16-related Zellweger-spectrum continuum. OMIM 614877; PEX16-related severe PBD8A/Zellweger phenotype is OMIM 614876. (rayana2026polyunsaturatedfattyacid pages 14-15) | Authoritative disease classification; human disease literature | OMIM:614877; MONDO:0013943 user supplied—verify against current MONDO release; MeSH/Orphanet/ICD exact mappings: verify |
| Causal gene | PEX16, encoding peroxisomal biogenesis factor 16; gene OMIM 603360. (rayana2026polyunsaturatedfattyacid pages 14-15) | Curated gene–disease and functional evidence | HGNC:8857 verify current HGNC record; OMIM:603360; GO:0005777 (peroxisome) |
| Inheritance | Biallelic germline PEX16 variants cause disease through an autosomal-recessive mechanism; the reported mild adult had compound-heterozygous variants inherited from the parents. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2) | Strong human segregation plus functional evidence | HP:0000007 (autosomal recessive inheritance) |
| Cardinal phenotype | A slowly progressive spastic-ataxia/leukodystrophy phenotype may begin in childhood with toe walking and falls and evolve into marked lower-limb spasticity, cerebellar ataxia/dysarthria, tremor, dystonia, white-matter abnormalities, and wheelchair dependence; cognition may remain substantially preserved. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2) | PEX16-specific human case evidence; very small sample | HP:0001257 (spasticity); HP:0001251 (ataxia); HP:0001260 (dysarthria); HP:0001332 (dystonia); HP:0002415 (leukodystrophy); HP:0002352 (white-matter abnormality) |
| Other possible manifestations | Across PEX16-related disease, reported ocular findings include cataract, optic atrophy, and abnormal retinal pigmentation; atypical cases require surveillance for hearing, vision, liver, adrenal, renal, skeletal, and neurologic complications. (rayana2026polyunsaturatedfattyacid pages 14-15, NCT01668186 chunk 1) | PEX16 ocular summary plus broader ZSD natural-history protocol; frequencies unknown | HP:0000518 (cataract); HP:0000648 (optic atrophy); HP:0007703 (abnormal retinal pigmentation); additional exact terms: verify |
| Biochemical caveat | Plasma VLCFAs may be normal or only mildly abnormal in mild PEX16 disease; normal VLCFAs therefore do not exclude PBD8B. Broader testing includes C26:0/C26:1 and C24:0/C22:0 and C26:0/C22:0 ratios, phytanic/pristanic acids, erythrocyte plasmalogens, pipecolic acid, and DHCA/THCA. (kumar2018expandingthespectrum pages 2-3, braverman2016peroxisomebiogenesisdisorders pages 3-4) | Direct PEX16 case observation plus expert diagnostic review | HP:0032312 (abnormal very-long-chain fatty-acid level)—exact applicability may be absent in mild disease; CHEBI identifiers for individual analytes: verify |
| Molecular mechanism | PEX16 is an integral peroxisomal membrane biogenesis factor and PEX3 docking component. Biallelic dysfunction disrupts early membrane assembly and protein trafficking, producing fewer, enlarged, or absent functional peroxisomes and downstream impairment of VLCFA/branched-chain fatty-acid oxidation, ether-lipid synthesis, bile-acid metabolism, and redox homeostasis. (kumar2018expandingthespectrum pages 1-2, wangler2017peroxisomalbiogenesisis pages 3-6, chen2024hepatocytespecificpex16abrogation pages 1-2) | Human patient-cell evidence supported by fly and mouse functional studies; some downstream tissue links remain inferred | GO:0007031 (peroxisome organization); GO:0016558 (protein import into peroxisome matrix); GO:0033540 (fatty-acid beta-oxidation using acyl-CoA oxidase); GO:0005777 (peroxisome); GO:0005783 (endoplasmic reticulum) |
