Peroxisome Biogenesis Disorder 11B

Mendelian MONDO:0013950 Pathograph 21 Show in embeddings browser Peroxisome Biogenesis Disorder

Peroxisome biogenesis disorder 11B is the OMIM designation for the milder end of the PEX13 disease spectrum, corresponding to the presentations historically called neonatal adrenoleukodystrophy and infantile Refsum disease rather than classic Zellweger syndrome. It shares its gene and its core mechanism with peroxisome biogenesis disorder 11A and is separated from it by disease severity, not by a different lesion. PEX13 encodes a peroxin of the docking/translocation module. It first homodimerises and then binds PEX14 to assemble the module at the peroxisomal membrane, which is where a cargo-loaded PTS receptor arrives. Loss of function therefore blocks import of peroxisomal matrix proteins, and the downstream metabolic consequences run in two directions: very-long-chain fatty acids, phytanic and pipecolic acid and bile acid intermediates accumulate because peroxisomal oxidation fails, while plasmalogens are not made. PEX13 is one of the rarest ZSD genes - PEX1 and PEX6 together account for about three quarters of cases. Two mechanistic findings specific to this locus are worth curating rather than generalising from the wider ZSD literature. The recurrent p.Arg294Trp variant sits in the SH3 domain at a residue implicated in homodimerisation, and docking analysis predicts it destabilises the PEX13/PEX14 translocation module rather than abolishing the protein. And patient muscle and fibroblasts show mitochondrial mislocalisation and biochemical abnormalities of mitochondrial function alongside a reduced number of peroxisomes, which has raised secondary mitochondrial dysfunction as a contributing mechanism rather than an incidental finding. The clinical picture at this end of the spectrum lacks the congenital malformations of severe ZSD. Instead there is progressive peroxisomal failure: sensorineural hearing loss and retinal dystrophy, ataxia, polyneuropathy and leukodystrophy, hepatic dysfunction, adrenal insufficiency and renal oxalate stones. Hypotonia and developmental delay are usual, but intellect can be normal. A nosological caveat belongs on the front of this entry rather than buried in it. GeneReviews states that the term Zellweger spectrum disorder is now used for all individuals with a ZSD-PEX gene defect regardless of phenotype, precisely because the Zellweger syndrome / neonatal adrenoleukodystrophy / infantile Refsum disease divisions predate the biochemical and molecular understanding of the spectrum. The 11A versus 11B split preserved by OMIM and MONDO is that superseded division applied to one gene. This entry is curated as the milder-end entity to match the ontology and the existing 11A entry, and the alternative - a single PEX13-related ZSD entry with severity subtypes - is recorded as an open question rather than silently taken.

Ask OpenScientist

Ask a research question about Peroxisome Biogenesis Disorder 11B. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
7
Pathophys.
14
Phenotypes
1
Gaps
21
Pathograph
1
Genes
5
Medical Actions
2
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic PEX13 variants are required, reported as homozygotes in consanguineous families and as compound heterozygotes combining a missense with a truncating allele.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:35854306 SUPPORT Human Clinical
"We report five families carrying biallelic variants in PEX13."
Establishes biallelic inheritance in the largest reported PEX13 series.
PMID:20301621 SUPPORT Human Clinical
"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 statement of the diagnostic and inheritance requirement across the ZSD-PEX genes.
PMID:20301621 SUPPORT Human Clinical
"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"
The recurrence risk quoted to families in genetic counselling.
?

Discussions and Knowledge Gaps

1
Should PEX13-related disease be curated as separate 11A and 11B entries, or as one PEX13-related Zellweger spectrum disorder entry with severity subtypes?
CONTROVERSY pbd11a_vs_11b_split
Attached to
disease#
11A and 11B are the same gene and the same lesion, separated only by residual function and therefore by severity. GeneReviews states that the Zellweger syndrome / neonatal adrenoleukodystrophy / infantile Refsum disease divisions predate the biochemical and molecular understanding of the spectrum and that ZSD is now used for all individuals with a ZSD-PEX gene defect regardless of phenotype - so the 11A/11B split is that superseded division applied to one gene. Against that, OMIM and MONDO both maintain the split, and the knowledge base already curates 11A as its own entry, so merging would mean revisiting that entry too. This entry follows the existing precedent and records the alternative here rather than taking it silently. Note that the reported PEX13 cohort spans both severities within single publications, which is itself an argument that the split does not carve the literature at a joint.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all..."
The authoritative clinical resource states that the phenotype divisions this split rests on have been superseded.
⚙

