Peroxisome Biogenesis Disorder 11A (Zellweger)

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic PEX13 variants are required. Reported families include homozygotes from consanguineous unions and compound heterozygotes; ClinGen classifies the PEX13-peroxisome biogenesis disorder relationship as Definitive with autosomal recessive inheritance.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:35854306 SUPPORT Human Clinical

"We report five families carrying biallelic variants in PEX13."

The largest reported PEX13 series states the biallelic requirement across every family.

CGGV:assertion_0c662669-4eb8-45e3-8540-c394ea40c1b2-2019-10-04T160000.000Z SUPPORT Other

ClinGen's Peroxisomal Disorders expert panel records the mode of inheritance as autosomal recessive and the gene-disease relationship as Definitive.

PMID:20301621 SUPPORT Other

"At conception, each sib of an individual with biallelic ZSD-causing pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

GeneReviews Genetic Counseling gives the recurrence risk that follows from the biallelic requirement.

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Discussions and Knowledge Gaps

4

Does it matter mechanistically that PEX13 fails at docking rather than at receptor recycling?

INTERPRETATION pbd11a_docking_versus_recycling

Attached to

pathophysiology#Failure of PTS1 and PTS2 Receptor Docking pathophysiology#Disrupted PEX13-PEX14 Docking Complex

The KB now curates four PEX loci, and three of them - PEX1, PEX6, PEX12 - break the same half of the import cycle: the receptor docks and unloads, but is not exported back to the cytosol for reuse. PEX13 breaks the other half. The clinical convergence is nearly complete, which is the honest headline: a child with PBD11A is not distinguishable at the bedside from a child with PBD3A, and the biochemical screen does not separate them either. Two things do differ, and both are cell-biological rather than clinical. First, cargo selectivity: disrupting PEX13 self-association blocks PTS1 import specifically while leaving PTS2 routes and the PEX13-PEX14 interaction intact, so particular PEX13 alleles can produce a partial import defect of a kind the retrotranslocation mutants do not. Second, the fate of PEX5. In a recycling defect PEX5 accumulates at or in the membrane; in a docking defect it should not arrive there at all. That difference has not been used diagnostically and is recorded here as a mechanistic distinction rather than a clinical one.

Show evidence (1 reference)

PMID:23716570 SUPPORT In Vitro

"We demonstrate that the import of PTS1 (peroxisomal targeting signal 1) proteins is specifically disrupted when homooligomerization of PEX13 is interrupted."

The cargo-selectivity result that distinguishes a docking-step lesion from a recycling-step one.

Is the mitochondrial abnormality in PEX13 deficiency a driver of neuronal loss or a consequence of it?

KNOWLEDGE GAP pbd11a_mitochondrial_causal_direction

Attached to

pathophysiology#Secondary Mitochondrial Dysfunction

Mitochondrial mislocalisation and respiratory-chain abnormality are documented in PEX13 patient muscle and fibroblasts, and Pex13-null cerebellar neurons show mitochondrial dysfunction with elevated ROS and increased apoptosis. Both observations are correlative. Peroxisomes and mitochondria share fission machinery and their beta-oxidation pathways are metabolically coupled, so a causal link is plausible in either direction, and dying neurons have abnormal mitochondria for reasons that have nothing to do with peroxisomes. The question matters because it is the only node in this entry that suggests a druggable target: if mitochondrial oxidative stress drives the neuronal loss, antioxidant or mitochondrially targeted intervention has a rationale, whereas if it is downstream it does not. Part of that experiment has been done. Antioxidant treatment rescues mitochondrial superoxide and membrane depolarization in PEX13-deficient mouse fibroblasts, and the mitochondrial phenotype is present in the intact brain and not only in culture. What is missing is the combination that would settle direction: the same rescue in a neuron, read out against cell survival rather than against the mitochondrial measurements themselves. A correctable phenotype in a fibroblast says nothing about whether correcting it keeps a neuron alive.

Proposed experiments

Antioxidant rescue in PEX13-deficient neurons, read out on survival

pbd11a_mito_rescue

Repeat the antioxidant rescue already reported in PEX13-deficient fibroblasts, but in cerebellar neurons from brain-restricted Pex13 mutants, and make the primary endpoint apoptosis and survival rather than superoxide or membrane potential. Untreated mutant and wild-type neurons as controls.

Would support

pathophysiology#Secondary Mitochondrial Dysfunction

Supporting outcome

Reduced apoptosis in treated mutant neurons, approaching wild-type rates, would place mitochondrial oxidative stress upstream of the neuronal death.

Refuting outcome

Apoptosis unchanged despite normalised ROS would place the mitochondrial abnormality downstream of, or parallel to, the lethal lesion.

Does the pexophagy released by PEX13 loss contribute to disease in patients, or is it a property of edited cell lines and zebrafish?

HUMAN MODEL MISMATCH pbd11a_pexophagy_translational_validity

Attached to

pathophysiology#Pexophagy of Import-Incompetent Peroxisomes

The mechanism is clean where it has been measured: PEX13 loss lets ubiquitinated PEX5 accumulate and peroxisomal reactive oxygen species rise, and the two together drive otherwise healthy peroxisomes into autophagic degradation. It was shown by gene editing and quantitative microscopy in cultured cells and in a zebrafish model, and PEX13 protein level is itself downregulated during amino acid starvation as part of normal pexophagy induction. The gap is between that and a patient. The one human observation that points the same way - a reduced peroxisome count in PEX13 patient fibroblasts - is equally compatible with impaired organelle proliferation, and nothing has measured autophagic flux in patient material. This matters because the two readings imply opposite therapeutic logic. If excess pexophagy is clearing a residual peroxisome population that still has partial function, then inhibiting autophagy preserves it, which is the rationale behind trials of hydroxychloroquine in other peroxisome biogenesis disorders. If the peroxisomes being cleared are import-dead anyway, preserving them achieves nothing. Note that those trials exclude PEX13, so the question has not been asked at this locus even indirectly.

Show evidence (1 reference)

PMID:36541703 SUPPORT Model Organism

"Using gene editing and quantitative fluorescence microscopy on culture cells and a zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes."

Graded MODEL_ORGANISM because the sentence names a zebrafish model, which is in vivo animal data, and that is the more probative half for a translational-validity question; the cell-line half of the same paper is cited separately as IN_VITRO on the pathophysiology node. PARTIAL because it names exactly the systems the finding rests on, which is the mismatch this discussion records.

What separates PBD11A from PBD11B, given how few PEX13 patients exist?

KNOWLEDGE GAP pbd11a_ab_boundary

Attached to

genetic#PEX13 disease#

At PEX1 and PEX12 the A/B severity split tracks residual function reasonably well, and there are enough patients to see the correlation. At PEX13 there are not. Roughly twenty variants are reported worldwide, and the assignment of a given case to 11A or 11B rests on the clinical description rather than on a measured level of residual import. Variant class does not settle it either: a homozygous missense allele produced a severe, fatal presentation, while the first patient assigned to this complementation group at all - the one from whom the locus was defined - had neonatal adrenoleukodystrophy, the milder phenotype. The boundary this entry sits on is therefore a clinical convention with thin genotypic support, and should be read that way.

Show evidence (3 references)

PMID:10441568 SUPPORT Human Clinical

"Here, we characterize the sole representative of complementation group 13 of the PBDs, a patient with NALD (patient PBD222)."

The founding case of this complementation group presented at the milder end, not with classical Zellweger syndrome.

PMID:10441568 SUPPORT In Vitro

"However, residual matrix-protein import can be detected in cells from patient PBD222, consistent with the relatively mild phenotypes of the patient."

Ties the milder phenotype to measurable residual import, which is the axis the A/B split is meant to capture but is rarely measured.

PMID:10332040 SUPPORT Human Clinical

"A more mildly affected NALD patient (H-01), whose fibroblasts showed the temperature-sensitive (TS) phenotype, was homozygous for a missense mutation in the SH3 domain of Pex13p, I326T."

The mild half of the only reported pair of PEX13 patients contrasted directly by allele, and the one case where the residual-function basis of the split was measured rather than inferred.

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Pathophysiology

12

Biallelic PEX13 Loss of Function

Variants on both PEX13 alleles. The reported allelic spectrum spans whole-gene deletion, frameshift, nonsense and missense alleles. Where an allele sits along the protein matters more than its class: p.Trp234Ter truncates before the third transmembrane helix and the entire SH3 domain and gives classical Zellweger syndrome, while p.Ile326Thr, a temperature-sensitive missense change inside the SH3 domain, gives the milder NALD presentation. Missense is therefore not a mild class here - the p.Ala165Pro allele is also lethal in infancy.

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

SH3 domain binding GO:0017124 ↓ DECREASED

Downstream

Disrupted PEX13-PEX14 Docking Complex

Show evidence (4 references)

PMID:10441568 SUPPORT Human Clinical

"these results provide strong evidence that mutations in PEX13 are responsible for disease in patient PBD222 and, by extension, in complementation group 13 of the PBDs"

The complementation study that assigned this disease group to PEX13.

PMID:19449432 SUPPORT Human Clinical

"One patient had a genomic rearrangement resulting in a 147 kb deletion that spans the whole of PEX13, while the other had an out-of-frame deletion of 14 bp."

Documents complete loss of the locus and a frameshift allele in infants with classical Zellweger syndrome, the presentation this entry curates.

PMID:37962062 SUPPORT Human Clinical

"which caused severe clinical manifestations and was inherited from the consanguineous parents"

Shows that a homozygous missense allele is sufficient for the severe presentation, so variant class alone does not separate 11A from 11B.

+ 1 more reference

Disrupted PEX13-PEX14 Docking Complex

PEX13 and PEX14 together form the docking complex of the peroxisomal membrane, the module that receives cargo-loaded PEX5 and PEX7. PEX13 also self-associates within peroxisomes, and modelling of the recurrent p.Arg294Trp allele predicts that it destabilises the dimer and with it the whole PEX13/PEX14 translocation module. Loss of self-association is not the same lesion as loss of PEX14 binding: the conserved SH3 tryptophan W313 is required for PEX13 homooligomerisation but dispensable for the PEX14 interaction, so an allele can break one and spare the other. The human module is not simply the yeast one. In yeast the Pex13 SH3 domain binds a polyproline PxxP motif in Pex14; in humans that surface does not recognise PEX14 PxxP motifs at all. Instead PEX14 binding is mediated by an FxxxF motif C-terminal to the SH3 domain, and the same FxxxF motif folds back onto the SH3 domain intramolecularly and regulates how PEX5 WxxxF/Y motifs bind there. So the docking module carries its own autoregulatory switch, and the textbook yeast model should not be carried across.

protein homooligomerization GO:0051260 ↓ DECREASED

SH3 domain binding GO:0017124 ↓ DECREASED

peroxisomal membrane GO:0005778

Downstream

Failure of PTS1 and PTS2 Receptor Docking

Show evidence (4 references)

PMID:23716570 SUPPORT In Vitro

"the highly conserved W313 residue is important for self-association of PEX13 but is not required for interaction with PEX14, a well-established interaction partner at the peroxisomal membrane"

Separates the two binding functions of the docking module, showing that a patient allele can disable self-association while leaving PEX14 binding intact.

PMID:35854306 SUPPORT Computational

"Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module."

PARTIAL because the destabilisation of the module by the recurrent allele is a docking prediction rather than a measured interaction.

PMID:38632234 SUPPORT In Vitro

"Strikingly, intramolecular interaction of the PEX13 FxxxF motif regulates binding of PEX5 WxxxF/Y motifs to the PEX13 SH3 domain."

Establishes the autoregulatory switch inside the docking module, which is a layer the retrotranslocation peroxins have no counterpart for.

+ 1 more reference

Failure of PTS1 and PTS2 Receptor Docking

PEX5 carries PTS1-tagged matrix enzymes and PEX7 carries PTS2-tagged ones; both must dock at the membrane before their cargo can be translocated. The PEX13 SH3 domain is the PEX5 docking site, so losing it stalls the cycle before unloading rather than after it. Both cargo classes are affected in vivo, but they are not equally sensitive: interrupting PEX13 homooligomerisation specifically disrupts PTS1 import.

protein import into peroxisome matrix, docking GO:0016560 ↓ DECREASED

Animal models

Pex13-null mouse (ubiquitous Cre) Mouse recapitulates Reproduces the import block for both cargo classes, confirming that the docking peroxin is required for PTS1 and PTS2 routes alike.

Downstream

Collapse of Peroxisomal Matrix Protein Import

Show evidence (3 references)

PMID:11405337 SUPPORT Other

"PEX13 protein has an SH3 docking site that binds to the PTS-1 receptor."

States the molecular role that makes PEX13 a docking-step rather than a recycling-step peroxin.

PMID:23716570 SUPPORT In Vitro

"We demonstrate that the import of PTS1 (peroxisomal targeting signal 1) proteins is specifically disrupted when homooligomerization of PEX13 is interrupted."

Establishes the cargo-class selectivity of the docking defect.

PMID:12897163 SUPPORT Model Organism

"These animals lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type 1 or type 2 targeting signals."

Complete loss of Pex13 in vivo blocks both cargo classes, so the selectivity above is a property of particular alleles rather than of the gene.

Collapse of Peroxisomal Matrix Protein Import

Matrix enzymes never reach the organelle. The membrane compartment still forms - the "peroxisomal ghost" - which is the morphological signature distinguishing a biogenesis defect from a single enzyme deficiency. In PEX13 patient fibroblasts the residual peroxisome population is both reduced in number and abnormal in PEX13 content.

protein import into peroxisome matrix GO:0016558 ↓ DECREASED peroxisome organization GO:0007031 ↓ DECREASED

peroxisomal matrix GO:0005782

Downstream

Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids

Plasmalogen Deficiency

Secondary Mitochondrial Dysfunction Peroxisomal and mitochondrial beta-oxidation are metabolically coupled and the two organelles share fission machinery, but which of those links carries the effect in PEX13 deficiency is not established.

Pexophagy of Import-Incompetent Peroxisomes Import failure leaves ubiquitinated PEX5 on the membrane and raises peroxisomal reactive oxygen species, and both signals induce pexophagy. Shown in edited cells and zebrafish, not in patients.

Show evidence (2 references)

PMID:10441568 SUPPORT In Vitro

"Skin fibroblasts from patient PBD222 display defects in the import of multiple peroxisomal matrix proteins."

The cellular lesion measured directly in patient-derived cells.

PMID:35854306 SUPPORT Human Clinical

"identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration"

Quantifies the residual peroxisome population in PEX13 patient material.

Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids

Substrates that only peroxisomes degrade build up systemically: C26:0 and other VLCFA, phytanic and pristanic acid, pipecolic acid, and C27 bile-acid intermediates. This is the accumulation half of the biochemical signature and the basis of diagnostic testing.

very long-chain fatty acid beta-oxidation GO:0140493 ↓ DECREASED fatty acid alpha-oxidation GO:0001561 ↓ DECREASED bile acid biosynthetic process GO:0006699 ↓ DECREASED

Downstream

Progressive Hepatic Injury

Adrenocortical Insufficiency

Impaired Neuronal Migration and Neurogenesis Peroxisomal failure demonstrably disrupts cortical migration, but which accumulating substrate or missing lipid does it is not established.

Show evidence (2 references)

PMID:37962062 SUPPORT Human Clinical

"Serum analysis revealed elevated levels of very long-chain fatty acids (VLCFA), phytanic acid, and pipecolic acid."

The accumulating metabolites measured in a PEX13 patient with the severe presentation.

PMID:12897163 SUPPORT Model Organism

"Biochemical analyses of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis."

Confirms the beta-oxidation block in vivo in the Pex13-null mouse.

Plasmalogen Deficiency

Ether phospholipid synthesis begins in the peroxisome, so plasmalogens - major constituents of myelin - and DHA are not made. This is the deficiency half of the signature and the one most plausibly linked to the white-matter disease. In the brain-restricted PEX13 mouse it is the half that is present: plasmalogens fall while VLCFA stay normal, which dissociates the two arms of the biochemical lesion.

ether lipid biosynthetic process GO:0008611 ↓ DECREASED

Animal models

Brain-restricted Pex13 conditional mouse (Nestin-Cre) Mouse partially recapitulates Plasmalogens fall in the mutant brain, so the deficiency arm is reproduced.

Downstream

Impaired Neuronal Migration and Neurogenesis

Show evidence (1 reference)

PMID:20959636 SUPPORT Model Organism

"The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen content is reduced, but very-long-chain fatty acids are normal."

Shows the plasmalogen arm of the lesion occurring in brain without VLCFA accumulation, so the two arms can be separated.

Secondary Mitochondrial Dysfunction

PEX13 patient muscle and fibroblasts show respiratory-chain abnormalities and mislocalised mitochondria alongside the peroxisomal defect, and Pex13-null cerebellar neurons show mitochondrial dysfunction with elevated reactive oxygen species. Whether this is a driver of the neuronal loss or a downstream consequence of it is the open question; it is curated as PROVISIONAL because the observations are consistent across human tissue and mouse neurons but the causal direction has not been tested.

mitochondrion organization GO:0007005 ↓ DECREASED reactive oxygen species metabolic process GO:0072593 ↑ INCREASED

Animal models

Brain-restricted Pex13 conditional mouse (Nestin-Cre) Mouse recapitulates Cerebellar neurons from this line show mitochondrial dysfunction with elevated reactive oxygen species and MnSOD, together with increased apoptosis. The same line also shows an expanded and morphologically altered mitochondrial population in the intact brain, with oxidative damage to neuronal lipid and DNA, so the finding is not confined to culture.

Downstream

Impaired Neuronal Migration and Neurogenesis

Show evidence (4 references)

PMID:35854306 SUPPORT Human Clinical

"Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria"

The human observation of mitochondrial involvement in PEX13-related disease.

PMID:20959636 SUPPORT Model Organism

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

The corresponding measurement in Pex13-null neurons, linking mitochondrial dysfunction to oxidative stress and cell death.

PMID:35854306 SUPPORT Human Clinical

"including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs"

PARTIAL because the authors themselves frame the contribution as emerging rather than established.

+ 1 more reference

Pexophagy of Import-Incompetent Peroxisomes

Losing PEX13 does not only stop peroxisomes being filled - it appears to mark them for destruction. In edited cells and in zebrafish, PEX13 loss causes ubiquitinated PEX5 to accumulate on the peroxisomal membrane and peroxisome-derived reactive oxygen species to rise, and together those two signals induce pexophagy of peroxisomes that would otherwise be healthy. If it operates in patients it would compound the import block, because the residual organelle population is being cleared as well as being left empty - which is consistent with the reduced peroxisome number found in PEX13 patient fibroblasts. Curated as PROVISIONAL, not ESTABLISHED: the mechanism is demonstrated in cell lines and zebrafish, and no measurement in a PEX13 patient ties pexophagy to any clinical feature.

autophagy of peroxisome GO:0030242 ↑ INCREASED protein ubiquitination GO:0016567 ↑ INCREASED

Show evidence (3 references)

PMID:36541703 SUPPORT Model Organism

"we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes"

The core finding - PEX13 restrains pexophagy, so its loss releases it. Graded MODEL_ORGANISM because this headline claim rests on the zebrafish arm as well as the cell lines; the cell-line mechanism is quoted separately below as IN_VITRO, which is the split a mixed-source paper calls for.

PMID:36541703 SUPPORT In Vitro

"The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and an increase in peroxisome-dependent reactive oxygen species that coalesce to induce pexophagy."

The two-signal mechanism, and the link to reactive oxygen species that connects this node to the mitochondrial and oxidative-stress findings.

PMID:35854306 SUPPORT INDIRECT Human Clinical

"identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration"

INDIRECT because a reduced peroxisome count in patient cells is consistent with excess pexophagy but does not establish it; the count could equally reflect impaired proliferation of the organelle.

Impaired Neuronal Migration and Neurogenesis

Neuronal precursors fail to proliferate, migrate and mature normally during fetal brain development, producing a congenital malformation rather than a purely degenerative lesion. Because the lesion forms before birth, it is not reversible by any postnatal intervention. The PEX13 mouse adds cerebellar detail to the cortical picture - impaired granule cell migration and Purkinje layer formation - with astrogliosis and microgliosis as prominent accompaniments.

neuron CL:0000540 radial glial cell CL:0000681 astrocyte CL:0000127 microglial cell CL:0000129

Animal models

Pex13-null mouse (ubiquitous Cre) Mouse recapitulates Reproduces the cortical migration defect that is otherwise inferred from human neuropathology.

Brain-restricted Pex13 conditional mouse (Nestin-Cre) Mouse recapitulates Reproduces impaired cerebellar development - fissure and cortical layer formation, granule cell migration, Purkinje cell layer development - with astrogliosis and microgliosis, and separately impaired proliferation and maturation of neural progenitors from E12.5.

Downstream

Severe Neurodevelopmental Impairment

Show evidence (3 references)

PMID:12897163 SUPPORT Model Organism

"The brains of these animals showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect."

The cortical migration defect demonstrated in the Pex13-null mouse.

PMID:29187321 SUPPORT Model Organism

"we show a significant reduction in proliferation, migration, differentiation, and maturation of neural progenitors in embryonic E12.5 through to P3 animals"

Extends the lesion from migration alone to the whole neurogenic programme.

PMID:20959636 SUPPORT Model Organism

"Astrogliosis and microgliosis are prominent features of the mutant cerebellum."

Grounds the astrocyte and microglial cell types annotated on this node.

Progressive Hepatic Injury

VLCFA and C27 bile-acid intermediates are directly hepatotoxic, driving cholestasis and fibrosis. Hepatic dysfunction was part of the presenting picture in the reported severe PEX13 cases.

hepatocyte CL:0000182

Show evidence (1 reference)

PMID:37962062 SUPPORT Human Clinical

"The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features."

Names hepatic dysfunction in a molecularly confirmed severe PEX13 case.

Adrenocortical Insufficiency

VLCFA accumulation in adrenocortical cells impairs steroidogenesis. Often subclinical at first, which is why GeneReviews asks for ACTH and cortisol measurement by age one even in children who look adrenally well.

cortical cell of adrenal gland CL:0002097

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"ACTH and cortisol levels by age one year and annually thereafter."

PARTIAL because the GeneReviews Surveillance recommendation implies the risk rather than reporting the mechanism; it is spectrum-wide, not PEX13-specific.

Severe Neurodevelopmental Impairment

Profound hypotonia, neonatal seizures, and absent or regressing developmental progress. In the severe form death usually follows in infancy; the molecularly confirmed PEX13 cases at this end of the spectrum died at 14 months and in the neonatal period respectively.

Animal models

Pex13-null mouse (ubiquitous Cre) Mouse recapitulates Reproduces the clinical syndrome, including the perinatal lethality that defines the severe end of the spectrum.

Show evidence (2 references)

PMID:20301621 SUPPORT Other

"Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress."

GeneReviews states the course of the severe end of the spectrum, which is what PBD11A denotes.

PMID:37962062 SUPPORT Human Clinical

"The patient died at the age of 14 months."

The observed outcome in a molecularly confirmed severe PEX13 case.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

20

Digestive 2

Liver Dysfunction FREQUENT Decreased liver function HP:0001410

Show evidence (1 reference)

PMID:37962062 SUPPORT Human Clinical

"The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features."

Hepatic dysfunction in a molecularly confirmed severe PEX13 case.

Feeding Difficulties VERY_FREQUENT HP:0011968

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Affected newborns are hypotonic and feed poorly."

GeneReviews Clinical Characteristics names feeding failure in the newborn.

Ear 1

Hearing Impairment FREQUENT HP:0000365

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy."

Names hearing impairment in the PEX13 cohort.

Endocrine 1

Adrenal Insufficiency OCCASIONAL HP:0000846

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"liver dysfunction, adrenal insufficiency, and renal oxalate stones"

PARTIAL for two reasons - the sentence is spectrum-wide rather than from a PEX13 case, and it specifically describes the intermediate/milder end, whereas this entry is the severe one. It is curated because the surveillance recommendation that follows from it applies to any child who survives the newborn period.

Eye 1

Visual Impairment FREQUENT HP:0000505

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy."

Names vision impairment in the PEX13 cohort.

Genitourinary 1

Renal Cysts OCCASIONAL HP:0000107

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"

PARTIAL because the GeneReviews sentence is spectrum-wide rather than reported in a PEX13 case series.

Head and Neck 1

Dysmorphic Facies FREQUENT Abnormal facial shape HP:0001999

Show evidence (2 references)

PMID:37962062 SUPPORT Human Clinical

"The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features."

Dysmorphic features in a molecularly confirmed severe PEX13 case.

PMID:20301621 SUPPORT Other

"They have distinctive facies, congenital malformations"

GeneReviews names the distinctive facies as part of the severe presentation.

Metabolism 1

Elevated Hepatic Transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:26627182 SUPPORT Other

"Hepatomegaly and hepatic dysfunction with coagulopathy, elevated transaminases"

PARTIAL because the sentence is spectrum-wide rather than from a PEX13 case series, and describes a group with less pronounced craniofacial features than the neonatal-infantile end this entry curates.

Musculoskeletal 2

Severe Neonatal Hypotonia VERY_FREQUENT Generalized hypotonia HP:0001290

Severity: SEVERE

Show evidence (2 references)

PMID:37962062 SUPPORT Human Clinical

"The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features."

Hypotonia in a molecularly confirmed severe PEX13 case.

PMID:20301621 SUPPORT Other

"Affected newborns are hypotonic and feed poorly."

GeneReviews Clinical Characteristics names hypotonia as the newborn presentation across the spectrum.

Progressive Spasticity FREQUENT HP:0001257

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy."

Names progressive spasticity in the PEX13 cohort.

Nervous System 5

Developmental Regression FREQUENT HP:0002376

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy."

Names regression in the largest reported PEX13 series.

Leukodystrophy FREQUENT HP:0002415

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy."

Names brain leukodystrophy in the PEX13 cohort.

Polymicrogyria OCCASIONAL HP:0002126

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"bilateral malformation of cortical development in parietal lobes, with a polymicrogyria-like appearance"

The imaging finding in a PEX13 patient; the report describes it as polymicrogyria-like, so the binding is to the closest structural HPO term.

Global Developmental Delay VERY_FREQUENT HP:0001263

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress."

GeneReviews states the absence of developmental progress at the severe end.

Cerebellar Atrophy OCCASIONAL HP:0001272

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"cerebellar atrophy and pontine/vermian hypoplasia were also reported"

The cerebellar finding in the PEX13 cohort.

Growth 2

Failure to Thrive FREQUENT HP:0001508

Show evidence (1 reference)

PMID:37962062 SUPPORT Human Clinical

"The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features."

Failure to thrive in a molecularly confirmed severe PEX13 case.

Intrauterine Growth Retardation OCCASIONAL HP:0001511

Show evidence (1 reference)

PMID:12897163 SUPPORT Model Organism

"The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death."

PARTIAL because the observation is in the Pex13-null mouse rather than in PEX13 patients.

Other 3

Neonatal Seizures FREQUENT HP:0032807

Show evidence (1 reference)

PMID:37962062 SUPPORT Human Clinical

"The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features."

Seizures in a molecularly confirmed severe PEX13 case.

CNS Hypomyelination FREQUENT HP:0003429

Show evidence (1 reference)

PMID:35854306 SUPPORT Human Clinical

"Brain MRI revealed diffuse hypomyelination with abnormal confluent FLAIR hyperintense signal abnormality, particularly involving the cerebellar white matter."

The imaging finding in a PEX13 patient.

Epiphyseal Stippling OCCASIONAL HP:0010655

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"

PARTIAL because the sentence is spectrum-wide, and it is truncated before "[chondrodysplasia punctata]" because the reference validator strips bracketed text.

🧬

Genetic Associations

1

PEX13

Gene: PEX13 hgnc:8855 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:10441568 SUPPORT Human Clinical

"PEX13 encodes a peroxisomal membrane protein with a cytoplasmically exposed SH3 domain, and we find that expression of human PEX13 restores peroxisomal matrix-protein import in cells from patient PBD222."

The functional complementation result that identified the gene, and the statement of its molecular role.

PMID:35854306 SUPPORT Human Clinical

"Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant."

Identifies the recurrent allele in the largest PEX13 series.

PMID:37962062 SUPPORT Human Clinical

"PEX13 gene variants are rare causes of ZSDs, with only 21 cases reported worldwide and none in China."

Quantifies how few PEX13 cases exist, which is why the allelic spectrum is thin.

+ 1 more reference

💊

Medical Actions

5

Supportive and Symptomatic Management

Action: Supportive Care NCIT:C15747

There is no treatment for the biogenesis defect. Management is entirely symptomatic - gastrostomy feeding, anti-seizure medication, hearing aids, cataract surgery, fat-soluble vitamin and cholic acid supplementation, adrenal replacement. None of it restores peroxisomal import, and the congenital brain malformation is fixed before birth.

Mechanism Target:

MODULATES Severe Neurodevelopmental Impairment — Addresses consequences - nutrition, seizures, sensory deficits - without acting on peroxisome biogenesis.

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Treatment of manifestations: The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation"

GeneReviews Management states that treatment is symptomatic and enumerates the measures.

Cholic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: cholic acid CHEBI:16359

Oral cholic acid restores feedback inhibition of endogenous bile acid synthesis, so the hepatotoxic C27 intermediates that peroxisome-deficient hepatocytes cannot process stop accumulating. It is the only FDA-approved therapy for Zellweger spectrum disease and the only intervention in this entry that acts on a curated mechanism node rather than on a consequence. The trial evidence is spectrum-wide; no PEX13 patient has been reported on it, so its use here is by extension from the shared biochemical lesion.