| Diagnostic approach | Confirm with biallelic PEX16 variants using a peroxisomal-disorder/leukodystrophy panel, exome, or genome sequencing, with deletion/duplication analysis as needed. Pair genetics with multianalyte peroxisomal biochemistry and, when results are equivocal, cultured-fibroblast assays of catalase localization, peroxisome number/morphology, VLCFA oxidation, and plasmalogen synthesis. (kumar2018expandingthespectrum pages 2-3, braverman2016peroxisomebiogenesisdisorders pages 3-4, braverman2016peroxisomebiogenesisdisorders pages 4-6) | Expert-review/technical-standard approach plus PEX16 patient-cell validation | NCIT:C15709 (genetic testing); NCIT:C101295 (whole-exome sequencing)—verify current NCIT labels; LOINC assay identifiers: laboratory-specific/verify |
| Treatment status | No approved PEX16-specific disease-modifying treatment is established. Management is multidisciplinary and supportive: physical/occupational/speech therapy, mobility and spasticity management, hearing/vision support, nutritional or gastrostomy support when needed, seizure treatment, and surveillance of liver, adrenal, renal, bone, dental, and neurologic status. (braverman2016peroxisomebiogenesisdisorders pages 4-6, braverman2016peroxisomebiogenesisdisorders pages 10-12) | Expert consensus extrapolated from Zellweger-spectrum care; no PEX16-specific response rates | NCIT:C15329 (supportive care); NCIT intervention identifiers for individual therapies: verify |
| Prognosis | PBD8B can permit survival into adulthood but is generally chronic and neurologically progressive; one individual progressed from childhood gait disturbance to wheelchair dependence while retaining near-normal cognition at age 41. Gene-specific survival rates, life expectancy, and validated prognostic biomarkers are unavailable. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2) | Direct longitudinal history from one adult plus major evidence gaps | HP:0003676 (progressive disorder); survival/prognosis ontology mapping: verify |
| Model evidence | Pex16-null Drosophila show reduced peroxisomes, locomotor impairment, bang sensitivity, and markedly shortened lifespan; human reference PEX16 rescues organelle and behavioral phenotypes, whereas variant rescue distinguishes severe from hypomorphic alleles. Hepatocyte-specific Pex16-knockout mice lack hepatic peroxisomes and show enlarged liver, hepatocyte proliferation, altered serum lipids/bile acids, and resistance to diet-induced steatosis. (gomez2024distinguishingpexgene pages 16-21, gomez2024distinguishingpexgene pages 32-39, chen2024hepatocytespecificpex16abrogation pages 1-2) | Strong experimental loss-of-function/rescue evidence; organismal models do not fully reproduce mild human neurologic disease | NCBI Taxon:7227 (Drosophila melanogaster); NCBI Taxon:10090 (Mus musculus); CL:0000182 (hepatocyte) |
| Current research/registries | The recruiting longitudinal PBD natural-history study NCT01668186 targets 244 participants with annual multisystem, imaging, biochemical, and genotype–phenotype follow-up; the recruiting ZSD retinopathy study NCT06190626 targets 30 participants. Neither provides PEX16-specific outcomes yet. (NCT01668186 chunk 1, NCT06190626 chunk 2) | Active observational research; no efficacy inference | ClinicalTrials.gov:NCT01668186; ClinicalTrials.gov:NCT06190626 |
| Key evidence gaps | No reliable PEX16/PBD8B prevalence, incidence, penetrance estimate, sex ratio, carrier frequency, founder effect, protective allele, environmental modifier, validated quality-of-life measure, genotype-specific treatment response, natural veterinary counterpart, or proven epigenomic/single-cell/spatial signature has been established. | Absence of adequate PEX16-specific cohorts; do not infer from aggregate ZSD data | Ontology mappings unavailable or not applicable; mark as unknown rather than negative where systematic study is lacking |
Table: Compact knowledge-base summary of mild PEX16 deficiency/PBD8B, integrating human, cellular, animal-model, diagnostic, and clinical-management evidence. Unverified or unavailable ontology mappings and major evidence gaps are explicitly identified.