Pathophysiology

7
PEX13 Hypomorphic Deficiency
Biallelic PEX13 variants retaining partial function. The exemplar allele for this milder end is p.Ile326Thr: it is the one PEX13 variant reported in a patient labelled neonatal adrenoleukodystrophy rather than Zellweger spectrum, and it too sits in the SH3 domain. The recurrent p.Arg294Trp allele is described here as well because it carries the only mechanistic characterisation available for this gene - docking analysis predicting destabilised homodimerisation - but it is not the 11B exemplar: every reported p.Arg294Trp patient is labelled ZSD rather than NALD. The mechanism and the severity label come from different alleles, and this entry does not merge them. Severity does not track allele dose in the naive direction either. Compound heterozygotes carrying a missense allele opposite a loss-of-function allele were milder than missense homozygotes, which is the opposite of what a simple dosage model predicts.
Genetic context PEX13 hgnc:8855 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PEX13 (hgnc:8855). hgnc:8855 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Downstream
Impaired Docking Translocation Module Assembly
Show evidence (3 references)
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."
Supports a destabilising rather than abolishing lesion, and is graded COMPUTATIONAL because the claim rests on modelling and docking rather than on a functional assay.
PMID:35854306 SUPPORT Human Clinical
"a more mildly affected patient with neonatal adrenoleukodystrophy (NALD), homozygous for a missense variant affecting a conserved residue (p.Ile326Thr) within the SH3 domain of PEX13"
Identifies the one reported PEX13 allele associated with the milder NALD label rather than with ZSD, which is why it is named as the exemplar for this entry.
PMID:35854306 SUPPORT Human Clinical
"individuals carrying the missense p.Arg294Trp and p.Gly324Arg variants in the compound heterozygous state (and a loss of function variant on the other allele) displayed a milder clinical severity, characterized by psychomotor regression and late-onset leukodystrophy, compared to Individual B.II-1"
Records that compound heterozygotes were milder than missense homozygotes, which contradicts a naive dosage expectation and is why the description does not assert one.
Impaired Docking Translocation Module Assembly
PEX13 homo-oligomerises and then binds PEX14 to complete the docking/translocation module at the peroxisomal membrane. A destabilised module cannot receive cargo-loaded PTS receptors efficiently.
peroxisome GO:0005777 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisome (GO:0005777). GO:0005777 is a cellular component from the Gene Ontology.
Downstream
Failed Peroxisomal Matrix Protein Import
Show evidence (1 reference)
PMID:35854306 SUPPORT Human Clinical
"First, PEX13 interacts with itself to form dimers of proteins, a process called homo-oligomerization and then interacts with the PEX14 protein to complete the assembly of the DTM complex at the peroxisomal membrane"
States the two-step assembly that this lesion disrupts.
Failed Peroxisomal Matrix Protein Import
Matrix enzymes are not imported, leaving reduced numbers of peroxisomes with abnormal PEX13 content in patient fibroblasts.
protein import into peroxisome matrix GO:0016558 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein import into peroxisome matrix (GO:0016558). GO:0016558 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Peroxisomal Metabolic Failure
Plasmalogen Deficiency
Pexophagy of Import-Incompetent Peroxisomes
Secondary Mitochondrial Dysfunction
Show evidence (1 reference)
PMID:35854306 SUPPORT In Vitro
"Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration."
Documents the peroxisomal deficit in patient-derived material.
Peroxisomal Metabolic Failure
Without imported matrix enzymes, very-long-chain fatty acid metabolism, phytanic and pipecolic acid oxidation and bile acid biosynthesis all fail. The DECREASED modifier below is a statement about pathway flux, not about the plasma measurement: every individual in the PEX13 cohort who had a metabolic work-up had normal plasma VLCFA, which is recorded under biochemical. Plasma level is a poor proxy for peroxisomal beta-oxidation capacity at the hypomorphic end, so the two are not in conflict.
very long-chain fatty acid catabolic process GO:0042760 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased very long-chain fatty acid catabolic process (GO:0042760). GO:0042760 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Leukodystrophy
Sensorineural hearing impairment
Retinal dystrophy
Hypotonia
Polyneuropathy
Show evidence (1 reference)
PMID:35854306 SUPPORT Human Clinical
"downstream functional impairments of peroxisomes may affect several intracellular pathways, such as very long-chain fatty acids (VLCFA) metabolism, phytanic and pipecolic acid oxidation, or bile acid biosynthesis"
Names the metabolic pathways that fail downstream of import failure.
Pexophagy of Import-Incompetent Peroxisomes
Mechanism confidence: Provisional
PEX13 is required to prevent degradation of otherwise healthy peroxisomes. Losing it lets ubiquitinated PEX5 accumulate on the peroxisomal membrane and raises peroxisome-dependent reactive oxygen species, and the two together trigger selective autophagy of the organelle. This matters more for a hypomorphic allele than for a null: it is a route by which residual, partly functional peroxisomes are cleared rather than retained, and it offers an account of the reduced peroxisome numbers seen in patient fibroblasts.
pexophagy GO:0030242 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased pexophagy, annotated with autophagy of peroxisome (GO:0030242). GO:0030242 is a biological process from the Gene Ontology. ↑ INCREASED PEX5 ubiquitination GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased PEX5 ubiquitination, annotated with protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Peroxisomal Metabolic Failure Clearing residual import-incompetent peroxisomes removes the partly functional organelles that a hypomorphic allele leaves behind, so pexophagy feeds back into the metabolic failure rather than terminating the chain. The edge is drawn with unknown intermediates because the reduced peroxisome count and the metabolic deficit were measured in different studies and never linked quantitatively.
Show evidence (3 references)
PMID:36541703 SUPPORT In Vitro
"PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes"
Establishes the protective role of PEX13 that is lost here.
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."
Gives the two-step mechanism - ubiquitinated PEX5 plus raised ROS - by which PEX13 loss induces pexophagy.
PMID:35854306 SUPPORT INDIRECT In Vitro
"a reduced number of peroxisomes with abnormal PEX13 concentration"
The reduced peroxisome count in patient fibroblasts is consistent with this route, but the patient study did not measure autophagy, so the link to pexophagy is inferred rather than demonstrated in patient cells.
Plasmalogen Deficiency
Plasmalogen synthesis begins in the peroxisome, so import failure removes the biosynthetic capacity rather than merely slowing degradation. This is the subtractive half of the biochemical lesion and runs in the opposite direction to the accumulating metabolites, which is why the two are curated as separate nodes.
ether lipid biosynthetic process GO:0008611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ether lipid biosynthetic process (GO:0008611). GO:0008611 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Leukodystrophy
Show evidence (1 reference)
PMID:12897163 SUPPORT Model Organism
"severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis"
Names plasmalogen synthesis failure directly, in the Pex13 mouse. The previous snippet on this node quoted a general statement about downstream peroxisomal pathways whose own list does not include plasmalogens, so it did not support the claim.
Secondary Mitochondrial Dysfunction
Patient muscle and fibroblasts show mitochondrial mislocalisation and biochemical abnormalities of mitochondrial function. Peroxisomes and mitochondria share convergent metabolic processes including reactive oxygen species handling, and similar findings have been reported for other PEX genes and in ZSD animal models. The contribution is described by its authors as potential and not fully understood, so this node is curated as contributory rather than as an established arm of the mechanism.
Show evidence (2 references)
PMID:35854306 SUPPORT In Vitro
"identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration"
Documents the mitochondrial abnormality in patient-derived material alongside the peroxisomal deficit.
PMID:35854306 SUPPORT INDIRECT Model Organism
"These findings from cellular and animal studies highlight a potential, and not yet fully understood, contributory role of mitochondrial dysfunction to pathophysiology of peroxisome biogenesis disorders (PBDs) and ZSD clinical phenotypes."
Supports the node while recording, in the authors' own hedged terms, that the contribution is not established - which is why the upstream edge is INDIRECT_UNKNOWN_INTERMEDIATES.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Peroxisome Biogenesis Disorder 11B Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Digestive 1
Decreased liver function HP:0001410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased liver function (HP:0001410). HP:0001410 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301621 SUPPORT Human Clinical
"liver dysfunction, adrenal insufficiency, and renal oxalate stones"
Names liver dysfunction among the manifestations of milder ZSD.
PMID:35854306 REFUTE Human Clinical
"None of the affected individuals presented other systemic features (i.e., liver dysfunction, adrenal insufficiency and renal oxalate stones)."
The PEX13-specific cohort explicitly reports the absence of this feature. It is retained as a spectrum-level manifestation because GeneReviews describes it across ZSD-PEX genes, but the gene-specific evidence points the other way and is recorded here rather than left out.
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss)"
GeneReviews characterisation of the milder end of the spectrum, which is the phenotype range this entry covers.
Endocrine 1
Adrenal insufficiency HP:0000846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adrenal insufficiency (HP:0000846). HP:0000846 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301621 SUPPORT Human Clinical
"liver dysfunction, adrenal insufficiency, and renal oxalate stones"
Names adrenal insufficiency among the manifestations of milder ZSD.
PMID:35854306 REFUTE Human Clinical
"None of the affected individuals presented other systemic features (i.e., liver dysfunction, adrenal insufficiency and renal oxalate stones)."
The PEX13-specific cohort explicitly reports the absence of this feature. It is retained as a spectrum-level manifestation because GeneReviews describes it across ZSD-PEX genes, but the gene-specific evidence points the other way and is recorded here rather than left out.
Eye 1
Retinal dystrophy HP:0000556 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal dystrophy (HP:0000556). HP:0000556 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss)"
Names retinal dystrophy as the visual component of milder ZSD.
Genitourinary 1
Nephrolithiasis HP:0000787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrolithiasis (HP:0000787). HP:0000787 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301621 SUPPORT Human Clinical
"liver dysfunction, adrenal insufficiency, and renal oxalate stones"
Names renal oxalate stones among the manifestations of milder ZSD.
PMID:35854306 REFUTE Human Clinical
"None of the affected individuals presented other systemic features (i.e., liver dysfunction, adrenal insufficiency and renal oxalate stones)."
The PEX13-specific cohort explicitly reports the absence of this feature. It is retained as a spectrum-level manifestation because GeneReviews describes it across ZSD-PEX genes, but the gene-specific evidence points the other way and is recorded here rather than left out.
Head and Neck 1
Amelogenesis imperfecta HP:0000705 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amelogenesis imperfecta (HP:0000705). HP:0000705 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
GeneReviews reports amelogenesis imperfecta as near-universal in this phenotype range.
Musculoskeletal 3
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35854306 SUPPORT Human Clinical
"including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy"
Reports hypotonia in the PEX13 series.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257), qualified as course progressive. HP:0001257 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:35854306 SUPPORT Human Clinical
"including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy"
Reports progressive spasticity in the PEX13 series.
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
Reports osteopenia in a subset of individuals with milder ZSD.
Nervous System 5
Leukodystrophy HP:0002415 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukodystrophy (HP:0002415). HP:0002415 is a phenotype from the Human Phenotype Ontology.
Sequelae: Developmental regression Spasticity Ataxia
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."
Reports leukodystrophy among the features of PEX13-related disease specifically, rather than of ZSD in general.
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35854306 SUPPORT Human Clinical
"including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy"
Reports developmental regression in the PEX13 series.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Reported in the PEX13 cohort, but in a severe-end patient homozygous for a truncating allele who died at 20 months - not in the milder range this entry covers. GeneReviews further ties neonatal seizures to the congenital malformations it says intermediate and milder ZSD lack. Retained with that caveat rather than asserted as a feature of the 11B phenotype.
Show evidence (1 reference)
PMID:35854306 SUPPORT INDIRECT Human Clinical
"hypotonia, seizures, hepatic dysfunction and death within the first months of life"
Seizures occur in PEX13 disease, but the sentence describes the severe end of the spectrum rather than the milder range this entry covers, which is why the item is marked INDIRECT and the caveat is recorded in notes.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)"
Names ataxia among the neurological features of milder ZSD.
Polyneuropathy HP:0001271 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyneuropathy (HP:0001271). HP:0001271 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)"
Names polyneuropathy among the neurological features of milder ZSD.
🧬

Genetic Associations

1
PEX13
Gene: PEX13 hgnc:8855 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PEX13 (hgnc:8855). hgnc:8855 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:35854306 SUPPORT Human Clinical
"PEX1 and PEX6 are the most commonly mutated genes in ZSDs, with a frequency of 60.5 and 14.5%, respectively. Conversely, only a few mutations have been identified so far in PEX13"
Quantifies how rare this genetic subtype is relative to the common ZSD genes.
PMID:35854306 SUPPORT Human Clinical
"Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant."
Documents the recurrent allele that dominates the reported PEX13 cohort.
💊

Medical Actions

5
Symptomatic and supportive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Management is symptomatic across the spectrum. GeneReviews lists gastrostomy for caloric intake, hearing aids, cataract removal, refractive correction, fat-soluble vitamin and cholic acid supplementation, sclerosing therapy for varices, anti-seizure medication, early intervention for developmental delay, adrenal replacement, vitamin D with consideration of bisphosphonates for osteopenia, and dental treatment for amelogenesis imperfecta.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"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"
The GeneReviews management statement, which is symptomatic rather than disease-modifying.
Cholic acid supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cholic acid CHEBI:16359 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cholic acid (CHEBI:16359). CHEBI:16359 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Bile acid replacement, given because peroxisomal bile-acid biosynthesis fails and C27 intermediates accumulate.
Mechanism Target:
Peroxisomal Metabolic Failure — Replaces the bile acid product that failed peroxisomal biosynthesis cannot make; it does not restore peroxisomal import.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"supplementation of fat-soluble vitamins, and cholic acid supplementation"
Names cholic acid supplementation among the standard measures.
Adrenal replacement therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Given for the adrenal insufficiency that develops as part of progressive peroxisomal failure.
Mechanism Target:
Adrenal insufficiency — Replaces the deficient adrenal hormones.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"anti-seizure medication, early intervention services for developmental delay and intellectual disability; adrenal replacement therapy"
Names adrenal replacement among the managed manifestations.
Multisystem surveillance
A defined surveillance schedule: growth and nutrition at each visit; annual audiology and ophthalmology; annual liver function, coagulation and liver imaging; seizure monitoring; head MRI for white matter change; developmental and educational review; ACTH and cortisol by age one and annually; six-monthly dental examination; annual urine oxalate-to-creatinine ratio.
Show evidence (2 references)
PMID:20301621 SUPPORT Human Clinical
"Annual audiology and ophthalmologic evaluations; annual monitoring of liver function and coagulation factors, and ultrasound and/or fibroscan to evaluate liver architecture"
Specifies the core surveillance intervals.
PMID:20301621 SUPPORT Human Clinical
"ACTH and cortisol levels by age one year and annually thereafter."
Adrenal surveillance is scheduled from infancy because insufficiency develops progressively rather than presenting at diagnosis.
Renal oxalate stone management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Hydration, lithotripsy and surgical intervention for renal oxalate stones.
Mechanism Target:
Nephrolithiasis — Treats the stone burden; does not modify oxalate handling.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Supportive treatment for renal oxalate stones has included hydration, lithotripsy, and surgical intervention."
The specific measures used for the renal stone manifestation.
🔬