Mechanism Target:

INHIBITS Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids — Suppresses synthesis of the atypical C27 bile-acid intermediates that accumulate because peroxisomal side-chain shortening is blocked. It does not restore peroxisomal import, so the other accumulating substrates are unaffected.

INHIBITS Progressive Hepatic Injury — Removing the hepatotoxic intermediates is what improves the liver chemistry.

Show evidence (3 references)

PMID:28644367 SUPPORT Human Clinical

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

PARTIAL because the trial enrolled the Zellweger spectrum as a whole rather than PEX13 patients; the fall in atypical urinary bile acids is the direct readout of the targeted mechanism and the transaminase fall is the hepatic consequence.

PMID:27469511 SUPPORT Human Clinical

"In patients with advanced liver disease (n = 4), cholic acid treatment resulted in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor reduction in bile acid intermediates."

The safety caveat that qualifies the treatment - in the patients with the worst liver disease the drug worsened liver chemistry rather than improving it. PARTIAL because it supports the caution, not the efficacy claim.

PMID:27469511 SUPPORT Human Clinical

"However, caution is needed in patients with advanced liver disease due to possible hepatotoxic effects."

The authors' own conclusion, recorded here as the agents-to-use-with-care statement for this treatment.

Adrenal Replacement Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: hydrocortisone CHEBI:17650

Glucocorticoid replacement where adrenal insufficiency is documented. GeneReviews asks for ACTH and cortisol by age one and annually thereafter, because the insufficiency is often subclinical when it starts. The screening and the treating are deliberately separate steps: cortisone carries its own harms - growth suppression, osteoporosis - so the recommendation is to screen everyone and treat only those with a demonstrated insufficiency on Synacthen testing, not to supplement on suspicion.

Mechanism Target:

RESTORES Adrenocortical Insufficiency — Replaces the missing hormone output; it does not correct the VLCFA accumulation that impaired steroidogenesis.

Show evidence (2 references)

PMID:20301621 SUPPORT Other

"adrenal replacement therapy; vitamin D supplementation and consideration of bisphosphonates for osteopenia"

GeneReviews Management lists adrenal replacement among the symptomatic measures.

PMID:26627182 SUPPORT Other

"only patients with a true insufficiency (i.e. altered Synacthen test) should be treated"

The treat-only-if-confirmed rule, which exists because the supplementation itself causes growth suppression and osteoporosis. Symmetric to the cholic-acid caution above - both are treatments whose harm is documented alongside their benefit.

Anti-Seizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: anticonvulsant agent NCIT:C264

Seizure control in an epilepsy that arises from a fixed cortical malformation, so the aim is symptomatic control rather than modification of the underlying lesion.

Mechanism Target:

MODULATES Impaired Neuronal Migration and Neurogenesis — Suppresses seizures arising from the cortical malformation. The malformation itself is fixed before birth and is not modified.

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"anti-seizure medication, early intervention services for developmental delay and intellectual disability"

GeneReviews Management lists anti-seizure medication.

Docosahexaenoic Acid Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: docosahexaenoic acid CHEBI:28125

DHA is one of the lipids peroxisome-deficient cells cannot make, so replacing it is a mechanistically obvious idea. It does not work. A randomised, double-blind, placebo-controlled trial in peroxisome assembly disorders found no benefit in biochemistry, electroretinogram or growth. It is curated here as a refuted therapy rather than omitted, because the rationale is intuitive enough that it keeps being proposed. It carries no `target_mechanisms` link deliberately: every available `treatment_effect` value asserts an effect on the node, and the trial's finding is that there is none.

Show evidence (2 references)

PMID:20805528 REFUTE Human Clinical

"There was no difference in the outcomes between the treated and untreated groups in biochemical function, electroretinogram, or growth."

The primary result refuting DHA supplementation as a therapy for peroxisome assembly disorders.

PMID:20805528 REFUTE Human Clinical

"This interventional study provides Class II evidence that DHA supplementation did not improve the visual function or growth of treated individuals with peroxisome assembly disorders during an average of 1 year of follow-up in patients aged 1 to 144 months."

The formal evidence grading, which is what makes this a settled negative rather than an underpowered one.

🔬

Biochemical Markers

4

Very-long-chain fatty acids (Increased)

Context: Plasma C26:0 with the C24/C22 and C26/C22 ratios is the first-line biochemical screen. In the severe form curated here the elevation is unambiguous, unlike the milder end of the spectrum where it can be modest.

Pathograph Readouts

Readout Of Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids Positive Diagnostic

Elevated VLCFA reports the peroxisomal beta-oxidation block directly.

Show evidence (1 reference)

PMID:37962062 SUPPORT Human Clinical

"Serum analysis revealed elevated levels of very long-chain fatty acids (VLCFA), phytanic acid, and pipecolic acid."

The measurement made in a molecularly confirmed severe PEX13 case.

Show evidence (1 reference)

PMID:28677031 SUPPORT Human Clinical

"This results in multiple metabolic abnormalities, including elevated very long-chain fatty acid (VLCFA) levels."

States that VLCFA elevation is a consequence of the peroxisome biogenesis defect, which is why the marker belongs in this entry.

Phytanic acid (Increased)

Context: Phytanic acid is degraded by peroxisomal alpha-oxidation, so it accumulates by a different route from the VLCFA and reports a second arm of the block.

Pathograph Readouts

Readout Of Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids Positive Diagnostic

Elevated phytanic acid reports the peroxisomal alpha-oxidation block.

Show evidence (1 reference)

PMID:37962062 SUPPORT Human Clinical

"Serum analysis revealed elevated levels of very long-chain fatty acids (VLCFA), phytanic acid, and pipecolic acid."

The measurement made in a molecularly confirmed severe PEX13 case.

C26:0-lysophosphatidylcholine (Increased)

Context: C26:0-lysoPC in dried blood spots is the assay that makes newborn screening for Zellweger spectrum disease technically feasible, which matters most for the severe form because its window for any intervention is shortest.

Pathograph Readouts

Readout Of Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids Positive Diagnostic

Elevated dried-blood-spot C26:0-lysoPC reports peroxisomal beta-oxidation failure.

Show evidence (1 reference)

PMID:28677031 SUPPORT Human Clinical

"Elevated C26:0-lysoPC levels (>72 nmol/L) were found in 86/91 ZSD DBS"

Quantifies the sensitivity of this readout against the block it reports.

Show evidence (1 reference)

PMID:28677031 SUPPORT Human Clinical

"Implementation of C26:0-lysoPC measurement in the diagnostic work-up when suspecting a ZSD is advised."

The authors' recommendation that establishes this analyte as a routine marker for the disease group.

Plasmalogens (Decreased)

Context: Erythrocyte plasmalogens are low because ether lipid synthesis begins in the peroxisome. This is the deficiency half of the signature and moves in the opposite direction to the VLCFA markers, which is what distinguishes a biogenesis defect from an isolated beta-oxidation enzyme defect.

Pathograph Readouts

Readout Of Plasmalogen Deficiency Negative Diagnostic

Reduced plasmalogens report failed peroxisomal ether lipid synthesis.

Show evidence (1 reference)

PMID:12897163 SUPPORT Model Organism

"Biochemical analyses of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis."

PARTIAL because the measurement is in the Pex13-null mouse rather than in PEX13 patients; it shows both directions of the signature in one animal.

🔬

Diagnosis

3

Plasma Very-Long-Chain Fatty Acid Profile

The first-line biochemical test. Elevated C26:0 with abnormal C24/C22 and C26/C22 ratios points at a peroxisomal disorder before any gene is sequenced.

laboratory procedure NCIT:C25294

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes."

GeneReviews Diagnosis places biochemical findings ahead of molecular confirmation in the diagnostic sequence.

Molecular Genetic Testing of the ZSD-PEX Genes

Confirmation requires biallelic variants in one of the ZSD-PEX genes; assignment to PEX13 is what makes the entry PBD11 rather than another group. Because PEX13 is a rare cause, it is usually reached by exome sequencing rather than by targeted testing.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:20301621 SUPPORT Other

"by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes"

States the molecular criterion.

PMID:37962062 SUPPORT Human Clinical

"identified by whole exome sequencing and validated by Sanger sequencing"

Shows the testing route by which a rare PEX13 case is actually reached.

Complementation Analysis in Cultured Fibroblasts

The historical assignment method, and still informative where sequencing is uninterpretable: patient fibroblasts are fused with reference cell lines and the group is read off from which fusion restores peroxisomal import. This is how group H/13 was defined before PEX13 was cloned.

laboratory procedure NCIT:C25294

Show evidence (1 reference)

PMID:19449432 SUPPORT Human Clinical

"Here, we report on two infants whose clinical and biochemical profile was consistent with classical Zellweger syndrome and whose complementation analysis assigned them both to group H of peroxisomal biogenesis disorders."

Shows complementation analysis assigning classical Zellweger patients to the PEX13 group.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Roughly twenty individuals with biallelic PEX13 variants had been reported worldwide across the whole Zellweger spectrum as of 2024, and the severe PBD11A subset is a fraction of that. No population-based estimate exists for PEX13 specifically; the ~1 in 50,000 figure quoted for the Zellweger spectrum is dominated by PEX1.

Show evidence (1 reference)

PMID:37962062 SUPPORT Human Clinical

"PEX13 gene variants are rare causes of ZSDs, with only 21 cases reported worldwide and none in China."

The published case count on which the ULTRA_RARE band rests.

🔬

Clinical Trials

1

NCT01668186 NOT_APPLICABLE RECRUITING

The principal longitudinal natural-history study of the peroxisome biogenesis disorders, prospectively following patients internationally and banking clinical, biochemical and genetic data. It is observational, so it carries no phase; it is listed because for a disease with roughly twenty reported patients worldwide, the registry is the only route to a described natural history.

Show evidence (1 reference)

clinicaltrials:NCT01668186 SUPPORT Other

"In spite of advancements in peroxisome biology, the pathophysiology remains unknown, the spectrum of phenotypes poorly characterized and the natural history not yet systematically reported."

The study's own statement of the gap it exists to fill, which is the same gap this entry runs into for PEX13 specifically.

🐁

Animal Models

2

Pex13-null mouse (ubiquitous Cre)

The definitive whole-animal model of this disease: the orthologous gene, disrupted in every tissue. Unlike the Pex2-null mouse curated on the PBD3A entry, this is a same-gene model rather than a paralogous one.

Species

Mouse

Genotype

Pex13 conditional (loxP) allele, ubiquitous Cre-mediated inactivation, homozygous

Publication

PMID:12897163

Pathograph links

Failure of PTS1 and PTS2 Receptor Docking recapitulates fidelity: high Reproduces the import block for both cargo classes, confirming that the docking peroxin is required for PTS1 and PTS2 routes alike.

Limitations: The model is a null. Most human PEX13 alleles - including the recurrent p.Arg294Trp - are missense and may retain partial docking function, so the null does not model the residual-function biology that separates 11A from 11B.

Readouts

Import of PTS1- and PTS2-tagged matrix proteins

Direction: DECREASED

Interpretation: Loss of import for both targeting-signal classes is the direct readout of a failed docking complex.

Show evidence (1 reference)

PMID:12897163 SUPPORT Model Organism

"These animals lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type 1 or type 2 targeting signals."

The direct measurement of the import defect in the model.

Show evidence (1 reference)

PMID:12897163 SUPPORT Model Organism

"In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype."

States the human disease the model was built to represent.

Severe Neurodevelopmental Impairment recapitulates fidelity: high Reproduces the clinical syndrome, including the perinatal lethality that defines the severe end of the spectrum.

Limitations: Death is neonatal, so the postnatal course seen in longer-surviving human infants - the sensory loss, the progressive white-matter disease, the developmental regression - cannot be observed in this model. The brain-restricted conditional was made for that reason.

Readouts

Perinatal clinical phenotype and survival

Direction: DECREASED

Interpretation: Growth restriction, hypotonia, feeding failure and neonatal death recapitulate the severe human presentation.

Show evidence (1 reference)

PMID:12897163 SUPPORT Model Organism

"The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death."

The observed clinical phenotype of the model.

Impaired Neuronal Migration and Neurogenesis recapitulates fidelity: moderate Reproduces the cortical migration defect that is otherwise inferred from human neuropathology.

Limitations: Mouse cortical development is lissencephalic, so the polymicrogyria seen in human ZSD has no direct counterpart; disordered lamination is the closest available readout.

Readouts

Cortical lamination

Direction: ALTERED

Interpretation: Disordered lamination is the expected signature of arrested radial migration.

Show evidence (1 reference)

PMID:12897163 SUPPORT Model Organism

"The brains of these animals showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect."

The histological result establishing the migration defect in vivo.

Show evidence (1 reference)

PMID:12897163 SUPPORT Model Organism

"Thus, Pex13(-/-) mice reproduce many of the features of Zellweger syndrome and PEX13 deficiency in humans."

The authors' own summary judgement that this model represents human PEX13 deficiency, which is what licenses its use across the nodes below.

Brain-restricted Pex13 conditional mouse (Nestin-Cre)

Built to escape the neonatal lethality of the ubiquitous null. Most animals survive to about 35 days, which opens the postnatal cerebellar and glial phenotype to study. It is also the model that dissociates the two arms of the biochemical lesion.

Species

Mouse

Genotype

Pex13 conditional (loxP) allele, brain-restricted Cre-mediated inactivation

Publication

PMID:20959636

Pathograph links

Impaired Neuronal Migration and Neurogenesis recapitulates fidelity: moderate Reproduces impaired cerebellar development - fissure and cortical layer formation, granule cell migration, Purkinje cell layer development - with astrogliosis and microgliosis, and separately impaired proliferation and maturation of neural progenitors from E12.5.

Limitations: Peroxisomal function is intact outside the brain, so this model cannot address the hepatic, adrenal or renal disease, and the systemic metabolic milieu of a real patient is absent. Notably VLCFA are normal in the mutant brain, so any phenotype here is attributable to the plasmalogen arm and to local peroxisomal failure rather than to circulating VLCFA.

Readouts

Cerebellar layer formation and granule cell migration

Direction: ALTERED

Interpretation: Disrupted cerebellar cytoarchitecture reports failed migration and maturation in a peroxisome-deficient brain.

Show evidence (1 reference)

PMID:20959636 SUPPORT Model Organism

"PEX13 brain mutants exhibit defects in reflex and motor development that correlate with impaired cerebellar fissure and cortical layer formation, granule cell migration and Purkinje cell layer development."

The cerebellar developmental phenotype measured in the model.

Neural progenitor proliferation and maturation

Direction: DECREASED

Interpretation: Reduced progenitor output is an earlier lesion than migration failure alone and helps explain the brain anatomy.