PEX16 is required early in peroxisomal membrane assembly. Biallelic dysfunction reduces the formation of competent peroxisomes and secondarily disrupts several lipid-metabolic and redox functions. PEX16-related disease spans severe neonatal Zellweger syndrome through atypical childhood/adult neurodegenerative disease. PBD8B should therefore be modeled as the mild end of a continuous PEX16-related ZSD spectrum, not as an entirely independent disorder. Historical labels such as neonatal adrenoleukodystrophy and infantile Refsum disease likewise describe severity positions rather than cleanly separable entities. (rayana2026polyunsaturatedfattyacid pages 14-15, braverman2016peroxisomebiogenesisdisorders pages 1-3)
The present entry is an aggregated disease-level synthesis, but much of the PEX16-specific clinical evidence originates from case reports or small case series rather than EHR-scale datasets. The 2022 PEX16 atypical-ZSD case series was published online February 2, 2022 (Neurogenetics 23:115–127; PMID 35106698; DOI: 10.1007/s10048-022-00684-7). (NCT01668186 chunk 2)
The primary cause is biallelic germline loss-of-function or hypomorphic variation in PEX16. The inheritance pattern is autosomal recessive. Severe null-like alleles are expected to abolish peroxisome formation more extensively, whereas residual-function missense or in-frame alleles may support survival into childhood or adulthood. Humanized-fly experiments support an allele-severity continuum rather than a simple variant-class rule. (kumar2018expandingthespectrum pages 1-2, gomez2024distinguishingpexgene pages 16-21)
A well-characterized 41-year-old woman carried compound-heterozygous variants NM_004813.2:c.658G>A, p.(Ala220Thr) and c.830G>A, p.(Arg277Gln). Both were absent or extremely rare in gnomAD, affected conserved residues, were computationally predicted to be damaging, segregated from the parents, and were accompanied by abnormal peroxisome morphology and function in patient-derived neural stem-like cells. These observations support pathogenicity, although current ClinVar classifications should be checked independently before clinical reporting. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2)
The atypical allele PEX16 p.Phe332del showed substantial rescue in humanized Drosophila, consistent with a hypomorphic effect. By contrast, p.Arg176Ter failed to rescue major phenotypes and behaved as a severe allele. This is experimental variant-functional evidence, not by itself an ACMG clinical classification. (gomez2024distinguishingpexgene pages 16-21, gomez2024distinguishingpexgene pages 32-39)
No toxin, infection, lifestyle, occupational exposure, or dietary pattern is established as a cause of PBD8B. No protective PEX16 allele or validated environmental protective factor is known. Nutritional state can, however, alter biomarker detectability: phytanic and pristanic acids may be normal in breastfed neonates because dietary exposure is limited. This is a diagnostic interaction, not evidence that diet prevents the genetic disease. (braverman2016peroxisomebiogenesisdisorders pages 3-4)
Fly data show disproportionate sensitivity to starvation and glucose deprivation, suggesting that systemic metabolic stress can modify phenotype after peroxisome loss. That observation remains preclinical and does not justify a PBD8B-specific high-carbohydrate regimen. (wangler2017peroxisomalbiogenesisis pages 1-2)
The most informative longitudinal case began toe-walking and falling frequently at age three. Gait impairment progressed to wheelchair dependence. Tremor, fine-motor impairment, and involuntary facial movements emerged around age 19; speech disturbance appeared in the mid-thirties. At 41 years, findings included severe lower-limb spasticity, upper-limb ataxia, cerebellar dysarthria, cervical dystonia, head tremor, and Meige-like orofacial movements. Cognition was nearly preserved (MMSE 29/30). MRI demonstrated confluent white-matter abnormalities and atrophy, and MR spectroscopy showed raised myoinositol. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2)
Suggested phenotype annotations include:
The same adult had no seizures, known liver disease, or adrenal insufficiency; VLCFAs, nerve-conduction studies, and needle EMG were normal. These are case-specific negative findings and must not be interpreted as universal exclusions. (kumar2018expandingthespectrum pages 2-3)
Reported PEX16-associated ocular manifestations include cataract, optic atrophy, and abnormal retinal pigmentation. Suggested HPO terms are HP:0000518, HP:0000648, and HP:0007703, respectively. Across ZSD, hearing loss, retinal degeneration, peripheral neuropathy, seizures, hypotonia, feeding difficulty, liver dysfunction, adrenal insufficiency, renal cortical cysts or oxalate stones, low bone density, fractures, and enamel defects may occur; their frequency specifically in PBD8B is unknown. (rayana2026polyunsaturatedfattyacid pages 14-15, braverman2016peroxisomebiogenesisdisorders pages 20-20)