Biochemical Markers

1
Very-long-chain fatty acids
Context: VLCFA accumulate because peroxisomal beta-oxidation fails, and are the first-line biochemical screen for the Zellweger spectrum.
Show evidence (3 references)
PMID:35854306 SUPPORT Human Clinical
"very long-chain fatty acids (VLCFA) metabolism, phytanic and pipecolic acid oxidation, or bile acid biosynthesis"
Names VLCFA metabolism among the peroxisomal pathways that fail.
PMID:35854306 REFUTE DIRECT Human Clinical
"In all the affected individuals from this cohort who underwent detailed metabolic work-up, VLCFA levels resulted within normal limits."
Refutes the use of plasma VLCFA as a screen at the milder end of PEX13 disease. Not some individuals - all of those worked up in this cohort had normal levels, so a normal result carries no exclusionary weight here.
PMID:35854306 SUPPORT DIRECT Human Clinical
"Our study further highlights the importance of genetic screening targeting peroxisomal disorders, even though plasma peroxisomal metabolites are unremarkable, in case of moderate clinical presentations of ZSDs"
The diagnostic consequence, in the authors' own words - go to genetic testing rather than stopping at a normal metabolite screen. Their scoping to moderate presentations is exactly the phenotype range this entry covers.
🔬

Diagnosis

1
Biochemical and molecular testing
Suggestive clinical and biochemical findings followed by identification of biallelic pathogenic variants in a ZSD-PEX gene.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"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."
States the diagnostic criterion.
{ }

Source YAML

click to show 
name: Peroxisome Biogenesis Disorder 11B
creation_date: "2026-09-02T00:00:00Z"
description: >-
  Peroxisome biogenesis disorder 11B is the OMIM designation for the milder end of the
  PEX13 disease spectrum, corresponding to the presentations historically called
  neonatal adrenoleukodystrophy and infantile Refsum disease rather than classic
  Zellweger syndrome. It shares its gene and its core mechanism with peroxisome
  biogenesis disorder 11A and is separated from it by disease severity, not by a
  different lesion.

  PEX13 encodes a peroxin of the docking/translocation module. It first homodimerises
  and then binds PEX14 to assemble the module at the peroxisomal membrane, which is
  where a cargo-loaded PTS receptor arrives. Loss of function therefore blocks import
  of peroxisomal matrix proteins, and the downstream metabolic consequences run in two
  directions: very-long-chain fatty acids, phytanic and pipecolic acid and bile acid
  intermediates accumulate because peroxisomal oxidation fails, while plasmalogens are
  not made. PEX13 is one of the rarest ZSD genes - PEX1 and PEX6 together account for
  about three quarters of cases.

  Two mechanistic findings specific to this locus are worth curating rather than
  generalising from the wider ZSD literature. The recurrent p.Arg294Trp variant sits in
  the SH3 domain at a residue implicated in homodimerisation, and docking analysis
  predicts it destabilises the PEX13/PEX14 translocation module rather than abolishing
  the protein. And patient muscle and fibroblasts show mitochondrial mislocalisation
  and biochemical abnormalities of mitochondrial function alongside a reduced number of
  peroxisomes, which has raised secondary mitochondrial dysfunction as a contributing
  mechanism rather than an incidental finding.

  The clinical picture at this end of the spectrum lacks the congenital malformations
  of severe ZSD. Instead there is progressive peroxisomal failure: sensorineural
  hearing loss and retinal dystrophy, ataxia, polyneuropathy and leukodystrophy,
  hepatic dysfunction, adrenal insufficiency and renal oxalate stones. Hypotonia and
  developmental delay are usual, but intellect can be normal.

  A nosological caveat belongs on the front of this entry rather than buried in it.
  GeneReviews states that the term Zellweger spectrum disorder is now used for all
  individuals with a ZSD-PEX gene defect regardless of phenotype, precisely because the
  Zellweger syndrome / neonatal adrenoleukodystrophy / infantile Refsum disease
  divisions predate the biochemical and molecular understanding of the spectrum. The
  11A versus 11B split preserved by OMIM and MONDO is that superseded division applied
  to one gene. This entry is curated as the milder-end entity to match the ontology and
  the existing 11A entry, and the alternative - a single PEX13-related ZSD entry with
  severity subtypes - is recorded as an open question rather than silently taken.
category: Mendelian
synonyms:
- PBD11B
- peroxisome biogenesis disorder type 11B
- PEX13-related neonatal adrenoleukodystrophy
- PEX13-related Zellweger spectrum disorder, milder end
parents:
- Peroxisome Biogenesis Disorder
disease_term:
  preferred_term: peroxisome biogenesis disorder 11B
  term:
    id: MONDO:0013950
    label: peroxisome biogenesis disorder 11B
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 as homozygotes in consanguineous
    families and as compound heterozygotes combining a missense with a truncating
    allele.
  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: Establishes biallelic inheritance in the largest reported PEX13 series.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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 statement of the diagnostic and inheritance requirement across the ZSD-PEX genes.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an individual with biallelic ZSD-causing pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"
    explanation: The recurrence risk quoted to families in genetic counselling.
pathophysiology:
- name: PEX13 Hypomorphic Deficiency
  biological_scale: MOLECULAR
  description: >-
    Biallelic PEX13 variants retaining partial function. The exemplar allele for this
    milder end is p.Ile326Thr: it is the one PEX13 variant reported in a patient
    labelled neonatal adrenoleukodystrophy rather than Zellweger spectrum, and it too
    sits in the SH3 domain.

    The recurrent p.Arg294Trp allele is described here as well because it carries the
    only mechanistic characterisation available for this gene - docking analysis
    predicting destabilised homodimerisation - but it is not the 11B exemplar: every
    reported p.Arg294Trp patient is labelled ZSD rather than NALD. The mechanism and
    the severity label come from different alleles, and this entry does not merge them.