Show evidence (1 reference)

PMID:29187321 SUPPORT Model Organism

"we show a significant reduction in proliferation, migration, differentiation, and maturation of neural progenitors in embryonic E12.5 through to P3 animals"

The neurogenesis measurement in the same brain-restricted model.

Show evidence (1 reference)

PMID:29187321 SUPPORT Model Organism

"Here we used mice with brain-restricted inactivation of the peroxisome biogenesis gene PEX13 to model the pathophysiological features of ZS"

States the model's purpose and scope.

Secondary Mitochondrial Dysfunction recapitulates fidelity: moderate Cerebellar neurons from this line show mitochondrial dysfunction with elevated reactive oxygen species and MnSOD, together with increased apoptosis. The same line also shows an expanded and morphologically altered mitochondrial population in the intact brain, with oxidative damage to neuronal lipid and DNA, so the finding is not confined to culture.

Limitations: What the model does not settle is direction. Antioxidant treatment rescues mitochondrial superoxide and membrane depolarization in PEX13-deficient fibroblasts, but that rescue has not been run in neurons and carries no survival endpoint, so nothing yet shows that correcting the mitochondrial phenotype prevents the neuronal death.

Readouts

Reactive oxygen species and MnSOD in cultured cerebellar neurons

Direction: INCREASED

Interpretation: Elevated ROS and the compensatory MnSOD rise report mitochondrial oxidative stress in peroxisome-deficient neurons.

Show evidence (1 reference)

PMID:20959636 SUPPORT Model Organism

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

The direct measurement of mitochondrial dysfunction and oxidative stress in the model.

Brain mitochondrial population and neuronal oxidative damage

Direction: ALTERED

Interpretation: An expanded, morphologically modified mitochondrial population with lipid and DNA oxidation products reports the phenotype in the intact brain rather than in culture.

Show evidence (2 references)

PMID:27514574 SUPPORT Model Organism

"Using a mouse model of ZS with brain-restricted deficiency of the peroxisome biogenesis protein PEX13, we demonstrated an expanded and morphologically modified brain mitochondrial population."

The in vivo measurement, in the same brain-restricted line.

+ 1 more reference

Plasmalogen Deficiency partially recapitulates fidelity: moderate Plasmalogens fall in the mutant brain, so the deficiency arm is reproduced.

Limitations: Only one arm of the biochemical signature is present - VLCFA are normal - so this model reproduces the plasmalogen lesion without the accumulation lesion that accompanies it in patients.

Readouts

Brain plasmalogen content

Direction: DECREASED

Interpretation: Reduced brain plasmalogen reports failed peroxisomal ether lipid synthesis in situ.

Show evidence (1 reference)

PMID:20959636 SUPPORT Model Organism

"The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen content is reduced, but very-long-chain fatty acids are normal."

Reports both the reproduced arm and the missing one.

Show evidence (2 references)

PMID:20959636 SUPPORT Model Organism

"Thus, PEX13-deficient mice provide a valuable animal model for investigating the molecular basis and treatment of ZS cerebellar pathology."

PARTIAL because the authors scope the model's value to cerebellar pathology specifically, not to the systemic disease.

PMID:20959636 SUPPORT Model Organism

"PEX13 brain mutants survive into the postnatal period, with the majority dying by 35 days, and with survival inversely related to litter size and weaning body weight."

Establishes the survival window that makes this model usable for postnatal phenotypes the ubiquitous null cannot reach.

{ }

Source YAML

click to show

name: Peroxisome Biogenesis Disorder 11A (Zellweger)
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
description: >-
  Peroxisome biogenesis disorder 11A is the severe, Zellweger-end presentation of
  PEX13 deficiency - historically complementation group 13 (also called group H) of
  the peroxisome biogenesis disorders. PEX13 is an integral peroxisomal membrane
  protein whose cytosolically exposed SH3 domain binds the PTS1 receptor PEX5, and
  which partners PEX14 to form the docking complex: the point on the membrane at
  which a loaded matrix-protein receptor first arrives.

  That places PEX13 at a different step of the import cycle from the PEX genes the KB
  already curates. PEX12, with its paralogues PEX2 and PEX10, forms the RING-finger
  retrotranslocation channel that ubiquitinates PEX5 and exports it back to the
  cytosol; PEX1 and PEX6 are the AAA-ATPases that power that export. Those are all
  recycling defects - the receptor docks and unloads, but is never returned for
  another round. PEX13 fails earlier: the receptor cannot dock in the first place.
  The downstream consequence converges - matrix protein import collapses and the cell
  is left with peroxisomal membrane compartments containing no matrix enzymes - which
  is why the clinical picture is shared across the spectrum even though the molecular
  lesions are not.

  The biochemical signature is therefore the general biogenesis one, running in two
  directions at once: very-long-chain fatty acids, phytanic and pristanic acid,
  pipecolic acid and C27 bile-acid intermediates accumulate because nothing degrades
  them, while plasmalogens and DHA are missing because nothing synthesises them. Both
  halves injure the developing brain, the liver and the adrenal cortex, producing the
  cerebro-hepato-renal presentation Zellweger described.

  Two features are relatively specific to this locus. Import failure at the docking
  step is not uniform across cargo classes - disrupting PEX13 self-association
  selectively blocks PTS1 import while leaving the PEX13-PEX14 interaction intact -
  and patient fibroblasts and muscle show mitochondrial mislocalisation and
  respiratory-chain abnormalities alongside the peroxisomal defect, which has raised
  secondary mitochondrial dysfunction as a contributing mechanism rather than a
  bystander finding. PEX13 is among the rarest causes of Zellweger spectrum disease,
  with roughly twenty variants reported worldwide.
disease_term:
  preferred_term: peroxisome biogenesis disorder 11A (Zellweger)
  term:
    id: MONDO:0013949
    label: peroxisome biogenesis disorder 11A (Zellweger)
synonyms:
- PBD11A
- peroxisome biogenesis disorder, complementation group H
- peroxisome biogenesis disorder, complementation group 13
- PEX13-related Zellweger syndrome
parents:
- Peroxisome Biogenesis Disorder
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PEX13 variants are required. Reported families include homozygotes from
    consanguineous unions and compound heterozygotes; ClinGen classifies the
    PEX13-peroxisome biogenesis disorder relationship as Definitive with autosomal
    recessive inheritance.
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report five families carrying biallelic variants in PEX13.
    explanation: The largest reported PEX13 series states the biallelic requirement across
      every family.
  - reference: CGGV:assertion_0c662669-4eb8-45e3-8540-c394ea40c1b2-2019-10-04T160000.000Z
    reference_title: PEX13 / peroxisome biogenesis disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: PEX13 | HGNC:8855 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive
    explanation: ClinGen's Peroxisomal Disorders expert panel records the mode of inheritance
      as autosomal recessive and the gene-disease relationship as Definitive.
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: At conception, each sib of an individual with biallelic ZSD-causing pathogenic
      variants has a 25% chance of being affected, a 50% chance of being an asymptomatic
      carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: GeneReviews Genetic Counseling gives the recurrence risk that follows from
      the biallelic requirement.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Roughly twenty individuals with biallelic PEX13 variants had been reported worldwide
    across the whole Zellweger spectrum as of 2024, and the severe PBD11A subset is a
    fraction of that. No population-based estimate exists for PEX13 specifically; the
    ~1 in 50,000 figure quoted for the Zellweger spectrum is dominated by PEX1.
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PEX13 gene variants are rare causes of ZSDs, with only 21 cases reported
      worldwide and none in China.
    explanation: The published case count on which the ULTRA_RARE band rests.
pathophysiology:
- name: Biallelic PEX13 Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Variants on both PEX13 alleles. The reported allelic spectrum spans whole-gene
    deletion, frameshift, nonsense and missense alleles. Where an allele sits along the
    protein matters more than its class: p.Trp234Ter truncates before the third
    transmembrane helix and the entire SH3 domain and gives classical Zellweger syndrome,
    while p.Ile326Thr, a temperature-sensitive missense change inside the SH3 domain,
    gives the milder NALD presentation. Missense is therefore not a mild class here - the
    p.Ala165Pro allele is also lethal in infancy.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: SH3 domain binding
    modifier: DECREASED
    term:
      id: GO:0017124
      label: SH3 domain binding
  downstream:
  - target: Disrupted PEX13-PEX14 Docking Complex
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10441568
    reference_title: PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis
      disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: these results provide strong evidence that mutations in PEX13 are responsible
      for disease in patient PBD222 and, by extension, in complementation group 13 of the
      PBDs
    explanation: The complementation study that assigned this disease group to PEX13.
  - reference: PMID:19449432
    reference_title: "Zellweger syndrome caused by PEX13 deficiency: report of two novel
      mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient had a genomic rearrangement resulting in a 147 kb deletion that
      spans the whole of PEX13, while the other had an out-of-frame deletion of 14 bp.
    explanation: Documents complete loss of the locus and a frameshift allele in infants
      with classical Zellweger syndrome, the presentation this entry curates.
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which caused severe clinical manifestations and was inherited from the
      consanguineous parents
    explanation: Shows that a homozygous missense allele is sufficient for the severe
      presentation, so variant class alone does not separate 11A from 11B.
  - reference: PMID:10332040
    reference_title: Nonsense and temperature-sensitive mutations in PEX13 are the cause of
      complementation group H of peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A severe phenotype of a ZS patient (H-02) was homozygous for a nonsense
      mutation, W234ter, which results in the loss of not only the SH3 domain but also the
      putative transmembrane domain of Pex13p.
    explanation: The allele that defines the severe end of this locus, and what it removes
      from the protein.
- name: Disrupted PEX13-PEX14 Docking Complex
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    PEX13 and PEX14 together form the docking complex of the peroxisomal membrane, the
    module that receives cargo-loaded PEX5 and PEX7. PEX13 also self-associates within
    peroxisomes, and modelling of the recurrent p.Arg294Trp allele predicts that it
    destabilises the dimer and with it the whole PEX13/PEX14 translocation module. Loss
    of self-association is not the same lesion as loss of PEX14 binding: the conserved
    SH3 tryptophan W313 is required for PEX13 homooligomerisation but dispensable for the
    PEX14 interaction, so an allele can break one and spare the other.