Laboratory abnormalities may include elevated C26:0/C26:1, abnormal C24:0/C22:0 or C26:0/C22:0 ratios, elevated phytanic/pristanic acids, DHCA/THCA and pipecolic acid, and reduced erythrocyte plasmalogens. Mild PEX16 disease can have normal plasma VLCFAs; the finding therefore has incomplete sensitivity. (braverman2016peroxisomebiogenesisdisorders pages 3-4)
The characteristic course is chronic and slowly progressive, but expressivity is broad. Mobility, speech, fine-motor function, vision, and hearing can substantially impair education, employment, independence, and caregiver burden. No PEX16-specific EQ-5D, SF-36, PROMIS, or validated quality-of-life dataset was identified. Aggregate ZSD caregiver work exists, but it cannot provide a PBD8B-specific estimate. (bose2020zellwegerspectrumdisorder pages 7-8)
PEX16 encodes an integral peroxisomal membrane protein. It provides a docking context for PEX3; PEX3 recruits PEX19 and supports delivery of newly synthesized peroxisomal membrane proteins. PEX16 participates in early membrane designation and de novo organelle formation associated with the endoplasmic reticulum. (wangler2017peroxisomalbiogenesisis pages 3-6, chen2024hepatocytespecificpex16abrogation pages 1-2)
Pathogenic variants are germline and biallelic. Reported disease alleles include missense, nonsense, and in-frame-deletion classes. The likely mechanism is loss or reduction of function, not gain of function or dominant negativity. Population frequencies are generally extremely low, but variant-level gnomAD values were not recoverable from the source set and should be queried against the current genome build and transcript.
No validated modifier gene, PEX16-specific methylation signature, histone abnormality, chromosomal rearrangement, or recurrent copy-number syndrome was identified. Chromosomal microarray may detect an exon-spanning or whole-gene deletion but is not the primary test for typical sequence-level PEX16 disease.
PEX16 deficiency is a Mendelian organelle-biogenesis disorder, not an infectious, toxic, radiation-associated, or lifestyle-acquired condition. Smoking, alcohol, physical activity, and pollution have not been shown to alter penetrance. General health maintenance remains appropriate, but it should not be represented as disease prevention. No infectious trigger or zoonotic process applies.
Relevant biological-process terms include GO:0007031 peroxisome organization, GO:0016558 protein import into peroxisome matrix, fatty-acid β-oxidation, ether-lipid biosynthesis, bile-acid biosynthesis, and cellular redox homeostasis. Relevant compartments are GO:0005777 peroxisome and GO:0005783 endoplasmic reticulum.
Suggested cell annotations are neuron (CL:0000540), oligodendrocyte (CL:0000128), astrocyte (CL:0000127), hepatocyte (CL:0000182), retinal pigment epithelial cell, photoreceptor, and peripheral myelinating Schwann cell. Direct PEX16-specific evidence is strongest for patient-derived olfactory neurosphere cells and mouse hepatocytes; involvement of other named cells is based mainly on anatomy and broader PBD models.
Patient-derived olfactory-neurosphere cells had reduced peroxisome density, increased organelle size, reduced catalase activity, and an altered hydrogen-peroxide response. Lower measured oxidative stress after H₂O₂ exposure was interpreted as possible compensation by other peroxide-metabolizing enzymes, not evidence that PEX16 loss is antioxidative. (kumar2018expandingthespectrum pages 1-2)
Drosophila pex16 mutants accumulated long-chain species including C24:0–C30:0, had decreased plasmalogen, and displayed changes in glycolysis, glycogen metabolism, and the pentose-phosphate pathway. No disease-specific human single-cell, spatial-transcriptomic, epigenomic, or integrated multi-omic atlas was identified. (wangler2017peroxisomalbiogenesisis pages 3-6, wangler2017peroxisomalbiogenesisis pages 1-2)
The central nervous system is the dominant organ system in mild disease: corticospinal tracts, cerebral white matter, cerebellar systems, and likely long axons are clinically implicated. The peripheral nervous system may be affected in the broader spectrum, although electrophysiology can remain normal. Other organs requiring surveillance include retina/optic nerve, inner ear, liver, adrenal glands, kidneys, skeleton, teeth, and gastrointestinal/nutritional systems. (kumar2018expandingthespectrum pages 2-3, NCT01668186 chunk 1, braverman2016peroxisomebiogenesisdisorders pages 20-20)
Suggested anatomy terms include brain (UBERON:0000955), cerebral white matter, cerebellum (UBERON:0002037), spinal cord (UBERON:0002240), liver (UBERON:0002107), retina (UBERON:0000966), optic nerve, kidney (UBERON:0002113), and adrenal gland (UBERON:0002369). Disease manifestations are generally bilateral/systemic rather than consistently lateralized.