    Severity does not track allele dose in the naive direction either. Compound
    heterozygotes carrying a missense allele opposite a loss-of-function allele were
    milder than missense homozygotes, which is the opposite of what a simple dosage
    model predicts.
  genetic_context:
    gene:
      preferred_term: PEX13
      term:
        id: hgnc:8855
        label: PEX13
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  evidence:
  - 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: Supports a destabilising rather than abolishing lesion, and is graded COMPUTATIONAL because the claim rests on modelling and docking rather than on a functional assay.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a more mildly affected patient with neonatal adrenoleukodystrophy (NALD), homozygous for a missense variant affecting a conserved residue (p.Ile326Thr) within the SH3 domain of PEX13"
    explanation: Identifies the one reported PEX13 allele associated with the milder NALD label rather than with ZSD, which is why it is named as the exemplar for this entry.
  - 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 carrying the missense p.Arg294Trp and p.Gly324Arg variants in the compound heterozygous state (and a loss of function variant on the other allele) displayed a milder clinical severity, characterized by psychomotor regression and late-onset leukodystrophy, compared to Individual B.II-1"
    explanation: Records that compound heterozygotes were milder than missense homozygotes, which contradicts a naive dosage expectation and is why the description does not assert one.
  downstream:
  - target: Impaired Docking Translocation Module Assembly
    causal_link_type: DIRECT
- name: Impaired Docking Translocation Module Assembly
  biological_scale: MOLECULAR
  description: >-
    PEX13 homo-oligomerises and then binds PEX14 to complete the docking/translocation
    module at the peroxisomal membrane. A destabilised module cannot receive
    cargo-loaded PTS receptors efficiently.
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  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: "First, PEX13 interacts with itself to form dimers of proteins, a process called homo-oligomerization and then interacts with the PEX14 protein to complete the assembly of the DTM complex at the peroxisomal membrane"
    explanation: States the two-step assembly that this lesion disrupts.
  downstream:
  - target: Failed Peroxisomal Matrix Protein Import
    causal_link_type: DIRECT
- name: Failed Peroxisomal Matrix Protein Import
  biological_scale: CELLULAR
  description: >-
    Matrix enzymes are not imported, leaving reduced numbers of peroxisomes with
    abnormal PEX13 content in patient fibroblasts.
  biological_processes:
  - preferred_term: protein import into peroxisome matrix
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
    modifier: DECREASED
  evidence:
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration."
    explanation: Documents the peroxisomal deficit in patient-derived material.
  downstream:
  - target: Peroxisomal Metabolic Failure
    causal_link_type: DIRECT
  - target: Plasmalogen Deficiency
    causal_link_type: DIRECT
  - target: Pexophagy of Import-Incompetent Peroxisomes
    causal_link_type: DIRECT
  - target: Secondary Mitochondrial Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Peroxisomal Metabolic Failure
  biological_scale: ORGANISM
  description: >-
    Without imported matrix enzymes, very-long-chain fatty acid metabolism, phytanic
    and pipecolic acid oxidation and bile acid biosynthesis all fail. The DECREASED
    modifier below is a statement about pathway flux, not about the plasma
    measurement: every individual in the PEX13 cohort who had a metabolic work-up had
    normal plasma VLCFA, which is recorded under biochemical. Plasma level is a poor
    proxy for peroxisomal beta-oxidation capacity at the hypomorphic end, so the two
    are not in conflict.
  biological_processes:
  - preferred_term: very long-chain fatty acid catabolic process
    term:
      id: GO:0042760
      label: very long-chain fatty acid catabolic process
    modifier: DECREASED
  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: "downstream functional impairments of peroxisomes may affect several intracellular pathways, such as very long-chain fatty acids (VLCFA) metabolism, phytanic and pipecolic acid oxidation, or bile acid biosynthesis"
    explanation: Names the metabolic pathways that fail downstream of import failure.
  downstream:
  - target: Leukodystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Retinal dystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Polyneuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Pexophagy of Import-Incompetent Peroxisomes
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    PEX13 is required to prevent degradation of otherwise healthy peroxisomes. Losing
    it lets ubiquitinated PEX5 accumulate on the peroxisomal membrane and raises
    peroxisome-dependent reactive oxygen species, and the two together trigger
    selective autophagy of the organelle. This matters more for a hypomorphic allele
    than for a null: it is a route by which residual, partly functional peroxisomes are
    cleared rather than retained, and it offers an account of the reduced peroxisome
    numbers seen in patient fibroblasts.
  biological_processes:
  - preferred_term: pexophagy
    term:
      id: GO:0030242
      label: autophagy of peroxisome
    modifier: INCREASED
  - preferred_term: PEX5 ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: INCREASED
  evidence:
  - reference: PMID:36541703
    reference_title: "PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes"
    explanation: Establishes the protective role of PEX13 that is lost here.
  - 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: Gives the two-step mechanism - ubiquitinated PEX5 plus raised ROS - by which PEX13 loss induces pexophagy.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "a reduced number of peroxisomes with abnormal PEX13 concentration"
    explanation: The reduced peroxisome count in patient fibroblasts is consistent with this route, but the patient study did not measure autophagy, so the link to pexophagy is inferred rather than demonstrated in patient cells.
  downstream:
  - target: Peroxisomal Metabolic Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clearing residual import-incompetent peroxisomes removes the partly functional
      organelles that a hypomorphic allele leaves behind, so pexophagy feeds back into
      the metabolic failure rather than terminating the chain. The edge is drawn with
      unknown intermediates because the reduced peroxisome count and the metabolic
      deficit were measured in different studies and never linked quantitatively.
- name: Plasmalogen Deficiency
  biological_scale: ORGANISM
  description: >-
    Plasmalogen synthesis begins in the peroxisome, so import failure removes the
    biosynthetic capacity rather than merely slowing degradation. This is the
    subtractive half of the biochemical lesion and runs in the opposite direction to
    the accumulating metabolites, which is why the two are curated as separate nodes.
  biological_processes:
  - preferred_term: ether lipid biosynthetic process
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
    modifier: DECREASED
  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: "severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis"
    explanation: Names plasmalogen synthesis failure directly, in the Pex13 mouse. The previous snippet on this node quoted a general statement about downstream peroxisomal pathways whose own list does not include plasmalogens, so it did not support the claim.
  downstream:
  - target: Leukodystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Secondary Mitochondrial Dysfunction
  biological_scale: CELLULAR
  description: >-
    Patient muscle and fibroblasts show mitochondrial mislocalisation and biochemical
    abnormalities of mitochondrial function. Peroxisomes and mitochondria share
    convergent metabolic processes including reactive oxygen species handling, and
    similar findings have been reported for other PEX genes and in ZSD animal models.
    The contribution is described by its authors as potential and not fully understood,
    so this node is curated as contributory rather than as an established arm of the
    mechanism.
  evidence:
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration"
    explanation: Documents the mitochondrial abnormality in patient-derived material alongside the peroxisomal deficit.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings from cellular and animal studies highlight a potential, and not yet fully understood, contributory role of mitochondrial dysfunction to pathophysiology of peroxisome biogenesis disorders (PBDs) and ZSD clinical phenotypes."
    explanation: Supports the node while recording, in the authors' own hedged terms, that the contribution is not established - which is why the upstream edge is INDIRECT_UNKNOWN_INTERMEDIATES.
phenotypes:
- category: Neurologic
  name: Leukodystrophy
  description: >-
    Progressive white matter disease on brain imaging was present in most individuals
    in the PEX13 series.
  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: Reports leukodystrophy among the features of PEX13-related disease specifically, rather than of ZSD in general.
  sequelae:
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Psychomotor regression tracks the white matter disease in this cohort, and the
      milder compound heterozygotes are described as having regression together with
      late-onset leukodystrophy. The intermediates are not established.
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progressive spasticity is the expected corticospinal consequence of progressive
      white matter disease, but no study in this series relates the two lesion by
      lesion.
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn with unknown intermediates for the same reason as spasticity - the
      cerebellar contribution is not separated from the cerebral white matter disease
      in the reported imaging.
- category: Neurologic
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  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: "including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy"
    explanation: Reports hypotonia in the PEX13 series.
- category: Neurologic
  name: Developmental regression
  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: "including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy"
    explanation: Reports developmental regression in the PEX13 series.
- category: Neurologic
  name: Spasticity
  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: "including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy"
    explanation: Reports progressive spasticity in the PEX13 series.
- category: Neurologic
  name: Seizure
  notes: >-
    Reported in the PEX13 cohort, but in a severe-end patient homozygous for a
    truncating allele who died at 20 months - not in the milder range this entry
    covers. GeneReviews further ties neonatal seizures to the congenital malformations
    it says intermediate and milder ZSD lack. Retained with that caveat rather than
    asserted as a feature of the 11B phenotype.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - 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: "hypotonia, seizures, hepatic dysfunction and death within the first months of life"
    explanation: Seizures occur in PEX13 disease, but the sentence describes the severe end of the spectrum rather than the milder range this entry covers, which is why the item is marked INDIRECT and the caveat is recorded in notes.
- category: Skeletal
  name: Osteopenia
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
    explanation: Reports osteopenia in a subset of individuals with milder ZSD.
- category: Otologic
  name: Sensorineural hearing impairment
  description: >-
    Sensory loss is a defining feature of the intermediate and milder end of the
    spectrum, where congenital malformations are absent.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss)"
    explanation: GeneReviews characterisation of the milder end of the spectrum, which is the phenotype range this entry covers.
- category: Ophthalmologic
  name: Retinal dystrophy
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss)"
    explanation: Names retinal dystrophy as the visual component of milder ZSD.
- category: Neurologic
  name: Ataxia
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)"
    explanation: Names ataxia among the neurological features of milder ZSD.
- category: Neurologic
  name: Polyneuropathy
  phenotype_term:
    preferred_term: Polyneuropathy
    term:
      id: HP:0001271
      label: Polyneuropathy
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)"
    explanation: Names polyneuropathy among the neurological features of milder ZSD.
- category: Endocrine
  name: Adrenal insufficiency
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liver dysfunction, adrenal insufficiency, and renal oxalate stones"
    explanation: Names adrenal insufficiency among the manifestations of milder ZSD.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the affected individuals presented other systemic features (i.e., liver dysfunction, adrenal insufficiency and renal oxalate stones)."
    explanation: The PEX13-specific cohort explicitly reports the absence of this feature. It is retained as a spectrum-level manifestation because GeneReviews describes it across ZSD-PEX genes, but the gene-specific evidence points the other way and is recorded here rather than left out.
- category: Hepatic
  name: Decreased liver function
  phenotype_term:
    preferred_term: Decreased liver function
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liver dysfunction, adrenal insufficiency, and renal oxalate stones"
    explanation: Names liver dysfunction among the manifestations of milder ZSD.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the affected individuals presented other systemic features (i.e., liver dysfunction, adrenal insufficiency and renal oxalate stones)."
    explanation: The PEX13-specific cohort explicitly reports the absence of this feature. It is retained as a spectrum-level manifestation because GeneReviews describes it across ZSD-PEX genes, but the gene-specific evidence points the other way and is recorded here rather than left out.
- category: Renal
  name: Nephrolithiasis
  description: >-
    Renal oxalate stones, a manifestation specific to the milder end of the spectrum.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liver dysfunction, adrenal insufficiency, and renal oxalate stones"
    explanation: Names renal oxalate stones among the manifestations of milder ZSD.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the affected individuals presented other systemic features (i.e., liver dysfunction, adrenal insufficiency and renal oxalate stones)."
    explanation: The PEX13-specific cohort explicitly reports the absence of this feature. It is retained as a spectrum-level manifestation because GeneReviews describes it across ZSD-PEX genes, but the gene-specific evidence points the other way and is recorded here rather than left out.
- category: Dental
  name: Amelogenesis imperfecta
  description: >-
    Almost universal in the secondary teeth of individuals with milder ZSD, and a
    useful clinical pointer because it is not a feature of most differential diagnoses.
  phenotype_term:
    preferred_term: Amelogenesis imperfecta
    term:
      id: HP:0000705
      label: Amelogenesis imperfecta
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
    explanation: GeneReviews reports amelogenesis imperfecta as near-universal in this phenotype range.
genetic:
- name: PEX13
  gene_term:
    preferred_term: PEX13
    term:
      id: hgnc:8855
      label: PEX13
  relationship_type: CAUSATIVE
  notes: >-
    PEX13 is one of the rarest ZSD genes. PEX1 and PEX6 account for about 60.5% and
    14.5% of ZSD respectively; only a few PEX13 variants had been reported before the
    2022 series. The recurrent p.Arg294Trp allele occurred in three of five families.
  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: "PEX1 and PEX6 are the most commonly mutated genes in ZSDs, with a frequency of 60.5 and 14.5%, respectively. Conversely, only a few mutations have been identified so far in PEX13"
    explanation: Quantifies how rare this genetic subtype is relative to the common ZSD genes.
  - 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: Documents the recurrent allele that dominates the reported PEX13 cohort.
biochemical:
- name: Very-long-chain fatty acids
  context: >-
    VLCFA accumulate because peroxisomal beta-oxidation fails, and are the first-line
    biochemical screen for the Zellweger spectrum.
  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: "very long-chain fatty acids (VLCFA) metabolism, phytanic and pipecolic acid oxidation, or bile acid biosynthesis"
    explanation: Names VLCFA metabolism among the peroxisomal pathways that fail.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all the affected individuals from this cohort who underwent detailed metabolic work-up, VLCFA levels resulted within normal limits."
    explanation: Refutes the use of plasma VLCFA as a screen at the milder end of PEX13 disease. Not some individuals - all of those worked up in this cohort had normal levels, so a normal result carries no exclusionary weight here.
  - reference: PMID:35854306
    reference_title: "Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study further highlights the importance of genetic screening targeting peroxisomal disorders, even though plasma peroxisomal metabolites are unremarkable, in case of moderate clinical presentations of ZSDs"
    explanation: The diagnostic consequence, in the authors' own words - go to genetic testing rather than stopping at a normal metabolite screen. Their scoping to moderate presentations is exactly the phenotype range this entry covers.
  notes: >-
    A normal plasma VLCFA does not exclude PEX13 disease at the milder end of the
    spectrum: every individual in the PEX13 cohort who had a detailed metabolic
    work-up had normal levels, and the authors recommend genetic screening regardless.
    This is the most diagnostically consequential statement in the entry and is
    evidenced above, on both sides - the marker's usual rationale, and the cohort
    result that negates it here.
treatments:
- name: Symptomatic and supportive care
  description: >-
    Management is symptomatic across the spectrum. GeneReviews lists gastrostomy for
    caloric intake, hearing aids, cataract removal, refractive correction,
    fat-soluble vitamin and cholic acid supplementation, sclerosing therapy for
    varices, anti-seizure medication, early intervention for developmental delay,
    adrenal replacement, vitamin D with consideration of bisphosphonates for
    osteopenia, and dental treatment for amelogenesis imperfecta.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation"
    explanation: The GeneReviews management statement, which is symptomatic rather than disease-modifying.
- name: Cholic acid supplementation
  description: >-
    Bile acid replacement, given because peroxisomal bile-acid biosynthesis fails and
    C27 intermediates accumulate.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supplementation of fat-soluble vitamins, and cholic acid supplementation"
    explanation: Names cholic acid supplementation among the standard measures.
  target_mechanisms:
  - target: Peroxisomal Metabolic Failure
    description: >-
      Replaces the bile acid product that failed peroxisomal biosynthesis cannot make;
      it does not restore peroxisomal import.
- name: Adrenal replacement therapy
  description: >-
    Given for the adrenal insufficiency that develops as part of progressive
    peroxisomal failure.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anti-seizure medication, early intervention services for developmental delay and intellectual disability; adrenal replacement therapy"
    explanation: Names adrenal replacement among the managed manifestations.
  target_mechanisms:
  - target: Adrenal insufficiency
    description: Replaces the deficient adrenal hormones.
- name: Multisystem surveillance
  description: >-
    A defined surveillance schedule: growth and nutrition at each visit; annual
    audiology and ophthalmology; annual liver function, coagulation and liver imaging;
    seizure monitoring; head MRI for white matter change; developmental and
    educational review; ACTH and cortisol by age one and annually; six-monthly dental
    examination; annual urine oxalate-to-creatinine ratio.
  treatment_term:
    preferred_term: multisystem surveillance schedule
  notes: >-
    Deliberately left unbound. The TreatmentActionTerm enum is rooted at NCIT:C25218
    and has no general non-oncological surveillance term; NCIT:C15406 Cancer Screening
    names the wrong concept. The meaning is carried in preferred_term.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual audiology and ophthalmologic evaluations; annual monitoring of liver function and coagulation factors, and ultrasound and/or fibroscan to evaluate liver architecture"
    explanation: Specifies the core surveillance intervals.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTH and cortisol levels by age one year and annually thereafter."
    explanation: Adrenal surveillance is scheduled from infancy because insufficiency develops progressively rather than presenting at diagnosis.
- name: Renal oxalate stone management
  description: >-
    Hydration, lithotripsy and surgical intervention for renal oxalate stones.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive treatment for renal oxalate stones has included hydration, lithotripsy, and surgical intervention."
    explanation: The specific measures used for the renal stone manifestation.
  target_mechanisms:
  - target: Nephrolithiasis
    description: Treats the stone burden; does not modify oxalate handling.
discussions:
- discussion_id: pbd11a_vs_11b_split
  kind: CONTROVERSY
  attaches_to:
  - disease#
  prompt: >-
    Should PEX13-related disease be curated as separate 11A and 11B entries, or as one
    PEX13-related Zellweger spectrum disorder entry with severity subtypes?
  rationale: >-
    11A and 11B are the same gene and the same lesion, separated only by residual
    function and therefore by severity. GeneReviews states that the Zellweger syndrome
    / neonatal adrenoleukodystrophy / infantile Refsum disease divisions predate the
    biochemical and molecular understanding of the spectrum and that ZSD is now used
    for all individuals with a ZSD-PEX gene defect regardless of phenotype - so the
    11A/11B split is that superseded division applied to one gene. Against that, OMIM
    and MONDO both maintain the split, and the knowledge base already curates 11A as
    its own entry, so merging would mean revisiting that entry too. This entry follows
    the existing precedent and records the alternative here rather than taking it
    silently. Note that the reported PEX13 cohort spans both severities within single
    publications, which is itself an argument that the split does not carve the
    literature at a joint.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term \"ZSD\" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype."
    explanation: The authoritative clinical resource states that the phenotype divisions this split rests on have been superseded.
diagnosis:
- name: Biochemical and molecular testing
  description: >-
    Suggestive clinical and biochemical findings followed by identification of biallelic
    pathogenic variants in a ZSD-PEX gene.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes."
    explanation: States the diagnostic criterion.
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."
📚