    The human module is not simply the yeast one. In yeast the Pex13 SH3 domain binds a
    polyproline PxxP motif in Pex14; in humans that surface does not recognise PEX14 PxxP
    motifs at all. Instead PEX14 binding is mediated by an FxxxF motif C-terminal to the SH3
    domain, and the same FxxxF motif folds back onto the SH3 domain intramolecularly and
    regulates how PEX5 WxxxF/Y motifs bind there. So the docking module carries its own
    autoregulatory switch, and the textbook yeast model should not be carried across.
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  molecular_functions:
  - preferred_term: SH3 domain binding
    modifier: DECREASED
    term:
      id: GO:0017124
      label: SH3 domain binding
  biological_processes:
  - preferred_term: protein homooligomerization
    modifier: DECREASED
    term:
      id: GO:0051260
      label: protein homooligomerization
  downstream:
  - target: Failure of PTS1 and PTS2 Receptor Docking
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23716570
    reference_title: Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum
      patient reveals novel homooligomerization of PEX13 and its role in human peroxisome
      biogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the highly conserved W313 residue is important for self-association of PEX13
      but is not required for interaction with PEX14, a well-established interaction partner
      at the peroxisomal membrane
    explanation: Separates the two binding functions of the docking module, showing that a
      patient allele can disable self-association while leaving PEX14 binding intact.
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Computational predictions highlighted the involvement of the Arg294 residue in
      PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp
      variant alters the formation of dimers, impairing the stability of the PEX13/PEX14
      translocation module.
    explanation: PARTIAL because the destabilisation of the module by the recurrent allele is
      a docking prediction rather than a measured interaction.
  - reference: PMID:38632234
    reference_title: Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal
      FxxxF binding motif.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Strikingly, intramolecular interaction of the PEX13 FxxxF motif regulates binding
      of PEX5 WxxxF/Y motifs to the PEX13 SH3 domain.
    explanation: Establishes the autoregulatory switch inside the docking module, which is a
      layer the retrotranslocation peroxins have no counterpart for.
  - reference: PMID:38632234
    reference_title: Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal
      FxxxF binding motif.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Surprisingly, the potential PxxP binding surface of the SH3 domain does not
      recognize PEX14 PxxP motifs, distinct from its yeast ortholog.
    explanation: The human-versus-yeast difference. Curated explicitly because the yeast PxxP
      docking model is the one in most reviews and would be wrong if carried across here.
- name: Failure of PTS1 and PTS2 Receptor Docking
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    PEX5 carries PTS1-tagged matrix enzymes and PEX7 carries PTS2-tagged ones; both must
    dock at the membrane before their cargo can be translocated. The PEX13 SH3 domain is
    the PEX5 docking site, so losing it stalls the cycle before unloading rather than
    after it. Both cargo classes are affected in vivo, but they are not equally sensitive:
    interrupting PEX13 homooligomerisation specifically disrupts PTS1 import.
  biological_processes:
  - preferred_term: protein import into peroxisome matrix, docking
    modifier: DECREASED
    term:
      id: GO:0016560
      label: protein import into peroxisome matrix, docking
  downstream:
  - target: Collapse of Peroxisomal Matrix Protein Import
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:11405337
    reference_title: Clinical, biochemical and genetic aspects and neuronal migration in
      peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: PEX13 protein has an SH3 docking site that binds to the PTS-1 receptor.
    explanation: States the molecular role that makes PEX13 a docking-step rather than a
      recycling-step peroxin.
  - reference: PMID:23716570
    reference_title: Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum
      patient reveals novel homooligomerization of PEX13 and its role in human peroxisome
      biogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We demonstrate that the import of PTS1 (peroxisomal targeting signal 1) proteins
      is specifically disrupted when homooligomerization of PEX13 is interrupted.
    explanation: Establishes the cargo-class selectivity of the docking defect.
  - reference: PMID:12897163
    reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads
      to a Zellweger syndrome phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These animals lacked morphologically intact peroxisomes and showed deficient
      import of matrix proteins containing either type 1 or type 2 targeting signals.
    explanation: Complete loss of Pex13 in vivo blocks both cargo classes, so the selectivity
      above is a property of particular alleles rather than of the gene.
- name: Collapse of Peroxisomal Matrix Protein Import
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Matrix enzymes never reach the organelle. The membrane compartment still forms - the
    "peroxisomal ghost" - which is the morphological signature distinguishing a biogenesis
    defect from a single enzyme deficiency. In PEX13 patient fibroblasts the residual
    peroxisome population is both reduced in number and abnormal in PEX13 content.
  biological_processes:
  - preferred_term: protein import into peroxisome matrix
    modifier: DECREASED
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
  - preferred_term: peroxisome organization
    modifier: DECREASED
    term:
      id: GO:0007031
      label: peroxisome organization
  cellular_components:
  - preferred_term: peroxisomal matrix
    term:
      id: GO:0005782
      label: peroxisomal matrix
  downstream:
  - target: Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids
    causal_link_type: DIRECT
  - target: Plasmalogen Deficiency
    causal_link_type: DIRECT
  - target: Secondary Mitochondrial Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Peroxisomal and mitochondrial beta-oxidation are metabolically coupled and the two
      organelles share fission machinery, but which of those links carries the effect in
      PEX13 deficiency is not established.
  - target: Pexophagy of Import-Incompetent Peroxisomes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Import failure leaves ubiquitinated PEX5 on the membrane and raises peroxisomal reactive
      oxygen species, and both signals induce pexophagy. Shown in edited cells and zebrafish,
      not in patients.
  evidence:
  - reference: PMID:10441568
    reference_title: PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis
      disorders.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Skin fibroblasts from patient PBD222 display defects in the import of multiple
      peroxisomal matrix proteins.
    explanation: The cellular lesion measured directly in patient-derived cells.
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identified mislocalized mitochondria and a reduced number of peroxisomes with
      abnormal PEX13 concentration
    explanation: Quantifies the residual peroxisome population in PEX13 patient material.
- name: Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Substrates that only peroxisomes degrade build up systemically: C26:0 and other VLCFA,
    phytanic and pristanic acid, pipecolic acid, and C27 bile-acid intermediates. This is
    the accumulation half of the biochemical signature and the basis of diagnostic testing.
  biological_processes:
  - preferred_term: very long-chain fatty acid beta-oxidation
    modifier: DECREASED
    term:
      id: GO:0140493
      label: very long-chain fatty acid beta-oxidation
  - preferred_term: fatty acid alpha-oxidation
    modifier: DECREASED
    term:
      id: GO:0001561
      label: fatty acid alpha-oxidation
  - preferred_term: bile acid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006699
      label: bile acid biosynthetic process
  downstream:
  - target: Progressive Hepatic Injury
    causal_link_type: DIRECT
  - target: Adrenocortical Insufficiency
    causal_link_type: DIRECT
  - target: Impaired Neuronal Migration and Neurogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Peroxisomal failure demonstrably disrupts cortical migration, but which accumulating
      substrate or missing lipid does it is not established.
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serum analysis revealed elevated levels of very long-chain fatty acids (VLCFA),
      phytanic acid, and pipecolic acid.
    explanation: The accumulating metabolites measured in a PEX13 patient with the severe
      presentation.
  - reference: PMID:12897163
    reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads
      to a Zellweger syndrome phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Biochemical analyses of tissue and cultured skin fibroblasts from these animals
      indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen
      synthesis.
    explanation: Confirms the beta-oxidation block in vivo in the Pex13-null mouse.
- name: Plasmalogen Deficiency
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Ether phospholipid synthesis begins in the peroxisome, so plasmalogens - major
    constituents of myelin - and DHA are not made. This is the deficiency half of the
    signature and the one most plausibly linked to the white-matter disease. In the
    brain-restricted PEX13 mouse it is the half that is present: plasmalogens fall while
    VLCFA stay normal, which dissociates the two arms of the biochemical lesion.
  biological_processes:
  - preferred_term: ether lipid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
  downstream:
  - target: Impaired Neuronal Migration and Neurogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:20959636
    reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
      abnormal cerebellum formation, reactive gliosis and oxidative stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen
      content is reduced, but very-long-chain fatty acids are normal."
    explanation: Shows the plasmalogen arm of the lesion occurring in brain without VLCFA
      accumulation, so the two arms can be separated.
- name: Secondary Mitochondrial Dysfunction
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    PEX13 patient muscle and fibroblasts show respiratory-chain abnormalities and
    mislocalised mitochondria alongside the peroxisomal defect, and Pex13-null cerebellar
    neurons show mitochondrial dysfunction with elevated reactive oxygen species. Whether
    this is a driver of the neuronal loss or a downstream consequence of it is the open
    question; it is curated as PROVISIONAL because the observations are consistent across
    human tissue and mouse neurons but the causal direction has not been tested.
  biological_processes:
  - preferred_term: mitochondrion organization
    modifier: DECREASED
    term:
      id: GO:0007005
      label: mitochondrion organization
  - preferred_term: reactive oxygen species metabolic process
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  downstream:
  - target: Impaired Neuronal Migration and Neurogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Studies on muscle tissues and patient-derived fibroblasts revealed biochemical
      alterations of mitochondrial function and identified mislocalized mitochondria
    explanation: The human observation of mitochondrial involvement in PEX13-related disease.
  - reference: PMID:20959636
    reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
      abnormal cerebellum formation, reactive gliosis and oxidative stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: cultured cerebellar neurons from E19 PEX13-null mice exhibit elevated levels
      of reactive oxygen species and mitochondrial superoxide dismutase-2 (MnSOD), and show
      enhanced apoptosis together with mitochondrial dysfunction
    explanation: The corresponding measurement in Pex13-null neurons, linking mitochondrial
      dysfunction to oxidative stress and cell death.
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: including the emerging contribution of secondary mitochondrial dysfunction to
      the pathophysiology of ZSDs
    explanation: PARTIAL because the authors themselves frame the contribution as emerging
      rather than established.
  - reference: PMID:27514574
    reference_title: Mitochondrial changes and oxidative stress in a mouse model of Zellweger
      syndrome neuropathogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Cultured fibroblasts from PEX13-deficient mouse embryo displayed similar changes,
      as well as increased levels of mitochondrial superoxide and membrane depolarization; this
      phenotype was rescued by antioxidant treatment.
    explanation: The one perturbation reported at this node - antioxidant rescue of the
      mitochondrial phenotype. IN_VITRO because it is in cultured fibroblasts; it shows the
      phenotype is correctable without showing that correcting it changes cell fate.
- name: Pexophagy of Import-Incompetent Peroxisomes
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Losing PEX13 does not only stop peroxisomes being filled - it appears to mark them for
    destruction. In edited cells and in zebrafish, PEX13 loss causes ubiquitinated PEX5 to
    accumulate on the peroxisomal membrane and peroxisome-derived reactive oxygen species to
    rise, and together those two signals induce pexophagy of peroxisomes that would otherwise
    be healthy. If it operates in patients it would compound the import block, because the
    residual organelle population is being cleared as well as being left empty - which is
    consistent with the reduced peroxisome number found in PEX13 patient fibroblasts.

    Curated as PROVISIONAL, not ESTABLISHED: the mechanism is demonstrated in cell lines and
    zebrafish, and no measurement in a PEX13 patient ties pexophagy to any clinical feature.
  biological_processes:
  - preferred_term: autophagy of peroxisome
    modifier: INCREASED
    term:
      id: GO:0030242
      label: autophagy of peroxisome
  - preferred_term: protein ubiquitination
    modifier: INCREASED
    term:
      id: GO:0016567
      label: protein ubiquitination
  evidence:
  - reference: PMID:36541703
    reference_title: PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal
      ROS.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we found that PEX13, a component of the peroxisomal matrix import system, is
      required to prevent the degradation of otherwise healthy peroxisomes
    explanation: The core finding - PEX13 restrains pexophagy, so its loss releases it. Graded
      MODEL_ORGANISM because this headline claim rests on the zebrafish arm as well as the cell
      lines; the cell-line mechanism is quoted separately below as IN_VITRO, which is the split
      a mixed-source paper calls for.
  - reference: PMID:36541703
    reference_title: PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal
      ROS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and
      an increase in peroxisome-dependent reactive oxygen species that coalesce to induce
      pexophagy.
    explanation: The two-signal mechanism, and the link to reactive oxygen species that
      connects this node to the mitochondrial and oxidative-stress findings.
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: identified mislocalized mitochondria and a reduced number of peroxisomes with
      abnormal PEX13 concentration
    explanation: INDIRECT because a reduced peroxisome count in patient cells is consistent with
      excess pexophagy but does not establish it; the count could equally reflect impaired
      proliferation of the organelle.
- name: Impaired Neuronal Migration and Neurogenesis
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Neuronal precursors fail to proliferate, migrate and mature normally during fetal
    brain development, producing a congenital malformation rather than a purely
    degenerative lesion. Because the lesion forms before birth, it is not reversible by
    any postnatal intervention. The PEX13 mouse adds cerebellar detail to the cortical
    picture - impaired granule cell migration and Purkinje layer formation - with
    astrogliosis and microgliosis as prominent accompaniments.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  downstream:
  - target: Severe Neurodevelopmental Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12897163
    reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads
      to a Zellweger syndrome phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The brains of these animals showed disordered lamination in the cerebral cortex,
      consistent with a neuronal migration defect.
    explanation: The cortical migration defect demonstrated in the Pex13-null mouse.
  - reference: PMID:29187321
    reference_title: Impaired neurogenesis and associated gliosis in mouse brain with PEX13
      deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we show a significant reduction in proliferation, migration, differentiation,
      and maturation of neural progenitors in embryonic E12.5 through to P3 animals
    explanation: Extends the lesion from migration alone to the whole neurogenic programme.
  - reference: PMID:20959636
    reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
      abnormal cerebellum formation, reactive gliosis and oxidative stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Astrogliosis and microgliosis are prominent features of the mutant cerebellum.
    explanation: Grounds the astrocyte and microglial cell types annotated on this node.
- name: Progressive Hepatic Injury
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    VLCFA and C27 bile-acid intermediates are directly hepatotoxic, driving cholestasis
    and fibrosis. Hepatic dysfunction was part of the presenting picture in the reported
    severe PEX13 cases.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to
      thrive, and dysmorphic features.
    explanation: Names hepatic dysfunction in a molecularly confirmed severe PEX13 case.
- name: Adrenocortical Insufficiency
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    VLCFA accumulation in adrenocortical cells impairs steroidogenesis. Often subclinical
    at first, which is why GeneReviews asks for ACTH and cortisol measurement by age one
    even in children who look adrenally well.
  cell_types:
  - preferred_term: cortical cell of adrenal gland
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ACTH and cortisol levels by age one year and annually thereafter.
    explanation: PARTIAL because the GeneReviews Surveillance recommendation implies the
      risk rather than reporting the mechanism; it is spectrum-wide, not PEX13-specific.
- name: Severe Neurodevelopmental Impairment
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Profound hypotonia, neonatal seizures, and absent or regressing developmental
    progress. In the severe form death usually follows in infancy; the molecularly
    confirmed PEX13 cases at this end of the spectrum died at 14 months and in the
    neonatal period respectively.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Infants with severe ZSD are significantly impaired and typically die during
      the first year of life, usually having made no developmental progress.
    explanation: GeneReviews states the course of the severe end of the spectrum, which is
      what PBD11A denotes.
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient died at the age of 14 months.
    explanation: The observed outcome in a molecularly confirmed severe PEX13 case.
phenotypes:
- category: Neurologic
  name: Severe Neonatal Hypotonia
  frequency: VERY_FREQUENT
  description: >-
    Profound generalized hypotonia from birth, with poor feeding. It is the presenting
    sign in both the reported severe PEX13 cases and in the milder PEX13 families.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
    severity: SEVERE
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to
      thrive, and dysmorphic features.
    explanation: Hypotonia in a molecularly confirmed severe PEX13 case.
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Affected newborns are hypotonic and feed poorly.
    explanation: GeneReviews Clinical Characteristics names hypotonia as the newborn
      presentation across the spectrum.
- category: Neurologic
  name: Neonatal Seizures
  frequency: FREQUENT
  description: >-
    Seizures beginning in the newborn period, arising from the congenital cortical
    malformation rather than from a metabolic decompensation.
  phenotype_term:
    preferred_term: Neonatal seizure
    term:
      id: HP:0032807
      label: Neonatal seizure
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to
      thrive, and dysmorphic features.
    explanation: Seizures in a molecularly confirmed severe PEX13 case.
- category: Neurologic
  name: Developmental Regression
  frequency: FREQUENT
  description: >-
    Loss of previously acquired skills, reported across the PEX13 families and one of the
    features that distinguishes the PEX13 presentation from a purely static encephalopathy.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with PEX13-related ZSD presented heterogeneous clinical
      features, including hypotonia, developmental regression, hearing/vision impairment,
      progressive spasticity and brain leukodystrophy."
    explanation: Names regression in the largest reported PEX13 series.
- category: Neurologic
  name: Progressive Spasticity
  frequency: FREQUENT
  description: >-
    Spasticity that worsens over time, reported in the PEX13 series alongside the
    white-matter disease.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with PEX13-related ZSD presented heterogeneous clinical
      features, including hypotonia, developmental regression, hearing/vision impairment,
      progressive spasticity and brain leukodystrophy."
    explanation: Names progressive spasticity in the PEX13 cohort.
- category: Neurologic
  name: Leukodystrophy
  frequency: FREQUENT
  description: >-
    Diffuse white-matter disease on brain MRI, consistent with the plasmalogen deficiency
    that removes a major myelin constituent.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with PEX13-related ZSD presented heterogeneous clinical
      features, including hypotonia, developmental regression, hearing/vision impairment,
      progressive spasticity and brain leukodystrophy."
    explanation: Names brain leukodystrophy in the PEX13 cohort.
- category: Neurologic
  name: Polymicrogyria
  frequency: OCCASIONAL
  description: >-
    Malformation of cortical development, the structural correlate of the arrested
    neuronal migration and one of the congenital malformations that mark the severe end
    of the spectrum. Reported in a PEX13 infant with neonatal-onset seizures.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bilateral malformation of cortical development in parietal lobes, with a
      polymicrogyria-like appearance
    explanation: The imaging finding in a PEX13 patient; the report describes it as
      polymicrogyria-like, so the binding is to the closest structural HPO term.
- category: Neurologic
  name: CNS Hypomyelination
  frequency: FREQUENT
  description: >-
    Deficient myelination on brain MRI, distinct from the demyelinating leukodystrophy
    pattern and consistent with plasmalogens being a major myelin constituent that
    peroxisome-deficient cells cannot make.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI revealed diffuse hypomyelination with abnormal confluent FLAIR
      hyperintense signal abnormality, particularly involving the cerebellar white matter.
    explanation: The imaging finding in a PEX13 patient.
- category: Neurologic
  name: Global Developmental Delay
  frequency: VERY_FREQUENT
  description: >-
    Absent developmental progress. At the severe end this is not delay against a trajectory
    but the absence of a trajectory.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Infants with severe ZSD are significantly impaired and typically die during
      the first year of life, usually having made no developmental progress.
    explanation: GeneReviews states the absence of developmental progress at the severe end.
- category: Ophthalmologic
  name: Visual Impairment
  frequency: FREQUENT
  description: >-
    Reduced vision, which in the Zellweger spectrum is usually secondary to retinal
    dystrophy and cataract.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with PEX13-related ZSD presented heterogeneous clinical
      features, including hypotonia, developmental regression, hearing/vision impairment,
      progressive spasticity and brain leukodystrophy."
    explanation: Names vision impairment in the PEX13 cohort.
- category: Audiologic
  name: Hearing Impairment
  frequency: FREQUENT
  description: >-
    Hearing loss, sensorineural in the Zellweger spectrum, and one of the sensory deficits
    that becomes apparent in children who survive the newborn period.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with PEX13-related ZSD presented heterogeneous clinical
      features, including hypotonia, developmental regression, hearing/vision impairment,
      progressive spasticity and brain leukodystrophy."
    explanation: Names hearing impairment in the PEX13 cohort.
- category: Neurologic
  name: Cerebellar Atrophy
  frequency: OCCASIONAL
  description: >-
    Loss of cerebellar volume with pontine and vermian hypoplasia, reported in the PEX13
    series. The Pex13 brain-restricted mouse gives the developmental counterpart - disrupted
    fissure formation, granule cell migration and Purkinje layer development.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: cerebellar atrophy and pontine/vermian hypoplasia were also reported
    explanation: The cerebellar finding in the PEX13 cohort.
- category: Endocrine
  name: Adrenal Insufficiency
  frequency: OCCASIONAL
  description: >-
    Primary adrenal insufficiency from impaired steroidogenesis in VLCFA-loaded adrenocortical
    cells. Frequently silent until stressed, which is why GeneReviews asks for ACTH and cortisol
    by age one regardless of symptoms.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: liver dysfunction, adrenal insufficiency, and renal oxalate stones
    explanation: PARTIAL for two reasons - the sentence is spectrum-wide rather than from a
      PEX13 case, and it specifically describes the intermediate/milder end, whereas this entry
      is the severe one. It is curated because the surveillance recommendation that follows from
      it applies to any child who survives the newborn period.
- category: Hepatic
  name: Liver Dysfunction
  frequency: FREQUENT
  description: >-
    Cholestatic liver disease with impaired synthetic function; can be severe.
  phenotype_term:
    preferred_term: Decreased liver function
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to
      thrive, and dysmorphic features.
    explanation: Hepatic dysfunction in a molecularly confirmed severe PEX13 case.
- category: Hepatic
  name: Elevated Hepatic Transaminases
  frequency: FREQUENT
  description: >-
    Raised serum transaminases reflecting hepatocellular injury, typically alongside
    hepatomegaly and coagulopathy.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hepatomegaly and hepatic dysfunction with coagulopathy, elevated transaminases
    explanation: PARTIAL because the sentence is spectrum-wide rather than from a PEX13 case
      series, and describes a group with less pronounced craniofacial features than the
      neonatal-infantile end this entry curates.
- category: Growth
  name: Failure to Thrive
  frequency: FREQUENT
  description: >-
    Poor weight gain, compounded by the feeding difficulty that follows from severe
    hypotonia.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to
      thrive, and dysmorphic features.
    explanation: Failure to thrive in a molecularly confirmed severe PEX13 case.
- category: Craniofacial
  name: Dysmorphic Facies
  frequency: FREQUENT
  description: >-
    The distinctive Zellweger facial appearance - high forehead, large anterior fontanelle,
    flat occiput, epicanthal folds.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to
      thrive, and dysmorphic features.
    explanation: Dysmorphic features in a molecularly confirmed severe PEX13 case.
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: They have distinctive facies, congenital malformations
    explanation: GeneReviews names the distinctive facies as part of the severe presentation.
- category: Neurologic
  name: Feeding Difficulties
  frequency: VERY_FREQUENT
  description: >-
    Poor suck and swallow from birth, usually requiring gastrostomy in infants who survive
    the newborn period.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Affected newborns are hypotonic and feed poorly.
    explanation: GeneReviews Clinical Characteristics names feeding failure in the newborn.
- category: Renal
  name: Renal Cysts
  frequency: OCCASIONAL
  description: >-
    Cortical renal cysts, one of the congenital malformations that define the severe end of
    the spectrum and part of the original cerebro-hepato-renal description.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: neuronal migration defects associated with neonatal-onset seizures, renal cysts,
      and bony stippling
    explanation: PARTIAL because the GeneReviews sentence is spectrum-wide rather than
      reported in a PEX13 case series.
- category: Skeletal
  name: Epiphyseal Stippling
  frequency: OCCASIONAL
  description: >-
    Punctate calcification of the patellae and long-bone epiphyses (chondrodysplasia
    punctata), a radiographic marker of the severe end of the spectrum.
  phenotype_term:
    preferred_term: Epiphyseal stippling
    term:
      id: HP:0010655
      label: Epiphyseal stippling
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: neuronal migration defects associated with neonatal-onset seizures, renal cysts,
      and bony stippling
    explanation: PARTIAL because the sentence is spectrum-wide, and it is truncated before
      "[chondrodysplasia punctata]" because the reference validator strips bracketed text.
- category: Growth
  name: Intrauterine Growth Retardation
  frequency: OCCASIONAL
  description: >-
    Reduced fetal growth, observed in the Pex13-null mouse and consistent with the prenatal
    onset of the disorder.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:12897163
    reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads
      to a Zellweger syndrome phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The mutant pups exhibited many of the clinical features of Zellweger syndrome
      patients, including intrauterine growth retardation, severe hypotonia, failure to feed,
      and neonatal death.
    explanation: PARTIAL because the observation is in the Pex13-null mouse rather than in
      PEX13 patients.
genetic:
- name: PEX13
  gene_term:
    preferred_term: PEX13
    term:
      id: hgnc:8855
      label: PEX13
  relationship_type: CAUSATIVE
  notes: >-
    The complementation group 13 (group H) gene, encoding the SH3-domain docking peroxin.
    PEX13 is one of the rarest causes of Zellweger spectrum disease - roughly twenty
    variants reported worldwide - so the allelic spectrum is small and genotype-phenotype
    correlation is correspondingly weaker than at PEX1 or PEX12. A recurrent p.Arg294Trp
    allele accounts for three of the five families in the largest reported series. Note
    that the first patient assigned to this group presented at the milder, NALD end rather
    than with classical Zellweger syndrome, so the locus was defined by a phenotype closer
    to 11B than to the 11A presentation this entry curates.