Onset may be congenital in severe PEX16 deficiency, but PBD8B often has childhood or occasionally later recognition. The documented adult case had insidious motor onset at three years, later extrapyramidal/cerebellar manifestations, and decades-long progression. PBD8B is lifelong; spontaneous remission has not been described. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2)
Critical periods are plausible during fetal neuronal migration, postnatal myelination, and retinal development, but the relative importance of developmental injury versus ongoing degeneration is unresolved. Early molecular diagnosis is valuable because hearing, vision, adrenal, nutritional, orthopedic, and renal complications may be treatable even when the primary biogenesis defect is not.
Inheritance is autosomal recessive. When both parents are confirmed heterozygous carriers, each pregnancy has a 25% probability of an affected child, 50% probability of a carrier child, and 25% probability of inheriting neither familial allele. Expression is variable and depends partly on residual allelic function. Penetrance for clearly pathogenic biallelic genotypes is presumed high but has not been quantified for hypomorphic combinations.
No defensible PBD8B-specific prevalence, incidence, carrier frequency, founder effect, geographic concentration, ethnic enrichment, sex ratio, or age distribution was found. The absence of estimates reflects extreme rarity and ascertainment bias, not proof of equal worldwide frequency. Consanguinity can increase occurrence of homozygous genotypes but is not required.
The ACMG-aligned technical framework is represented by the 2020 laboratory standard, while the major clinical overview is Braverman et al., published online December 23, 2015 and in March 2016 (PMID 26750748; DOI: 10.1016/j.ymgme.2015.12.009). (NCT06190626 chunk 2)
Important alternatives include other PEX-related ZSDs; single-enzyme peroxisomal disorders such as ACOX1 or HSD17B4 deficiency; X-linked adrenoleukodystrophy; Refsum disease; complicated hereditary spastic paraplegias; mitochondrial leukodystrophies; metachromatic leukodystrophy; Krabbe disease; cerebrotendinous xanthomatosis; and adult-onset genetic ataxias. Approximately 10–15% of suspected patients with elevated VLCFAs may instead have a single-enzyme defect, reinforcing the need for multianalyte and molecular confirmation. (braverman2016peroxisomebiogenesisdisorders pages 3-4)
CMA, karyotyping, FISH, mitochondrial-DNA testing, and repeat-expansion assays are not first-line PEX16 tests unless the phenotype or sequencing data indicate an alternative mechanism. RNA sequencing can help resolve suspected splice variants, but no validated PEX16 transcriptomic diagnostic signature exists.
Population newborn screening specifically for PBD8B is not established. X-ALD newborn-screening assays based on elevated VLCFAs may incidentally detect many ZSD cases but can miss biochemically mild PEX16 disease. Cascade testing of relatives is appropriate after familial variants are established. (braverman2016peroxisomebiogenesisdisorders pages 4-6)
PBD8B is compatible with survival into adulthood. It is nevertheless potentially progressive and disabling: the most detailed patient advanced from early-childhood gait difficulty to wheelchair dependence while retaining near-normal cognition at 41. No PEX16-specific five- or ten-year survival, mortality rate, median life expectancy, or validated prognostic model exists. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2)
Likely prognostic factors include residual PEX16 function, age at onset, severity of developmental brain disease, rate of white-matter progression, sensory loss, liver/adrenal involvement, and nutritional/respiratory complications. These are biologically and clinically plausible but have not been quantified for PBD8B. Recovery of established neurodegeneration is not documented; rehabilitation may preserve function and prevent secondary complications.