References & Deep Research

References

2
PMID:20301621
Zellweger Spectrum Disorder.
No top-level findings curated for this source.
PMID:35854306
Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Peroxisome Biogenesis Disorder 11B · 2026-09-02T17:36:55Z · View source

Created the entry for the milder end of the PEX13 Zellweger spectrum. Deep research was run with falcon; the report resolved 9/9 references but cited only DOIs, so each was converted to a PMID and cited as a PMID. The GeneReviews Zellweger Spectrum Disorder chapter (PMID:20301621, tagged GeneReviews) was retrieved and used as the phenotype baseline for the intermediate/milder range, and Borgia et al. 2022 (PMID:35854306) supplied the PEX13-specific genotype-phenotype and mechanism content. A gene-identifier error in my first draft was caught before use: I had written hgnc:8850 for PEX13, which is PEX1; the correct id is hgnc:8855, confirmed against the HGNC REST API. Three curation judgements. The p.Arg294Trp destabilisation claim is graded COMPUTATIONAL because it rests on modelling and blind docking rather than a functional assay. The secondary mitochondrial dysfunction node is curated as contributory with an INDIRECT_UNKNOWN_INTERMEDIATES incoming edge, quoting the authors' own statement that the role is potential and not yet fully understood. Most importantly, a CONTROVERSY discussion records that the 11A/11B split is the superseded ZS/NALD/IRD phenotype division applied to one gene: GeneReviews states ZSD is now used for all ZSD-PEX gene defects regardless of phenotype, and the reported PEX13 cohort spans both severities within single publications. The entry follows the existing KB precedent (Peroxisome_Biogenesis_Disorder_11A_Zellweger is already its own entry) and surfaces the merge alternative rather than taking it silently. Validated with just validate (23/23 snippets verified, term validation passed), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 32 citations 2026-09-02T17:15:35.315406

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Peroxisome Biogenesis Disorder 11B
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Peroxisome Biogenesis Disorder 11B covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Peroxisome Biogenesis Disorder 11B (PEX13-related Zellweger spectrum disorder)

Scope and evidence grading

Peroxisome biogenesis disorder 11B (PBD11B) is an ultra-rare, autosomal-recessive PEX13-related Zellweger spectrum disorder (ZSD). Because only about 22 affected individuals and 20 variant types had been reported worldwide by 2024, reliable PEX13-specific prevalence, phenotype-frequency, penetrance, survival, and treatment-response estimates do not exist. This report therefore distinguishes PEX13-specific human evidence from broader ZSD-wide evidence and experimental evidence from cells or animals. The primary sources retrieved did not consistently expose PMID metadata; DOI links and publication dates are supplied rather than inventing PMIDs.

Domain PEX13-specific finding Evidence type Key source/date
Identity and inheritance Peroxisome biogenesis disorder 11B is PEX13-related Zellweger spectrum disorder, caused by biallelic germline PEX13 variants and inherited in an autosomal-recessive manner. Human genetic; PEX13-specific Borgia et al., July 2022, DOI; Su et al., November 2024, DOI (su2024severezellwegerspectrum pages 1-2, borgia2022genotype–phenotypecorrelationsand pages 1-2)
Reported case count A 2024 review counted 22 reported patients worldwide and approximately 20 variant types, demonstrating extreme rarity. This is a literature case count, not a population-prevalence estimate. Human literature review; PEX13-specific Su et al., November 2024, DOI (su2024severezellwegerspectrum pages 4-6)
Representative variants Reported alleles include c.493G>C (p.Ala165Pro), c.880C>T (p.Arg294Trp), p.Trp313Gly, p.Trp313Ter, p.Gly324Arg, truncating variants, and partial or large deletions. p.Arg294Trp recurred in three of five families in a 2022 series. Human genetic plus functional or computational; PEX13-specific Borgia et al., July 2022, DOI; Su et al., November 2024, DOI (borgia2022genotype–phenotypecorrelationsand pages 6-9, su2024severezellwegerspectrum pages 4-6, krause2006identificationofnovel pages 3-4)
Core mechanism PEX13 is a peroxisomal-membrane docking and translocation factor for PEX5/PEX14-mediated matrix-protein import. Pathogenic variants impair PEX13 self-association or partner binding, reducing PTS1 or PTS2 import and functional peroxisomes; secondary mitochondrial dysfunction may contribute. Human cells, structural biology, computational modeling, and mouse experiments Krause et al., October 2013, DOI; Borgia et al., July 2022, DOI (krause2013functionalanalysisof pages 1-2, borgia2022genotype–phenotypecorrelationsand pages 11-13, borgia2022genotype–phenotypecorrelationsand pages 1-2)
2024 mechanistic advance Structural work showed that the PEX13 SH3 domain and proximal FxxxF motif regulate binding to PEX5 WxxxF/Y motifs and PEX14. PEX14 bound the PEX13 FxxxF motif with a dissociation constant of 9.2 micromolar. In vitro biochemical and structural; PEX13-specific Gaussmann et al., April 2024, DOI (gaussmann2024modulationofperoxisomal pages 3-4, gaussmann2024modulationofperoxisomal pages 11-12, gaussmann2024modulationofperoxisomal pages 1-2)
Phenotype PEX13-related disease ranges from severe neonatal multisystem illness to childhood progressive neurologic disease. Findings include hypotonia, seizures, developmental delay or regression, spasticity, leukodystrophy, hearing or vision impairment, feeding or respiratory difficulty, and hepatic or renal involvement. Frequencies cannot be estimated reliably from the small reported population. Human clinical; PEX13-specific Borgia et al., July 2022, DOI; Su et al., November 2024, DOI (borgia2022genotype–phenotypecorrelationsand pages 6-9, su2024severezellwegerspectrum pages 2-4, borgia2022genotype–phenotypecorrelationsand pages 2-4)
Diagnostics Diagnosis combines plasma very-long-chain fatty acids, especially C26:0 and the C26:0/C22:0 ratio, with phytanic and pristanic acids, pipecolic acid, bile-acid intermediates, plasmalogens, and molecular confirmation by a PEX panel or exome or genome sequencing. Normal or mildly abnormal VLCFA does not exclude PEX13 disease. PEX13 cases plus ZSD-wide diagnostic evidence Borgia et al., July 2022, DOI; Bose et al., June 2022, DOI; Su et al., November 2024, DOI (su2024severezellwegerspectrum pages 2-4, bose2022characterizationofseverity pages 1-2, borgia2022genotype–phenotypecorrelationsand pages 13-15)
Prognosis PEX13-specific prognosis is genotype-dependent and incompletely quantified. Severe homozygous disease can cause early death; the 2024 p.Ala165Pro case died at 14 months. Hypomorphic genotypes may permit survival into later childhood with progressive disability. ZSD-wide survival estimates are not PEX13-specific. Human case reports with ZSD-wide contextual evidence Su et al., November 2024, DOI; Bose et al., June 2022, DOI (su2024severezellwegerspectrum pages 2-4, bose2022characterizationofseverity pages 12-13, bose2022characterizationofseverity pages 9-10)
Treatment and trials No curative or established PEX13-specific disease-modifying therapy exists. Care is supportive and may include antiseizure treatment, feeding support, hearing and vision services, rehabilitation, liver and adrenal surveillance, and respiratory care. Current ZSD studies are not PEX13-specific; recruiting NCT06190626 follows retinopathy in 30 participants, while evidence for cholic acid, betaine, and hydroxychloroquine remains limited or conflicting. Clinical management and ZSD-wide trials; not PEX13-specific ClinicalTrials.gov, 2023, NCT06190626; Bose et al., June 2022, DOI (NCT06190626 chunk 1, bose2022characterizationofseverity pages 2-3)