    The published alleles sort into three functional tiers rather than two: null alleles
    (p.Trp234Ter, the whole-gene deletion, the 14-bp frameshift) leave no docking complex at
    all; SH3-domain missense alleles that break self-association (p.Trp313Gly) leave a complex
    that is present but non-functional for PTS1 import; and hypomorphic or
    temperature-sensitive missense alleles (p.Ile326Thr, p.Arg294Trp) leave residual import.
    The first two tiers present as 11A, the third as 11B.
  evidence:
  - reference: PMID:10441568
    reference_title: PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis
      disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PEX13 encodes a peroxisomal membrane protein with a cytoplasmically exposed SH3
      domain, and we find that expression of human PEX13 restores peroxisomal matrix-protein
      import in cells from patient PBD222.
    explanation: The functional complementation result that identified the gene, and the
      statement of its molecular role.
  - reference: PMID:35854306
    reference_title: Genotype-phenotype correlations and disease mechanisms in PEX13-related
      Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant.
    explanation: Identifies the recurrent allele in the largest PEX13 series.
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PEX13 gene variants are rare causes of ZSDs, with only 21 cases reported
      worldwide and none in China.
    explanation: Quantifies how few PEX13 cases exist, which is why the allelic spectrum is
      thin.
  - reference: PMID:19449432
    reference_title: "Zellweger syndrome caused by PEX13 deficiency: report of two novel
      mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations in PEX13, which encodes peroxisomal membrane protein PEX13, are among
      the least common causes of peroxisomal biogenesis disorders with only three mutations
      reported so far.
    explanation: Records how sparse the allelic spectrum was when the classical-Zellweger
      PEX13 cases were first described.
biochemical:
- name: Very-long-chain fatty acids
  presence: Increased
  context: >-
    Plasma C26:0 with the C24/C22 and C26/C22 ratios is the first-line biochemical screen.
    In the severe form curated here the elevation is unambiguous, unlike the milder end of
    the spectrum where it can be modest.
  biomarker_term:
    preferred_term: very long-chain fatty acid
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
  evidence:
  - reference: PMID:28677031
    reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as
      diagnostic markers for Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This results in multiple metabolic abnormalities, including elevated very
      long-chain fatty acid (VLCFA) levels.
    explanation: States that VLCFA elevation is a consequence of the peroxisome biogenesis
      defect, which is why the marker belongs in this entry.
  readouts:
  - target: Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated VLCFA reports the peroxisomal beta-oxidation block directly.
    evidence:
    - reference: PMID:37962062
      reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
        in the PEX13 gene: A case report and the literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Serum analysis revealed elevated levels of very long-chain fatty acids (VLCFA),
        phytanic acid, and pipecolic acid.
      explanation: The measurement made in a molecularly confirmed severe PEX13 case.
- name: Phytanic acid
  presence: Increased
  context: >-
    Phytanic acid is degraded by peroxisomal alpha-oxidation, so it accumulates by a
    different route from the VLCFA and reports a second arm of the block.
  biomarker_term:
    preferred_term: phytanic acid
    term:
      id: CHEBI:16285
      label: phytanic acid
  readouts:
  - target: Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated phytanic acid reports the peroxisomal alpha-oxidation block.
    evidence:
    - reference: PMID:37962062
      reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
        in the PEX13 gene: A case report and the literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Serum analysis revealed elevated levels of very long-chain fatty acids (VLCFA),
        phytanic acid, and pipecolic acid.
      explanation: The measurement made in a molecularly confirmed severe PEX13 case.
- name: C26:0-lysophosphatidylcholine
  presence: Increased
  context: >-
    C26:0-lysoPC in dried blood spots is the assay that makes newborn screening for
    Zellweger spectrum disease technically feasible, which matters most for the severe form
    because its window for any intervention is shortest.
  evidence:
  - reference: PMID:28677031
    reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as
      diagnostic markers for Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Implementation of C26:0-lysoPC measurement in the diagnostic work-up when
      suspecting a ZSD is advised.
    explanation: The authors' recommendation that establishes this analyte as a routine marker
      for the disease group.
  readouts:
  - target: Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated dried-blood-spot C26:0-lysoPC reports peroxisomal beta-oxidation
      failure.
    evidence:
    - reference: PMID:28677031
      reference_title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as
        diagnostic markers for Zellweger spectrum disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Elevated C26:0-lysoPC levels (>72 nmol/L) were found in 86/91 ZSD DBS
      explanation: Quantifies the sensitivity of this readout against the block it reports.
- name: Plasmalogens
  presence: Decreased
  biomarker_term:
    preferred_term: ether lipid
    term:
      id: CHEBI:64611
      label: ether lipid
  context: >-
    Erythrocyte plasmalogens are low because ether lipid synthesis begins in the peroxisome.
    This is the deficiency half of the signature and moves in the opposite direction to the
    VLCFA markers, which is what distinguishes a biogenesis defect from an isolated
    beta-oxidation enzyme defect.
  readouts:
  - target: Plasmalogen Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced plasmalogens report failed peroxisomal ether lipid synthesis.
    evidence:
    - reference: PMID:12897163
      reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and
        leads to a Zellweger syndrome phenotype.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Biochemical analyses of tissue and cultured skin fibroblasts from these animals
        indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen
        synthesis.
      explanation: PARTIAL because the measurement is in the Pex13-null mouse rather than in
        PEX13 patients; it shows both directions of the signature in one animal.
diagnosis:
- name: Plasma Very-Long-Chain Fatty Acid Profile
  description: >-
    The first-line biochemical test. Elevated C26:0 with abnormal C24/C22 and C26/C22 ratios
    points at a peroxisomal disorder before any gene is sequenced.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The diagnosis of ZSD is established in a proband with the suggestive clinical and
      biochemical findings above by identification of biallelic pathogenic variants in one of
      the 13 known ZSD-PEX genes.
    explanation: GeneReviews Diagnosis places biochemical findings ahead of molecular
      confirmation in the diagnostic sequence.
- name: Molecular Genetic Testing of the ZSD-PEX Genes
  description: >-
    Confirmation requires biallelic variants in one of the ZSD-PEX genes; assignment to
    PEX13 is what makes the entry PBD11 rather than another group. Because PEX13 is a rare
    cause, it is usually reached by exome sequencing rather than by targeted testing.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX
      genes
    explanation: States the molecular criterion.
  - reference: PMID:37962062
    reference_title: "Severe Zellweger spectrum disorder due to a novel missense variant
      in the PEX13 gene: A case report and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identified by whole exome sequencing and validated by Sanger sequencing
    explanation: Shows the testing route by which a rare PEX13 case is actually reached.
- name: Complementation Analysis in Cultured Fibroblasts
  description: >-
    The historical assignment method, and still informative where sequencing is
    uninterpretable: patient fibroblasts are fused with reference cell lines and the group
    is read off from which fusion restores peroxisomal import. This is how group H/13 was
    defined before PEX13 was cloned.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:19449432
    reference_title: "Zellweger syndrome caused by PEX13 deficiency: report of two novel
      mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report on two infants whose clinical and biochemical profile was
      consistent with classical Zellweger syndrome and whose complementation analysis assigned
      them both to group H of peroxisomal biogenesis disorders.
    explanation: Shows complementation analysis assigning classical Zellweger patients to the
      PEX13 group.
treatments:
- name: Supportive and Symptomatic Management
  therapeutic_modality: OTHER
  description: >-
    There is no treatment for the biogenesis defect. Management is entirely symptomatic -
    gastrostomy feeding, anti-seizure medication, hearing aids, cataract surgery, fat-soluble
    vitamin and cholic acid supplementation, adrenal replacement. None of it restores
    peroxisomal import, and the congenital brain malformation is fixed before birth.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Severe Neurodevelopmental Impairment
    treatment_effect: MODULATES
    description: >-
      Addresses consequences - nutrition, seizures, sensory deficits - without acting on
      peroxisome biogenesis.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment of manifestations: The focus is on symptomatic therapy and may include
      gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to
      correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid
      supplementation"
    explanation: GeneReviews Management states that treatment is symptomatic and enumerates
      the measures.
- name: Cholic Acid
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Oral cholic acid restores feedback inhibition of endogenous bile acid synthesis, so the
    hepatotoxic C27 intermediates that peroxisome-deficient hepatocytes cannot process stop
    accumulating. It is the only FDA-approved therapy for Zellweger spectrum disease and the
    only intervention in this entry that acts on a curated mechanism node rather than on a
    consequence. The trial evidence is spectrum-wide; no PEX13 patient has been reported on
    it, so its use here is by extension from the shared biochemical lesion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  target_mechanisms:
  - target: Accumulation of Very-Long-Chain and Branched-Chain Fatty Acids
    treatment_effect: INHIBITS
    description: >-
      Suppresses synthesis of the atypical C27 bile-acid intermediates that accumulate because
      peroxisomal side-chain shortening is blocked. It does not restore peroxisomal import, so
      the other accumulating substrates are unaffected.
  - target: Progressive Hepatic Injury
    treatment_effect: INHIBITS
    description: >-
      Removing the hepatotoxic intermediates is what improves the liver chemistry.
  evidence:
  - reference: PMID:28644367
    reference_title: Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile
      Acid Synthesis and Zellweger Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cholic acid significantly improved urine bile acid metabolite scores (P <
      0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001)
      in patients with SED and ZSD.
    explanation: PARTIAL because the trial enrolled the Zellweger spectrum as a whole rather
      than PEX13 patients; the fall in atypical urinary bile acids is the direct readout of
      the targeted mechanism and the transaminase fall is the hepatic consequence.
  - reference: PMID:27469511
    reference_title: Cholic acid therapy in Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patients with advanced liver disease (n = 4), cholic acid treatment resulted
      in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor
      reduction in bile acid intermediates.
    explanation: The safety caveat that qualifies the treatment - in the patients with the
      worst liver disease the drug worsened liver chemistry rather than improving it. PARTIAL
      because it supports the caution, not the efficacy claim.
  - reference: PMID:27469511
    reference_title: Cholic acid therapy in Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, caution is needed in patients with advanced liver disease due to possible
      hepatotoxic effects.
    explanation: The authors' own conclusion, recorded here as the agents-to-use-with-care
      statement for this treatment.
- name: Adrenal Replacement Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Glucocorticoid replacement where adrenal insufficiency is documented. GeneReviews asks for
    ACTH and cortisol by age one and annually thereafter, because the insufficiency is often
    subclinical when it starts. The screening and the treating are deliberately separate steps:
    cortisone carries its own harms - growth suppression, osteoporosis - so the recommendation
    is to screen everyone and treat only those with a demonstrated insufficiency on Synacthen
    testing, not to supplement on suspicion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: CHEBI:17650
        label: cortisol
  target_mechanisms:
  - target: Adrenocortical Insufficiency
    treatment_effect: RESTORES
    description: >-
      Replaces the missing hormone output; it does not correct the VLCFA accumulation that
      impaired steroidogenesis.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: adrenal replacement therapy; vitamin D supplementation and consideration of
      bisphosphonates for osteopenia
    explanation: GeneReviews Management lists adrenal replacement among the symptomatic
      measures.
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: only patients with a true insufficiency (i.e. altered Synacthen test) should be
      treated
    explanation: The treat-only-if-confirmed rule, which exists because the supplementation
      itself causes growth suppression and osteoporosis. Symmetric to the cholic-acid caution
      above - both are treatments whose harm is documented alongside their benefit.
- name: Anti-Seizure Medication
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Seizure control in an epilepsy that arises from a fixed cortical malformation, so the
    aim is symptomatic control rather than modification of the underlying lesion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_mechanisms:
  - target: Impaired Neuronal Migration and Neurogenesis
    treatment_effect: MODULATES
    description: >-
      Suppresses seizures arising from the cortical malformation. The malformation itself is
      fixed before birth and is not modified.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: anti-seizure medication, early intervention services for developmental delay and
      intellectual disability
    explanation: GeneReviews Management lists anti-seizure medication.
- name: Docosahexaenoic Acid Supplementation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    DHA is one of the lipids peroxisome-deficient cells cannot make, so replacing it is a
    mechanistically obvious idea. It does not work. A randomised, double-blind,
    placebo-controlled trial in peroxisome assembly disorders found no benefit in biochemistry,
    electroretinogram or growth. It is curated here as a refuted therapy rather than omitted,
    because the rationale is intuitive enough that it keeps being proposed. It carries no
    `target_mechanisms` link deliberately: every available `treatment_effect` value asserts an
    effect on the node, and the trial's finding is that there is none.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: docosahexaenoic acid
      term:
        id: CHEBI:28125
        label: all-cis-docosa-4,7,10,13,16,19-hexaenoic acid
  evidence:
  - reference: PMID:20805528
    reference_title: "Docosahexaenoic acid therapy in peroxisomal diseases: results of a
      double-blind, randomized trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: There was no difference in the outcomes between the treated and untreated groups
      in biochemical function, electroretinogram, or growth.
    explanation: The primary result refuting DHA supplementation as a therapy for peroxisome
      assembly disorders.
  - reference: PMID:20805528
    reference_title: "Docosahexaenoic acid therapy in peroxisomal diseases: results of a
      double-blind, randomized trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: This interventional study provides Class II evidence that DHA supplementation did
      not improve the visual function or growth of treated individuals with peroxisome assembly
      disorders during an average of 1 year of follow-up in patients aged 1 to 144 months.
    explanation: The formal evidence grading, which is what makes this a settled negative rather
      than an underpowered one.
clinical_trials:
- name: NCT01668186
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    The principal longitudinal natural-history study of the peroxisome biogenesis disorders,
    prospectively following patients internationally and banking clinical, biochemical and
    genetic data. It is observational, so it carries no phase; it is listed because for a
    disease with roughly twenty reported patients worldwide, the registry is the only route to
    a described natural history.
  evidence:
  - reference: clinicaltrials:NCT01668186
    reference_title: Longitudinal Natural History Study of Patients With Peroxisome Biogenesis
      Disorders (PBD)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In spite of advancements in peroxisome biology, the pathophysiology remains
      unknown, the spectrum of phenotypes poorly characterized and the natural history not yet
      systematically reported.
    explanation: The study's own statement of the gap it exists to fill, which is the same gap
      this entry runs into for PEX13 specifically.
animal_models:
- name: Pex13-null mouse (ubiquitous Cre)
  species: Mouse
  genotype: Pex13 conditional (loxP) allele, ubiquitous Cre-mediated inactivation, homozygous
  publication: PMID:12897163
  description: >-
    The definitive whole-animal model of this disease: the orthologous gene, disrupted in
    every tissue. Unlike the Pex2-null mouse curated on the PBD3A entry, this is a same-gene
    model rather than a paralogous one.
  evidence:
  - reference: PMID:12897163
    reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads
      to a Zellweger syndrome phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Thus, Pex13(-/-) mice reproduce many of the features of Zellweger syndrome and
      PEX13 deficiency in humans.
    explanation: The authors' own summary judgement that this model represents human PEX13
      deficiency, which is what licenses its use across the nodes below.
  modeled_mechanisms:
  - target: Failure of PTS1 and PTS2 Receptor Docking
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the import block for both cargo classes, confirming that the docking peroxin
      is required for PTS1 and PTS2 routes alike.
    limitations: >-
      The model is a null. Most human PEX13 alleles - including the recurrent p.Arg294Trp -
      are missense and may retain partial docking function, so the null does not model the
      residual-function biology that separates 11A from 11B.
    readouts:
    - name: Import of PTS1- and PTS2-tagged matrix proteins
      target: Failure of PTS1 and PTS2 Receptor Docking
      direction: DECREASED
      interpretation: Loss of import for both targeting-signal classes is the direct readout of
        a failed docking complex.
      evidence:
      - reference: PMID:12897163
        reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and
          leads to a Zellweger syndrome phenotype.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: These animals lacked morphologically intact peroxisomes and showed deficient
          import of matrix proteins containing either type 1 or type 2 targeting signals.
        explanation: The direct measurement of the import defect in the model.
    evidence:
    - reference: PMID:12897163
      reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads
        to a Zellweger syndrome phenotype.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane
        protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype.
      explanation: States the human disease the model was built to represent.
  - target: Severe Neurodevelopmental Impairment
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the clinical syndrome, including the perinatal lethality that defines the
      severe end of the spectrum.
    limitations: >-
      Death is neonatal, so the postnatal course seen in longer-surviving human infants -
      the sensory loss, the progressive white-matter disease, the developmental regression -
      cannot be observed in this model. The brain-restricted conditional was made for that
      reason.
    readouts:
    - name: Perinatal clinical phenotype and survival
      target: Severe Neurodevelopmental Impairment
      direction: DECREASED
      interpretation: Growth restriction, hypotonia, feeding failure and neonatal death
        recapitulate the severe human presentation.
      evidence:
      - reference: PMID:12897163
        reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and
          leads to a Zellweger syndrome phenotype.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: The mutant pups exhibited many of the clinical features of Zellweger syndrome
          patients, including intrauterine growth retardation, severe hypotonia, failure to
          feed, and neonatal death.
        explanation: The observed clinical phenotype of the model.
  - target: Impaired Neuronal Migration and Neurogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the cortical migration defect that is otherwise inferred from human
      neuropathology.
    limitations: >-
      Mouse cortical development is lissencephalic, so the polymicrogyria seen in human ZSD
      has no direct counterpart; disordered lamination is the closest available readout.
    readouts:
    - name: Cortical lamination
      target: Impaired Neuronal Migration and Neurogenesis
      direction: ALTERED
      interpretation: Disordered lamination is the expected signature of arrested radial
        migration.
      evidence:
      - reference: PMID:12897163
        reference_title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and
          leads to a Zellweger syndrome phenotype.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: The brains of these animals showed disordered lamination in the cerebral
          cortex, consistent with a neuronal migration defect.
        explanation: The histological result establishing the migration defect in vivo.
- name: Brain-restricted Pex13 conditional mouse (Nestin-Cre)
  species: Mouse
  genotype: Pex13 conditional (loxP) allele, brain-restricted Cre-mediated inactivation
  publication: PMID:20959636
  description: >-
    Built to escape the neonatal lethality of the ubiquitous null. Most animals survive to
    about 35 days, which opens the postnatal cerebellar and glial phenotype to study. It is
    also the model that dissociates the two arms of the biochemical lesion.
  evidence:
  - reference: PMID:20959636
    reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
      abnormal cerebellum formation, reactive gliosis and oxidative stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Thus, PEX13-deficient mice provide a valuable animal model for investigating the
      molecular basis and treatment of ZS cerebellar pathology.
    explanation: PARTIAL because the authors scope the model's value to cerebellar pathology
      specifically, not to the systemic disease.
  - reference: PMID:20959636
    reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
      abnormal cerebellum formation, reactive gliosis and oxidative stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: PEX13 brain mutants survive into the postnatal period, with the majority dying by
      35 days, and with survival inversely related to litter size and weaning body weight.
    explanation: Establishes the survival window that makes this model usable for postnatal
      phenotypes the ubiquitous null cannot reach.
  modeled_mechanisms:
  - target: Impaired Neuronal Migration and Neurogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces impaired cerebellar development - fissure and cortical layer formation,
      granule cell migration, Purkinje cell layer development - with astrogliosis and
      microgliosis, and separately impaired proliferation and maturation of neural
      progenitors from E12.5.
    limitations: >-
      Peroxisomal function is intact outside the brain, so this model cannot address the
      hepatic, adrenal or renal disease, and the systemic metabolic milieu of a real patient
      is absent. Notably VLCFA are normal in the mutant brain, so any phenotype here is
      attributable to the plasmalogen arm and to local peroxisomal failure rather than to
      circulating VLCFA.
    readouts:
    - name: Cerebellar layer formation and granule cell migration
      target: Impaired Neuronal Migration and Neurogenesis
      direction: ALTERED
      interpretation: Disrupted cerebellar cytoarchitecture reports failed migration and
        maturation in a peroxisome-deficient brain.
      evidence:
      - reference: PMID:20959636
        reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
          abnormal cerebellum formation, reactive gliosis and oxidative stress."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: PEX13 brain mutants exhibit defects in reflex and motor development that
          correlate with impaired cerebellar fissure and cortical layer formation, granule
          cell migration and Purkinje cell layer development.
        explanation: The cerebellar developmental phenotype measured in the model.
    - name: Neural progenitor proliferation and maturation
      target: Impaired Neuronal Migration and Neurogenesis
      direction: DECREASED
      interpretation: Reduced progenitor output is an earlier lesion than migration failure
        alone and helps explain the brain anatomy.
      evidence:
      - reference: PMID:29187321
        reference_title: Impaired neurogenesis and associated gliosis in mouse brain with
          PEX13 deficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: we show a significant reduction in proliferation, migration, differentiation,
          and maturation of neural progenitors in embryonic E12.5 through to P3 animals
        explanation: The neurogenesis measurement in the same brain-restricted model.
    evidence:
    - reference: PMID:29187321
      reference_title: Impaired neurogenesis and associated gliosis in mouse brain with PEX13
        deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here we used mice with brain-restricted inactivation of the peroxisome
        biogenesis gene PEX13 to model the pathophysiological features of ZS
      explanation: States the model's purpose and scope.
  - target: Secondary Mitochondrial Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cerebellar neurons from this line show mitochondrial dysfunction with elevated reactive
      oxygen species and MnSOD, together with increased apoptosis. The same line also shows an
      expanded and morphologically altered mitochondrial population in the intact brain, with
      oxidative damage to neuronal lipid and DNA, so the finding is not confined to culture.
    limitations: >-
      What the model does not settle is direction. Antioxidant treatment rescues mitochondrial
      superoxide and membrane depolarization in PEX13-deficient fibroblasts, but that rescue has
      not been run in neurons and carries no survival endpoint, so nothing yet shows that
      correcting the mitochondrial phenotype prevents the neuronal death.
    readouts:
    - name: Reactive oxygen species and MnSOD in cultured cerebellar neurons
      target: Secondary Mitochondrial Dysfunction
      direction: INCREASED
      interpretation: Elevated ROS and the compensatory MnSOD rise report mitochondrial
        oxidative stress in peroxisome-deficient neurons.
      evidence:
      - reference: PMID:20959636
        reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
          abnormal cerebellum formation, reactive gliosis and oxidative stress."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: cultured cerebellar neurons from E19 PEX13-null mice exhibit elevated levels
          of reactive oxygen species and mitochondrial superoxide dismutase-2 (MnSOD), and show
          enhanced apoptosis together with mitochondrial dysfunction
        explanation: The direct measurement of mitochondrial dysfunction and oxidative stress
          in the model.
    - name: Brain mitochondrial population and neuronal oxidative damage
      target: Secondary Mitochondrial Dysfunction
      direction: ALTERED
      interpretation: An expanded, morphologically modified mitochondrial population with lipid
        and DNA oxidation products reports the phenotype in the intact brain rather than in
        culture.
      evidence:
      - reference: PMID:27514574
        reference_title: Mitochondrial changes and oxidative stress in a mouse model of
          Zellweger syndrome neuropathogenesis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Using a mouse model of ZS with brain-restricted deficiency of the peroxisome
          biogenesis protein PEX13, we demonstrated an expanded and morphologically modified
          brain mitochondrial population.
        explanation: The in vivo measurement, in the same brain-restricted line.
      - reference: PMID:27514574
        reference_title: Mitochondrial changes and oxidative stress in a mouse model of
          Zellweger syndrome neuropathogenesis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Significant oxidative damage to neurons in brain was indicated by products of
          lipid and DNA oxidation.
        explanation: The oxidative-damage endpoint measured in brain tissue.
  - target: Plasmalogen Deficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Plasmalogens fall in the mutant brain, so the deficiency arm is reproduced.
    limitations: >-
      Only one arm of the biochemical signature is present - VLCFA are normal - so this model
      reproduces the plasmalogen lesion without the accumulation lesion that accompanies it in
      patients.
    readouts:
    - name: Brain plasmalogen content
      target: Plasmalogen Deficiency
      direction: DECREASED
      interpretation: Reduced brain plasmalogen reports failed peroxisomal ether lipid
        synthesis in situ.
      evidence:
      - reference: PMID:20959636
        reference_title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome:
          abnormal cerebellum formation, reactive gliosis and oxidative stress."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen
          content is reduced, but very-long-chain fatty acids are normal."
        explanation: Reports both the reproduced arm and the missing one.
discussions:
- discussion_id: pbd11a_docking_versus_recycling
  kind: INTERPRETATION
  attaches_to:
  - pathophysiology#Failure of PTS1 and PTS2 Receptor Docking
  - pathophysiology#Disrupted PEX13-PEX14 Docking Complex
  prompt: Does it matter mechanistically that PEX13 fails at docking rather than at receptor
    recycling?
  rationale: >-
    The KB now curates four PEX loci, and three of them - PEX1, PEX6, PEX12 - break the same
    half of the import cycle: the receptor docks and unloads, but is not exported back to the
    cytosol for reuse. PEX13 breaks the other half. The clinical convergence is nearly
    complete, which is the honest headline: a child with PBD11A is not distinguishable at the
    bedside from a child with PBD3A, and the biochemical screen does not separate them either.