No approved pharmacologic, gene, RNA, cell, or genome-editing therapy corrects PEX16 deficiency. Care is individualized and multidisciplinary:
These are expert ZSD recommendations rather than therapies proven in PEX16-specific trials. No reliable response percentages or PEX16 pharmacogenomic associations exist. Suggested NCIT intervention concepts include supportive care, physical therapy, occupational therapy, speech-language therapy, hearing aid, cochlear implantation, gastrostomy, anticonvulsant therapy, and genetic counseling; exact NCIT codes should be validated in the target terminology release.
AAV9 gene augmentation for ZSD-associated visual disease has been discussed preclinically, but no human PEX16 gene-replacement trial or efficacy result was identified. (braverman2016peroxisomebiogenesisdisorders pages 10-12)
The inherited biochemical defect cannot be prevented by vaccination, lifestyle modification, or environmental avoidance.
There is no PEX16-specific prophylactic medication.
No well-established naturally occurring PEX16-deficiency syndrome in companion animals, livestock, or wildlife was identified, and there is no zoonotic transmission. Orthologues are conserved in Mus musculus (NCBI Taxon 10090), Drosophila melanogaster (7227), and other model species. Veterinary breed/VBO associations and natural-disease prevalence are unavailable.
Pex16-null flies have markedly reduced peroxisomal puncta, locomotor impairment, bang sensitivity, and shortened lifespan. In the 2024 humanized-fly preprint, null females and males lived on average 13.2 and 8.5 days, versus approximately 49–51 days in controls. Human reference PEX16 partially rescued lifespan to 26.2 and 23 days; p.Phe332del rescued to 26.3 and 26.2 days, whereas p.Arg176Ter did not meaningfully rescue. Human PEX16 also restored peroxisome number and nerve-fiber morphology. These data provide functional evidence for an allele-severity spectrum. (gomez2024distinguishingpexgene pages 16-21, gomez2024distinguishingpexgene pages 32-39)
Earlier fly studies demonstrated loss of punctate GFP-SKL localization, reduced Pex3 staining, increased C24:0–C30:0 species, decreased plasmalogen, locomotor dysfunction, and altered carbohydrate metabolism. Rescue constructs restored organelle markers, strongly linking the phenotype to Pex16 loss. (wangler2017peroxisomalbiogenesisis pages 3-6, wangler2017peroxisomalbiogenesisis pages 1-2)
In a 2024 hepatocyte-specific Pex16 knockout, hepatocyte peroxisomes were absent, hepatocytes proliferated, and liver mass increased. Basal serum triglycerides, free fatty acids, and cholesterol decreased, whereas bile acids increased. Unlike controls and adipocyte-specific knockouts, hepatocyte knockouts resisted high-fat-diet-induced obesity and hepatic steatosis. This is valuable tissue-specific mechanistic evidence but does not recapitulate the mild human neurologic phenotype. DOI: 10.3390/biomedicines12050988, April 2024. (chen2024hepatocytespecificpex16abrogation pages 1-2)
Patient-derived olfactory neurosphere cells reproduce reduced peroxisome density, increased organelle size, reduced catalase activity, and altered oxidative-stress handling. They are useful for variant validation and candidate-drug testing, but they do not reproduce whole-body pharmacology or decades-long tract degeneration. (kumar2018expandingthespectrum pages 2-3, kumar2018expandingthespectrum pages 1-2)
No validated PEX16 patient iPSC-derived organoid, single-cell atlas, spatial-transcriptomic study, or CRISPR therapeutic correction study was identified in the retrieved literature.
The strongest PBD8B evidence comprises biallelic human genotypes with segregation, cellular peroxisome abnormalities, and conserved rescue in model organisms. The most important unresolved questions are the number and spectrum of living patients; variant-level penetrance; tissue-specific biochemical signatures when plasma VLCFAs are normal; longitudinal MRI, vision, hearing, and mobility trajectories; disease-specific quality of life; and whether early restoration of PEX16 can prevent rather than reverse neurologic injury.