Table: Compact evidence summary for PEX13-related peroxisome biogenesis disorder 11B. It distinguishes disease-specific observations from broader Zellweger spectrum disorder evidence and highlights recent mechanistic and clinical developments.

1. Disease information

PBD11B is a Mendelian disorder in which biallelic pathogenic variants in PEX13 impair peroxisomal matrix-protein import. The resulting peroxisomal dysfunction causes a variable multisystem phenotype ranging from severe neonatal cerebro-hepato-renal disease to a predominantly neurologic childhood disorder with progressive spasticity and leukodystrophy. In 2024, Su et al. stated that only 22 PEX13-related cases had been reported worldwide, emphasizing that published knowledge is based chiefly on individual families and aggregated case literature—not population EHR cohorts. (su2024severezellwegerspectrum pages 1-2, borgia2022genotype–phenotypecorrelationsand pages 1-2, su2024severezellwegerspectrum pages 4-6)

Identifiers and names

  • Disease names: peroxisome biogenesis disorder 11B, PEX13-related Zellweger spectrum disorder, PEX13 deficiency, and historically Zellweger syndrome caused by PEX13 deficiency.
  • Gene: PEX13, OMIM gene 601789; reference transcript used in recent reports: NM_002618.3. (su2024severezellwegerspectrum pages 1-2)
  • Disease-level OMIM, MONDO, Orphanet, MeSH, ICD-10, and ICD-11 identifiers were not recoverable from the primary full-text evidence and should be verified directly against the current releases before database ingestion. ZSD is generally coded under broader peroxisomal-disorder categories because no PEX13-specific ICD code is established.
  • Data provenance: individual case reports/series, patient fibroblasts and muscle, literature-level ZSD meta-analysis, and observational registries. It is not derived from a representative population sample.

2. Etiology

Causal factors

The established cause is biallelic germline PEX13 dysfunction. PEX13 encodes an integral peroxisomal membrane component of the PEX5–PEX13–PEX14 docking/translocation machinery. Loss or alteration of this component impairs import of PTS1- and/or PTS2-bearing matrix enzymes. (jiang2025modellingperoxisomaldisorders pages 11-13, krause2013functionalanalysisof pages 1-2)

Genetic risk

  • Affected individuals are homozygous or compound heterozygous for pathogenic/likely pathogenic PEX13 alleles.
  • Reported classes include missense, nonsense, frameshift, partial-gene deletion, and an approximately 147-kb deletion. Representative alleles include c.493G>C (p.Ala165Pro), c.880C>T (p.Arg294Trp), p.Trp313Gly, p.Trp313Ter, p.Gly324Arg, and truncating/deletion alleles. (borgia2022genotype–phenotypecorrelationsand pages 6-9, su2024severezellwegerspectrum pages 4-6, borgia2022genotype–phenotypecorrelationsand pages 2-4)
  • The recurrent p.Arg294Trp allele occurred in three of five families in the 2022 series. It is not established as a population-wide founder allele. (borgia2022genotype–phenotypecorrelationsand pages 1-2)
  • Consanguinity is an important family-level risk: three of five families in the 2022 series were consanguineous, and the 2024 p.Ala165Pro patient was born to first-cousin parents. (su2024severezellwegerspectrum pages 1-2, borgia2022genotype–phenotypecorrelationsand pages 6-9)
  • Family history may be negative because carrier parents are clinically unaffected.

No validated susceptibility loci, modifier genes, genetic protective alleles, anticipation, or PEX13-specific germline-mosaicism cases have been established. Residual PEX13 function probably modifies severity, but genotype–phenotype prediction remains imperfect.

Environmental, protective, and gene–environment factors

No toxin, infection, lifestyle, diet, sex, or occupational exposure causes PBD11B. There are no validated environmental protective factors. Fever, fasting, illness, anesthesia, and nutritional stress may exacerbate metabolic vulnerability in peroxisomal disease, but direct PEX13-patient evidence is inadequate. Thus, these should be treated as clinical stressors rather than etiologic factors.

3. Phenotypes

PEX13-specific frequencies cannot be estimated reliably from 22 heterogeneous published cases. Suggested HPO annotations are therefore qualitative.

Phenotype Characterization in PEX13 disease Suggested HPO term
Hypotonia Commonly neonatal/infantile; severe in classic disease Hypotonia, HP:0001252
Developmental delay/regression Global delay, absent milestones, or later loss of motor/language skills; variable severity Global developmental delay, HP:0001263; Developmental regression, HP:0002376
Seizures Neonatal or infantile in severe disease; variable in milder disease Seizure, HP:0001250
Spasticity/tetraparesis Progressive childhood manifestation in neurologically predominant disease Spasticity, HP:0001257
Leukodystrophy Progressive posterior/periventricular, internal-capsule, corpus-callosal, brainstem, and cerebellar abnormalities reported Leukodystrophy, HP:0002415
Hearing impairment Usually sensorineural; may be early presenting feature Sensorineural hearing impairment, HP:0000407
Visual impairment Myopia, nystagmus, retinal/optic abnormalities, or reduced vision Visual impairment, HP:0000505; Myopia, HP:0000545; Nystagmus, HP:0000639
Feeding difficulty/failure to thrive Especially in severe infantile disease Feeding difficulties, HP:0011968; Failure to thrive, HP:0001508
Hepatic disease Hepatomegaly, transaminase/bile-acid abnormalities, dysfunction Hepatomegaly, HP:0002240; Elevated transaminases, HP:0002910
Respiratory difficulty Neonatal dyspnea, apnea, aspiration risk, or respiratory compromise secondary to hypotonia Respiratory distress, HP:0002098; Apnea, HP:0002104
Dysmorphism Prominent forehead and other variable craniofacial findings Abnormal facial shape, HP:0001999
Biochemical abnormalities Elevated C26:0/C22:0, phytanic/pristanic acids, pipecolic acid and bile-acid intermediates; abnormalities can be mild or absent Increased VLCFA level, HP:0008166

The 2022 cohort documented hypotonia, weakness, sensory impairment, progressive spasticity, developmental regression, and leukodystrophy. One child progressed to wheelchair dependence by approximately 7–9 years and had spastic tetraparesis, dystonia, ataxia, dysarthria, nystagmus, tremor, and mild cognitive regression. (borgia2022genotype–phenotypecorrelationsand pages 6-9, borgia2022genotype–phenotypecorrelationsand pages 1-2)

The 2024 p.Ala165Pro infant had neonatal hypotonia and respiratory compromise, seizures by three months, profound developmental impairment, hearing and visual dysfunction, hepatomegaly, biochemical abnormalities, and death at 14 months. (su2024severezellwegerspectrum pages 1-2, su2024severezellwegerspectrum pages 2-4)

ZSD-wide—not PEX13-specific—context: in a natural-history cohort, severe ZSD showed seizures and hypotonia in 100% of evaluated patients, MRI abnormalities in 95%, feeding difficulty in 90%, liver dysfunction in 94.4%, renal microcysts in 79%, and cardiac abnormalities in 81.3%. Intermediate ZSD commonly involved hypotonia, developmental delay, vision loss, feeding difficulty, failure to thrive, liver disease, and adrenal insufficiency. These values must not be assigned directly to PBD11B. (bose2022characterizationofseverity pages 10-12, bose2022characterizationofseverity pages 9-10)

Quality of life is strongly affected by sensory loss, impaired communication, feeding dependence, seizures, reduced mobility, and caregiver burden. However, no validated PEX13-specific EQ-5D, SF-36, or PROMIS dataset exists. NCT03440905 enrolled 92 caregivers and used symptom, Pediatric Inventory for Parents, and Family Quality of Life surveys, but available registry text did not report outcome values. (NCT03440905 chunk 1)

4. Genetic and molecular information

PEX13 lies on chromosome 2 and contains four exons in the cited clinical report. Its protein includes an N-terminal region required for peroxisomal localization, a transmembrane region, a proximal FxxxF motif, and a C-terminal SH3 domain; the recent clinical paper described Peroxin-13_N at residues 117–254 and SH3_PEX13_eumet at 276–333. (su2024severezellwegerspectrum pages 4-6, krause2013functionalanalysisof pages 1-2)

Pathogenic alleles are germline and primarily produce loss or severe reduction of function, not gain of function or dominant-negative disease. Consequences differ by allele:

  • p.Trp313Gly: disrupts PEX13 homooligomerization and selectively impairs PTS1 import while preserving PTS2 import in the studied system. (krause2013functionalanalysisof pages 1-2)
  • p.Arg294Trp: computationally predicted to alter dimerization and reduce accessibility/stability of the PEX13–PEX14 module; patient cells show reduced PEX13-positive peroxisomes and mitochondrial abnormalities. (borgia2022genotype–phenotypecorrelationsand pages 11-13, borgia2022genotype–phenotypecorrelationsand pages 1-2)
  • p.Gly324Arg: predicted to disrupt folding and formation of the PEX13–PEX14–PEX5 complex. (borgia2022genotype–phenotypecorrelationsand pages 11-13)
  • p.Ala165Pro: classified likely pathogenic in the 2024 report and associated homozygously with severe neonatal disease. (su2024severezellwegerspectrum pages 2-4)

Variant-specific gnomAD/TOPMed frequencies and ClinVar review status were not available in the retrieved primary texts and require direct variant-by-variant database queries using a normalized transcript. No established modifier gene, disease-specific epigenetic signature, recurrent aneuploidy, or balanced chromosomal rearrangement is known. Large deletions can cause disease when they disrupt PEX13, but routine PBD11B is a sequence-level recessive disorder.