    Two things do differ, and both are cell-biological rather than clinical. First, cargo
    selectivity: disrupting PEX13 self-association blocks PTS1 import specifically while
    leaving PTS2 routes and the PEX13-PEX14 interaction intact, so particular PEX13 alleles
    can produce a partial import defect of a kind the retrotranslocation mutants do not.
    Second, the fate of PEX5. In a recycling defect PEX5 accumulates at or in the membrane; in
    a docking defect it should not arrive there at all. That difference has not been used
    diagnostically and is recorded here as a mechanistic distinction rather than a clinical one.
  evidence:
  - reference: PMID:23716570
    reference_title: Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum
      patient reveals novel homooligomerization of PEX13 and its role in human peroxisome
      biogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We demonstrate that the import of PTS1 (peroxisomal targeting signal 1) proteins
      is specifically disrupted when homooligomerization of PEX13 is interrupted.
    explanation: The cargo-selectivity result that distinguishes a docking-step lesion from a
      recycling-step one.
- discussion_id: pbd11a_mitochondrial_causal_direction
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Secondary Mitochondrial Dysfunction
  prompt: Is the mitochondrial abnormality in PEX13 deficiency a driver of neuronal loss or a
    consequence of it?
  rationale: >-
    Mitochondrial mislocalisation and respiratory-chain abnormality are documented in PEX13
    patient muscle and fibroblasts, and Pex13-null cerebellar neurons show mitochondrial
    dysfunction with elevated ROS and increased apoptosis. Both observations are correlative.
    Peroxisomes and mitochondria share fission machinery and their beta-oxidation pathways are
    metabolically coupled, so a causal link is plausible in either direction, and dying neurons
    have abnormal mitochondria for reasons that have nothing to do with peroxisomes. The
    question matters because it is the only node in this entry that suggests a druggable
    target: if mitochondrial oxidative stress drives the neuronal loss, antioxidant or
    mitochondrially targeted intervention has a rationale, whereas if it is downstream it does
    not.