Exact abstract quotations were not reproduced where the retrieved full-text evidence did not provide the original abstract wording. This avoids presenting reconstructed summaries as verbatim quotations. The key contemporary experimental conclusion is nevertheless quantitative: hypomorphic and null-like human PEX16 alleles separate in rescue assays, while the major current clinical conclusion is that normal plasma VLCFAs cannot exclude mild PEX16 disease. (braverman2016peroxisomebiogenesisdisorders pages 3-4, gomez2024distinguishingpexgene pages 16-21)
References
(kumar2018expandingthespectrum pages 2-3): Kishore R. Kumar, Gautam Wali, Ryan L. Davis, Amali C. Mallawaarachchi, Elizabeth E. Palmer, Velimir Gayevskiy, Andre E. Minoche, David Veivers, Marcel E. Dinger, Alan Mackay-Sim, Mark J. Cowley, and Carolyn M. Sue. Expanding the spectrum of pex16 mutations and novel insights into disease mechanisms. Sep 2018. URL: https://doi.org/10.1016/j.ymgmr.2018.07.003, doi:10.1016/j.ymgmr.2018.07.003. This article has 16 citations.
(kumar2018expandingthespectrum pages 1-2): Kishore R. Kumar, Gautam Wali, Ryan L. Davis, Amali C. Mallawaarachchi, Elizabeth E. Palmer, Velimir Gayevskiy, Andre E. Minoche, David Veivers, Marcel E. Dinger, Alan Mackay-Sim, Mark J. Cowley, and Carolyn M. Sue. Expanding the spectrum of pex16 mutations and novel insights into disease mechanisms. Sep 2018. URL: https://doi.org/10.1016/j.ymgmr.2018.07.003, doi:10.1016/j.ymgmr.2018.07.003. This article has 16 citations.
(rayana2026polyunsaturatedfattyacid pages 14-15): Naga Pradeep Rayana, Navdeep Gogna, Mark P. Krebs, Gayle B. Collin, Jürgen K. Naggert, and Patsy M. Nishina. Polyunsaturated fatty acid metabolism in the retinal pigment epithelium and its association with outer retinal disease. Mammalian Genome, May 2026. URL: https://doi.org/10.1007/s00335-026-10239-y, doi:10.1007/s00335-026-10239-y. This article has 0 citations and is from a peer-reviewed journal.
(NCT01668186 chunk 1): Nancy Braverman. Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD). McGill University Health Centre/Research Institute of the McGill University Health Centre. 2012. ClinicalTrials.gov Identifier: NCT01668186
(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 353 citations and is from a peer-reviewed journal.
(wangler2017peroxisomalbiogenesisis pages 3-6): Michael F. Wangler, Yu-Hsin Chao, Vafa Bayat, Nikolaos Giagtzoglou, Abhijit Babaji Shinde, Nagireddy Putluri, Cristian Coarfa, Taraka Donti, Brett H. Graham, Joseph E. Faust, James A. McNew, Ann Moser, Marco Sardiello, Myriam Baes, and Hugo J. Bellen. Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in drosophila and mouse. Jun 2017. URL: https://doi.org/10.1371/journal.pgen.1006825, doi:10.1371/journal.pgen.1006825. This article has 58 citations and is from a domain leading peer-reviewed journal.
(chen2024hepatocytespecificpex16abrogation pages 1-2): Xue Chen, Long Wang, Krista L. Denning, Anna Mazur, Yujuan Xu, Kesheng Wang, Logan M. Lawrence, Xiaodong Wang, and Yongke Lu. Hepatocyte-specific pex16 abrogation in mice leads to hepatocyte proliferation, alteration of hepatic lipid metabolism, and resistance to high-fat diet (hfd)-induced hepatic steatosis and obesity. Biomedicines, 12(5):988, Apr 2024. URL: https://doi.org/10.3390/biomedicines12050988, doi:10.3390/biomedicines12050988. This article has 11 citations.
(braverman2016peroxisomebiogenesisdisorders pages 4-6): 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 353 citations and is from a peer-reviewed journal.
(braverman2016peroxisomebiogenesisdisorders pages 10-12): 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 353 citations and is from a peer-reviewed journal.
(gomez2024distinguishingpexgene pages 16-21): Vanessa A. Gomez, Oguz Kanca, Sharayu V. Jangam, Saurabh Srivastav, Jonathan C. Andrews, and Michael F. Wangler. Distinguishing pex gene variant severity for mild, severe, and atypical peroxisome biogenesis disorders in drosophila. bioRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.11.14.623590, doi:10.1101/2024.11.14.623590. This article has 1 citations.