5. Environmental information

Environmental toxins, radiation, smoking, alcohol, diet, and infectious agents are not established causes. PBD11B is not transmissible or zoonotic. Environmental and lifestyle data are clinically relevant mainly for avoiding secondary complications—for example, malnutrition, aspiration, prolonged fasting, and unmanaged infection—not for altering the inherited causal lesion.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic pathogenic PEX13 variants lead to absent, unstable, mislocalized, or interaction-defective PEX13 at the peroxisomal membrane.
  2. Defective PEX13 leads to impaired PEX13 homooligomerization and/or disturbed binding among PEX13, PEX14, and the PEX5 cargo receptor.
  3. Docking/translocation failure leads to deficient import of PTS1 and, depending on allele, PTS2 matrix proteins into PMP70/ABCD3-positive membrane “ghosts.”
  4. Loss of matrix enzymes leads to impaired VLCFA and branched-chain fatty-acid oxidation, reduced ether-phospholipid/plasmalogen synthesis, abnormal bile-acid intermediates, and disturbed redox homeostasis.
  5. PEX13 loss also leads to accumulation of ubiquitinated PEX5 and increased peroxisomal ROS, which recruit autophagy machinery and increase pexophagy; this branch is demonstrated in cells and zebrafish but remains incompletely proven in patients. (demers2023pex13preventspexophagy pages 14-15, demers2023pex13preventspexophagy pages 6-7)
  6. Peroxisomal metabolic/redox failure leads to secondary mitochondrial mislocalization, impaired membrane potential, abnormal cristae, oxidative stress, and apoptosis; the complete sequence is supported by patient cells and mouse brain but is partly inferred in humans. (maxwell2003pex13inactivationin pages 6-8, borgia2022genotype–phenotypecorrelationsand pages 13-15)
  7. Lipid imbalance, oxidative injury, and defective organelle cooperation lead to abnormal neuronal migration/development, dysmyelination or leukodystrophy, neuronal loss, gliosis, hepatic lipid accumulation, renal developmental abnormalities, and sensory-organ dysfunction.
  8. Tissue injury leads to neonatal hypotonia, seizures, developmental failure or regression, progressive spasticity, hearing/vision loss, liver disease, feeding/respiratory compromise, and—in severe disease—early death.

Molecular details and recent research

PEX13 is part of the matrix-protein docking/translocation module. PEX5 carries PTS1 cargo and binds PEX13/PEX14; PEX7 supports PTS2 import. Pex13-null mouse cells retained membrane structures but failed to import matrix proteins: post-organellar catalase increased from 18% ±1% to 81%, C26:0/C22:0 rose 9-fold in liver, 6.5-fold in brain, and 50-fold in fibroblasts, phytanic/pristanic oxidation fell 50–100-fold, and liver C16:0 and C18:0 plasmalogens fell approximately 20-fold and 3-fold. Wild-type PEX13 re-expression restored PTS1 and PTS2 import. (maxwell2003pex13inactivationin pages 6-8)

A major 2024 structural advance showed that the PEX13 SH3 domain binds a proximal intramolecular FxxxF motif, regulating access to noncanonical binding surfaces for PEX5 WxxxF/Y motifs. PEX14 binds the PEX13 FxxxF motif with KD 9.2 μM, releasing or remodeling this autoinhibitory arrangement. The data support dynamic or sequential receptor handover rather than a rigid, stable PEX5–PEX13–PEX14 ternary complex. (gaussmann2024modulationofperoxisomal pages 3-4, gaussmann2024modulationofperoxisomal pages 11-12, gaussmann2024modulationofperoxisomal pages 1-2)

A short exact statement from the 2024 abstract is: “Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14.” The authors further concluded that the interaction network “modulates peroxisomal matrix import.” (gaussmann2024modulationofperoxisomal pages 1-2)

A 2023 pexophagy study found that PEX13 loss caused ubiquitinated PEX5 accumulation and elevated ROS, jointly promoting selective autophagic loss of peroxisomes. Wild-type PEX13, but not W313G or I326T, rescued starvation-associated peroxisome loss in HeLa cells. In maternal-zygotic pex13-null zebrafish, approximately 90–95% of more than 400 larvae died at 9–11 days post-fertilization; chloroquine restored peroxisome-membrane structures but not matrix import or hepatic lipid accumulation. Human PEX13 mRNA partially rescued the dark-liver phenotype. (demers2023pex13preventspexophagy pages 14-15, demers2023pex13preventspexophagy pages 6-7)

Suggested ontology annotations

  • GO biological process: peroxisome organization; protein import into peroxisome matrix; fatty-acid beta-oxidation; ether-lipid biosynthetic process; reactive-oxygen-species metabolic process; selective autophagy of peroxisome; nervous-system development.
  • GO cellular component: peroxisomal membrane (GO:0005778), peroxisome, PEX13–PEX14 docking complex, mitochondrion.
  • Cell Ontology candidates: neuron (CL:0000540), astrocyte (CL:0000127), microglial cell (CL:0000129), hepatocyte (CL:0000182), renal epithelial cell, Purkinje cell (CL:0000121), cerebellar granule cell, fibroblast (CL:0000057), retinal photoreceptor, and retinal pigment epithelial cell.

No PEX13-patient single-cell, spatial-transcriptomic, or integrated multi-omics study was identified. Available molecular profiling consists principally of targeted lipid/biochemical assays, histology, imaging, mitochondrial functional measurements, and structural biology.

7. Anatomical structures affected

Primary systems: central and peripheral nervous systems, liver, eye/retina, auditory system, skeletal muscle, and—particularly in severe ZSD—kidney and adrenal gland. Brain involvement includes cerebral and cerebellar white matter, cortex, corpus callosum, internal capsule, brainstem, basal ganglia, and cerebellar/dentate pathways. (borgia2022genotype–phenotypecorrelationsand pages 6-9, su2024severezellwegerspectrum pages 2-4)

Tissue/cell level: neurons and myelinating systems are central to developmental regression, spasticity, and leukodystrophy. Mouse models implicate cerebellar granule-cell migration, Purkinje-layer development, astrocytes, and microglia. Hepatocytes accumulate lipid; renal glomerular development is delayed in null mice; skeletal muscle can show abnormal mitochondrial distribution. (maxwell2003pex13inactivationin pages 6-8, borgia2022genotype–phenotypecorrelationsand pages 13-15)

Subcellular level: the initiating compartment is the peroxisomal membrane and matrix-import machinery, with secondary mitochondrial and autophagosome involvement. Suggested anatomy terms include UBERON:0000955 brain, UBERON:0002107 liver, UBERON:0002113 kidney, UBERON:0000966 retina, UBERON:0002037 cerebellum, and UBERON:0002240 spinal cord. No consistent lateralization is reported; involvement is generally bilateral/systemic.

8. Temporal development

Severe PBD11B begins prenatally or neonatally, with hypotonia, poor feeding, respiratory compromise, seizures, dysmorphism, and liver dysfunction. Less severe disease may present in infancy or childhood with developmental delay, hearing/visual impairment, then progressive motor regression, spasticity, dystonia, ataxia, and leukodystrophy. (su2024severezellwegerspectrum pages 1-2, borgia2022genotype–phenotypecorrelationsand pages 6-9)

The course is chronic and generally progressive, not relapsing-remitting. Severe disease may be fatal in infancy; partial-function alleles can permit survival into later childhood or beyond but with progressive disability. No spontaneous remission is documented. Prenatal development and early infancy are critical periods because peroxisomes are required for neuronal migration, membrane-lipid synthesis, and organ maturation. Early recognition permits anticipatory management but currently does not reverse the molecular defect.

9. Inheritance and population

Inheritance is autosomal recessive. For two carrier parents, each pregnancy has a 25% probability of an affected child, 50% probability of a carrier, and 25% probability of inheriting neither familial allele. Penetrance for truly biallelic severe loss-of-function genotypes appears high, but expressivity is markedly variable. Anticipation is not expected.

The often-cited ZSD cumulative incidence is approximately 1 in 50,000 births, but this is for all causal PEX genes, not PEX13. PEX1 accounts for nearly two-thirds of ZSD, whereas PEX13 is exceptionally rare. A 2024 review found only 22 PEX13 cases worldwide; that count cannot be converted into incidence or prevalence because of underdiagnosis, publication bias, and unknown denominator. (su2024severezellwegerspectrum pages 4-6, bose2022characterizationofseverity pages 1-2)

Both sexes are affected; the 2022 series included three males and three females, consistent with autosomal inheritance rather than a sex effect. No reliable ethnicity-specific prevalence or carrier frequency is available. Reported families span Europe, the Middle East, North America, and China. Consanguinity increases the probability of homozygosity but is not required. (borgia2022genotype–phenotypecorrelationsand pages 6-9, borgia2022genotype–phenotypecorrelationsand pages 2-4)

10. Diagnostics

Recommended workflow

  1. Clinical suspicion: neonatal hypotonia/seizures/liver disease, or childhood developmental regression, spasticity, sensory impairment, and leukodystrophy.
  2. Biochemical testing: plasma VLCFAs including C26:0, C24:0/C22:0 and C26:0/C22:0; C26:0-lysophosphatidylcholine where available; phytanic and pristanic acids; pipecolic acid; plasma/urine C27 bile-acid intermediates DHCA and THCA; erythrocyte plasmalogens; liver function and coagulation; ACTH/cortisol surveillance.
  3. Molecular confirmation: a comprehensive peroxisomal/PBD multigene panel or trio WES/WGS with copy-number calling. Confirm candidate variants and segregation by Sanger sequencing or an orthogonal assay.
  4. Functional confirmation when needed: fibroblast catalase/PTS1 immunofluorescence, matrix-import assay, plasmalogen synthesis, VLCFA oxidation, and complementation studies.