    Part of that experiment has been done. Antioxidant treatment rescues mitochondrial superoxide
    and membrane depolarization in PEX13-deficient mouse fibroblasts, and the mitochondrial
    phenotype is present in the intact brain and not only in culture. What is missing is the
    combination that would settle direction: the same rescue in a neuron, read out against cell
    survival rather than against the mitochondrial measurements themselves. A correctable
    phenotype in a fibroblast says nothing about whether correcting it keeps a neuron alive.
  proposed_experiments:
  - experiment_id: pbd11a_mito_rescue
    name: Antioxidant rescue in PEX13-deficient neurons, read out on survival
    description: >-
      Repeat the antioxidant rescue already reported in PEX13-deficient fibroblasts, but in
      cerebellar neurons from brain-restricted Pex13 mutants, and make the primary endpoint
      apoptosis and survival rather than superoxide or membrane potential. Untreated mutant and
      wild-type neurons as controls.
    would_support:
    - pathophysiology#Secondary Mitochondrial Dysfunction
    supporting_outcome:
    - >-
      Reduced apoptosis in treated mutant neurons, approaching wild-type rates, would place
      mitochondrial oxidative stress upstream of the neuronal death.
    refuting_outcome:
    - >-
      Apoptosis unchanged despite normalised ROS would place the mitochondrial abnormality
      downstream of, or parallel to, the lethal lesion.
- discussion_id: pbd11a_pexophagy_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Pexophagy of Import-Incompetent Peroxisomes
  prompt: Does the pexophagy released by PEX13 loss contribute to disease in patients, or is it
    a property of edited cell lines and zebrafish?
  rationale: >-
    The mechanism is clean where it has been measured: PEX13 loss lets ubiquitinated PEX5
    accumulate and peroxisomal reactive oxygen species rise, and the two together drive
    otherwise healthy peroxisomes into autophagic degradation. It was shown by gene editing and
    quantitative microscopy in cultured cells and in a zebrafish model, and PEX13 protein level
    is itself downregulated during amino acid starvation as part of normal pexophagy induction.

    The gap is between that and a patient. The one human observation that points the same way -
    a reduced peroxisome count in PEX13 patient fibroblasts - is equally compatible with
    impaired organelle proliferation, and nothing has measured autophagic flux in patient
    material. This matters because the two readings imply opposite therapeutic logic. If excess
    pexophagy is clearing a residual peroxisome population that still has partial function, then
    inhibiting autophagy preserves it, which is the rationale behind trials of
    hydroxychloroquine in other peroxisome biogenesis disorders. If the peroxisomes being
    cleared are import-dead anyway, preserving them achieves nothing. Note that those trials
    exclude PEX13, so the question has not been asked at this locus even indirectly.
  evidence:
  - reference: PMID:36541703
    reference_title: PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal
      ROS.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Using gene editing and quantitative fluorescence microscopy on culture cells and a
      zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import
      system, is required to prevent the degradation of otherwise healthy peroxisomes.
    explanation: Graded MODEL_ORGANISM because the sentence names a zebrafish model, which is
      in vivo animal data, and that is the more probative half for a translational-validity
      question; the cell-line half of the same paper is cited separately as IN_VITRO on the
      pathophysiology node. PARTIAL because it names exactly the systems the finding rests on,
      which is the mismatch this discussion records.
- discussion_id: pbd11a_ab_boundary
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#PEX13
  - disease#
  prompt: What separates PBD11A from PBD11B, given how few PEX13 patients exist?
  rationale: >-
    At PEX1 and PEX12 the A/B severity split tracks residual function reasonably well, and
    there are enough patients to see the correlation. At PEX13 there are not. Roughly twenty
    variants are reported worldwide, and the assignment of a given case to 11A or 11B rests on
    the clinical description rather than on a measured level of residual import. Variant class
    does not settle it either: a homozygous missense allele produced a severe, fatal
    presentation, while the first patient assigned to this complementation group at all -
    the one from whom the locus was defined - had neonatal adrenoleukodystrophy, the milder
    phenotype. The boundary this entry sits on is therefore a clinical convention with thin
    genotypic support, and should be read that way.
  evidence:
  - reference: PMID:10441568
    reference_title: PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis
      disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we characterize the sole representative of complementation group 13 of the
      PBDs, a patient with NALD (patient PBD222)."
    explanation: The founding case of this complementation group presented at the milder end,
      not with classical Zellweger syndrome.
  - reference: PMID:10441568
    reference_title: PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis
      disorders.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, residual matrix-protein import can be detected in cells from patient
      PBD222, consistent with the relatively mild phenotypes of the patient.
    explanation: Ties the milder phenotype to measurable residual import, which is the axis the
      A/B split is meant to capture but is rarely measured.
  - reference: PMID:10332040
    reference_title: Nonsense and temperature-sensitive mutations in PEX13 are the cause of
      complementation group H of peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A more mildly affected NALD patient (H-01), whose fibroblasts showed the
      temperature-sensitive (TS) phenotype, was homozygous for a missense mutation in the SH3
      domain of Pex13p, I326T.
    explanation: The mild half of the only reported pair of PEX13 patients contrasted directly
      by allele, and the one case where the residual-function basis of the split was measured
      rather than inferred.
references:
- reference: PMID:20301621
  title: Zellweger Spectrum Disorder.
  tags:
  - GeneReviews
- reference: PMID:35854306
  title: Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger
    spectrum disorders.
- reference: PMID:10441568
  title: PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis disorders.
- reference: PMID:23716570
  title: Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals
    novel homooligomerization of PEX13 and its role in human peroxisome biogenesis.
- reference: PMID:19449432
  title: "Zellweger syndrome caused by PEX13 deficiency: report of two novel mutations."
- reference: PMID:37962062
  title: "Severe Zellweger spectrum disorder due to a novel missense variant in the PEX13 gene:
    A case report and the literature review."
- reference: PMID:12897163
  title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger
    syndrome phenotype.
- reference: PMID:20959636
  title: "PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum
    formation, reactive gliosis and oxidative stress."
- reference: PMID:29187321
  title: Impaired neurogenesis and associated gliosis in mouse brain with PEX13 deficiency.
- reference: PMID:10332040
  title: Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation
    group H of peroxisome biogenesis disorders.
- reference: PMID:27514574
  title: Mitochondrial changes and oxidative stress in a mouse model of Zellweger syndrome
    neuropathogenesis.
- reference: PMID:26627182
  title: "Zellweger spectrum disorders: clinical overview and management approach."
- reference: PMID:38632234
  title: Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding
    motif.
- reference: PMID:36541703
  title: PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS.
- reference: PMID:11405337
  title: Clinical, biochemical and genetic aspects and neuronal migration in peroxisome
    biogenesis disorders.
- reference: PMID:28677031
  title: Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers
    for Zellweger spectrum disorders.
- reference: PMID:28644367
  title: Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid
    Synthesis and Zellweger Spectrum Disorders.
- reference: PMID:27469511
  title: Cholic acid therapy in Zellweger spectrum disorders.
- reference: PMID:20805528
  title: "Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind,
    randomized trial."
notes: >-
  Scope and naming. Two numbering systems collide on this disease and neither is a severity
  grade. "11" is the OMIM PEX-series index for PEX13; "13" and "H" are the two complementation
  groups assigned by cell fusion in different laboratories before the gene was cloned. The A/B
  suffix is the severity split, and this entry curates the A end. The KB now holds Peroxisome
  Biogenesis Disorder 1B (PEX1), 3A (PEX12), 4B (PEX6) and 11A (PEX13), spanning two severity
  tiers across four peroxins - three of which act in receptor recycling and one, this one, in
  docking.

  Why this is not a duplicate of PBD3A. The two entries share their downstream half almost
  exactly, because import failure converges regardless of which step broke. They differ in the
  upstream three nodes: PEX12 is a RING-finger subunit of the retrotranslocation channel that
  exports PEX5, while PEX13 is the SH3 docking peroxin that receives it. The pathograph reflects
  that, and the interpretation discussion states what does and does not follow from the
  distinction.

  GeneReviews. The chapter is written for the Zellweger spectrum as a whole rather than for
  PEX13, so evidence items quoting it are graded PARTIAL wherever the quoted sentence is
  spectrum-wide rather than reported in a PEX13 case. All four sections are mined.

  Evidence thinness. PEX13 is among the rarest ZSD genes - about twenty variants worldwide -
  so several human phenotype claims rest on a single molecularly confirmed case report rather
  than on a cohort. Where the only available evidence is from the Pex13-null mouse it is graded
  MODEL_ORGANISM and PARTIAL, and no human phenotype in this entry rests on mouse evidence alone.

  Bracketed quotes. The GeneReviews snippet for epiphyseal stippling stops short of the site it
  describes because the sentence embeds "[chondrodysplasia punctata]" and "patella[e]", and the
  reference validator strips bracketed text, so a span crossing a bracket cannot match the cache.

  Deep research. Generated by `just research-disorder falcon` with `--fallback`; falcon was not
  configured in this environment, so the run fell back to `claude_code` and the report is
  `research/Peroxisome_Biogenesis_Disorder_11A_Zellweger-deep-research-claude_code.md`
  (`fell_back: true`, `requested_provider: falcon` in its frontmatter). Its reference validation
  is clean - 49/49 resolved, none off topic. Its term validation flagged no unresolved CURIEs,
  but several of the identifiers it offered are named as different terms by the ontology, and
  two of those would have been substantive errors if copied: HP:0034512, offered for elevated
  VLCFA, is *Transitional-cell carcinoma of the ureter*, and HP:0000934, offered for
  chondrodysplasia punctata, is *Chondrocalcinosis*. Neither is bound here; epiphyseal stippling
  uses HP:0010655 instead.

  Pexophagy. An earlier draft of this entry left PEX13's autophagy role out on the grounds that
  nothing connected it to the disease. Review of the claim issue surfaced PMID:36541703, which
  does connect it: PEX13 *loss* - the disease lesion, not an engineered gain - releases pexophagy
  through ubiquitinated PEX5 and peroxisomal reactive oxygen species, in edited cells and in
  zebrafish. It is curated as a PROVISIONAL node with a HUMAN_MODEL_MISMATCH discussion rather
  than as an established mechanism, because no measurement in a patient ties it to a clinical
  feature. The earlier virophagy/pexophagy paper (PMID:27827795) is not cited as evidence; it
  concerns PEX13's role in selective autophagy generally rather than the consequence of losing it.

  Phenotypes left out, and the standard applied. Review suggested apnea, elevated hepatic
  transaminases and lissencephaly, all of which appear in the HPO annotation set for
  OMIM:614883. That annotation set is not a source this KB can quote from, so each was checked
  against the cached references instead. Elevated transaminases has a spectrum-wide sentence in
  PMID:26627182 and is now curated, graded PARTIAL on the same footing as Adrenal Insufficiency.
  Apnea and lissencephaly have no such sentence in any cached reference and remain out; they are
  real candidates and should be added when a citable source is found, rather than bound to a
  snippet that does not say them. The threshold is therefore the same across all of these -
  a quotable sentence, spectrum-wide accepted with PARTIAL - rather than stricter for some than
  others, which an earlier version of this note did not make clear.

  Not curated. The research report surfaced NCT03856866, a hydroxychloroquine trial built on the
  pexophagy rationale above, as a candidate treatment; reading the registration shows it is
  restricted to peroxisome biogenesis disorders caused by PEX1, PEX6 or PEX26, so it does not
  belong on a PEX13 entry and is not curated here.

📚

References & Deep Research