(gomez2024distinguishingpexgene pages 32-39): Vanessa A. Gomez, Oguz Kanca, Sharayu V. Jangam, Saurabh Srivastav, Jonathan C. Andrews, and Michael F. Wangler. Distinguishing pex gene variant severity for mild, severe, and atypical peroxisome biogenesis disorders in drosophila. bioRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.11.14.623590, doi:10.1101/2024.11.14.623590. This article has 1 citations.
(NCT06190626 chunk 2): 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
(braverman2016peroxisomebiogenesisdisorders pages 1-3): 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 353 citations and is from a peer-reviewed journal.
(OpenTargets Search: peroxisome biogenesis disorder 8B-PEX16): Open Targets Query (peroxisome biogenesis disorder 8B-PEX16, 0 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(NCT01668186 chunk 2): Nancy Braverman. Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD). McGill University Health Centre/Research Institute of the McGill University Health Centre. 2012. ClinicalTrials.gov Identifier: NCT01668186
(wangler2017peroxisomalbiogenesisis pages 1-2): Michael F. Wangler, Yu-Hsin Chao, Vafa Bayat, Nikolaos Giagtzoglou, Abhijit Babaji Shinde, Nagireddy Putluri, Cristian Coarfa, Taraka Donti, Brett H. Graham, Joseph E. Faust, James A. McNew, Ann Moser, Marco Sardiello, Myriam Baes, and Hugo J. Bellen. Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in drosophila and mouse. Jun 2017. URL: https://doi.org/10.1371/journal.pgen.1006825, doi:10.1371/journal.pgen.1006825. This article has 58 citations and is from a domain leading peer-reviewed journal.
(braverman2016peroxisomebiogenesisdisorders pages 20-20): 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 353 citations and is from a peer-reviewed journal.
(bose2020zellwegerspectrumdisorder pages 7-8): Mousumi Bose, David D. Cuthbertson, Marsha A. Fraser, Jean-Baptiste Roullet, K. Michael Gibson, Dana R. Schules, Kelly M. Gawron, Melissa B. Gamble, Kathryn M. Sacra, Melisa J. Lopez, and William B. Rizzo. Zellweger spectrum disorder: a cross-sectional study of symptom prevalence using input from family caregivers. Molecular Genetics and Metabolism Reports, 25:100694, Dec 2020. URL: https://doi.org/10.1016/j.ymgmr.2020.100694, doi:10.1016/j.ymgmr.2020.100694. This article has 4 citations.
(wangler2017peroxisomalbiogenesisis pages 2-3): Michael F. Wangler, Yu-Hsin Chao, Vafa Bayat, Nikolaos Giagtzoglou, Abhijit Babaji Shinde, Nagireddy Putluri, Cristian Coarfa, Taraka Donti, Brett H. Graham, Joseph E. Faust, James A. McNew, Ann Moser, Marco Sardiello, Myriam Baes, and Hugo J. Bellen. Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in drosophila and mouse. Jun 2017. URL: https://doi.org/10.1371/journal.pgen.1006825, doi:10.1371/journal.pgen.1006825. This article has 58 citations and is from a domain leading peer-reviewed journal.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 12 |
| Resolved | 12 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 12 |
| On topic | 3 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 43 |
| Resolved | 34 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 1 |
| Unverifiable | 7 |
| Terms whose name was checked | 5 |
| Terms named correctly | 1 |
| Terms named as a different term | 2 |
| Terms whose name is worth a second look | 2 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0013943 (3 mentions) - the report calls it "if available"; MONDO calls it peroxisome biogenesis disorder 8BHP:0032312 (1 mention) - the report calls it "abnormal very-long-chain fatty-acid level"; HP calls it Decreased circulating globulin concentrationThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:000 (1 mention) - HP does not contain this termThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
HP:0040083 (obsolete Toe walking) (1 mention) - replaced by HP:0030051The 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:
NCIT:C15329 (1 mention) - the report calls it "supportive care"; NCIT calls it Surgical Procedure, and lists "Surgical" among its other namesHP:0003676 (1 mention) - the report calls it "progressive disorder"; HP calls it Progressive, and lists "Progressive disorder" among its other namesTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, Taxon, ClinicalTrials.gov.