A critical caveat is that VLCFAs may be minimally abnormal or normal in some PEX13 patients despite severe neurologic disease; normal VLCFA alone must not exclude the diagnosis. (su2024severezellwegerspectrum pages 4-6, borgia2022genotype–phenotypecorrelationsand pages 13-15)

Imaging and functional evaluation: brain MRI for cortical malformation, delayed myelination/leukodystrophy, corpus-callosal, cerebellar, brainstem, or basal-ganglia abnormalities; EEG for seizures; BAEP/audiology; ophthalmologic examination, OCT, electroretinography and visual fields; renal and liver ultrasonography; echocardiography when indicated. MRI severity does not necessarily track clinical severity. (su2024severezellwegerspectrum pages 4-6, su2024severezellwegerspectrum pages 2-4)

Genetic-test roles: WES and panels are high-yield for sequence variants; WGS is useful for noncoding and structural variants and can improve deletion detection. CMA may detect large PEX13 deletions but is not a first-line standalone test for this recessive sequence disorder. Karyotype, FISH, mitochondrial DNA, and repeat-expansion tests have no routine role unless the phenotype suggests another diagnosis.

Differential diagnoses: other PEX-gene ZSDs; D-bifunctional protein deficiency/HSD17B4 disease; acyl-CoA oxidase-1 deficiency; X-linked adrenoleukodystrophy; rhizomelic chondrodysplasia punctata; isolated bile-acid synthesis disorders; mitochondrial encephalopathy; congenital disorders of glycosylation; and other leukodystrophies. Molecular testing is required because clinical and biochemical overlap is substantial.

There are no universally adopted PEX13-specific clinical criteria. Routine population newborn screening for ZSD/PBD11B is not established. C26:0-LPC and bile-acid-metabolite approaches are investigational screening possibilities.

11. Outcome and prognosis

PEX13-specific prognosis depends on residual function and cannot be summarized by a validated survival curve. Severe homozygous disease can lead to death in infancy; the 2024 p.Ala165Pro patient died at 14 months despite supportive care. Other patients survive into childhood with progressive spasticity, sensory loss, leukodystrophy, and dependence for mobility and daily activities. (borgia2022genotype–phenotypecorrelationsand pages 6-9, su2024severezellwegerspectrum pages 2-4)

For context only, a ZSD-wide cohort reported survival at age 0–1 years of 36.1% severe, 75.0% intermediate, and 95.8% mild; at age 8–9 years it was 0%, 54.6%, and 85.6%, respectively. In the severe natural-history group, 95.7% died by age two. These estimates must not be represented as PEX13-specific. (bose2022characterizationofseverity pages 12-13, bose2022characterizationofseverity pages 9-10)

Potential adverse prognostic indicators across ZSD include seizures, abnormal EEG, renal cortical microcysts, cardiac abnormalities, elevated C26:0, severe plasmalogen deficiency, feeding/respiratory compromise, and early multisystem involvement. In ZSD-wide modeling, C26:0 values of 1.08 μg/mL and 5.18 μg/mL marked equal predicted probabilities between mild/intermediate and intermediate/severe categories, respectively; these are research thresholds, not validated PBD11B clinical cutoffs. (bose2022characterizationofseverity pages 16-17)

12. Treatment

No curative or approved PEX13-specific disease-modifying treatment exists. Current care is multidisciplinary and supportive:

  • seizures: individualized antiseizure medication, such as levetiracetam in the 2024 case;
  • nutrition: feeding assessment, aspiration precautions, high-calorie support, gastrostomy/jejunostomy when appropriate, and fat-soluble-vitamin replacement if deficient;
  • liver: liver tests, coagulation, bile acids, ultrasound, and management of cholestasis; ursodeoxycholic acid was used symptomatically in one case but is not proven to alter PBD11B progression;
  • adrenal: periodic ACTH/cortisol assessment and glucocorticoid replacement if insufficiency is confirmed;
  • hearing/vision: hearing aids or cochlear evaluation, low-vision services, refraction, retinal monitoring;
  • motor/communication: physical, occupational, speech and augmentative-communication therapy; mobility and contracture-management devices; baclofen may be used for spasticity;
  • respiratory/palliative care: secretion and aspiration management, ventilation when indicated, vaccinations and prompt infection treatment, and family-centered goals-of-care planning. (borgia2022genotype–phenotypecorrelationsand pages 6-9, su2024severezellwegerspectrum pages 2-4)

Suggested NCIt intervention concepts include Anticonvulsant Therapy, Enteral Nutrition, Gastrostomy, Physical Therapy, Occupational Therapy, Speech Therapy, Hearing Aid, Cochlear Implantation, Glucocorticoid Therapy, Mechanical Ventilation, and Palliative Care; current NCIt codes should be validated at ingestion.

Evidence for proposed systemic therapies is weak: a randomized DHA trial in ZSD showed no benefit; cholic-acid reports are conflicting; betaine and hydroxychloroquine/pexophagy inhibition remain experimental; and isolated liver-transplant reports cannot establish neurologic benefit or long-term survival. (bose2022characterizationofseverity pages 2-3)

Current ZSD/PBD studies are not PEX13-specific:

  • NCT06190626, recruiting observational retinopathy study, target n=30, annual ophthalmic and peroxisomal assessments through an estimated 2029 completion. (NCT06190626 chunk 1)
  • NCT01668186, recruiting longitudinal PBD natural-history study, listed enrollment 244.
  • NCT03440905, completed caregiver symptom/QoL survey, n=92. (NCT03440905 chunk 1)
  • NCT03856866, completed phase 2 hydroxychloroquine pexophagy study, n=3.
  • NCT01838941, completed phase 3 betaine study, n=12.
  • NCT03115086, active-not-recruiting Cholbam/cholic-acid registry, n=55.

No response rate can be assigned to PBD11B from these studies, and no gene therapy, CRISPR, RNA therapy, or cell therapy has reached established clinical use.

13. Prevention

The inherited biochemical defect cannot presently be prevented by lifestyle change, vaccination, or prophylactic medication.

Primary prevention at family level: genetic counseling, identification of both familial PEX13 alleles, carrier testing of adult relatives, partner testing where appropriate, preimplantation genetic testing for monogenic disease, and prenatal diagnosis by chorionic-villus sampling or amniocentesis. Donor gametes are another reproductive option.

Secondary prevention: cascade testing and early biochemical/molecular diagnosis in at-risk newborns or siblings. Population newborn screening is not standard. Early diagnosis supports seizure control, nutrition, sensory intervention, adrenal surveillance, and complication prevention.

Tertiary prevention: aspiration precautions, nutritional support, physiotherapy to limit contractures, seizure management, hearing/vision support, liver/renal/adrenal monitoring, immunization according to routine schedules, and rapid treatment of intercurrent illness.

14. Other species and natural disease

No well-documented naturally occurring veterinary counterpart specifically caused by biallelic PEX13 variants was identified. PBD11B is not infectious and has no zoonotic or cross-species transmission.

PEX13 and the peroxisomal import machinery are evolutionarily conserved across eukaryotes. Experimental orthologs include mouse Pex13 (Mus musculus, NCBI Taxonomy 10090) and zebrafish pex13 (Danio rerio, Taxonomy 7955). Conserved rescue is demonstrated by partial correction of the zebrafish phenotype with human PEX13 mRNA. (demers2023pex13preventspexophagy pages 6-7)

15. Model organisms

Mouse

A constitutive Pex13 knockout reproduces major severe ZSD features: defective PTS1/PTS2 import, profound lipid abnormalities, hypotonia, failure to feed, cortical disorganization, neuronal degeneration, hepatic lipid droplets, abnormal mitochondrial cristae, delayed glomerular development, and neonatal death. Wild-type PEX13 complementation restores import in deficient cells. Its limitation is early lethality, which restricts study of later progressive disease. (jiang2025modellingperoxisomaldisorders pages 11-13, maxwell2003pex13inactivationin pages 6-8)

A brain-restricted conditional knockout survives postnatally—most died by approximately 35 days—and shows impaired cerebellar fissure/layer formation, granule-cell migration and Purkinje-layer development, motor/reflex deficits, astrogliosis, microgliosis, ROS elevation, mitochondrial dysfunction, and enhanced neuronal apoptosis. It models neurologic pathogenesis but not systemic liver/kidney disease.

A germ-cell-specific Pex13 knockout causes spermatogenic arrest at the round-spermatid stage and altered testicular lipids. This establishes a tissue-specific role but is not a full clinical PBD11B model.

Zebrafish

CRISPR maternal-zygotic pex13-null zebrafish show matrix-import failure, reduced peroxisomes, hepatic lipid accumulation, and 90–95% mortality at 9–11 days post-fertilization. Chloroquine restores membrane-organelle counts but not matrix function, distinguishing enhanced pexophagy from the underlying import defect. Human PEX13 mRNA partially rescues hepatic phenotype. Advantages include live imaging and drug screening; limitations include maternal contribution, model-dependent survival, and species-specific lipid metabolism. (jiang2025modellingperoxisomaldisorders pages 11-13, demers2023pex13preventspexophagy pages 6-7)

Cellular and structural models

Patient fibroblasts, HEK293/HeLa knockout or knockdown cells, FRET/co-immunoprecipitation systems, matrix-import reporters, and purified-protein NMR/crystallography are the most direct tools for allele-specific functional classification. They demonstrate peroxisome number/size changes, PEX13 self-association, PEX5 ubiquitination, pexophagy, and the FxxxF–SH3 interaction network, but cannot reproduce organ development or long-term neurodegeneration. (krause2013functionalanalysisof pages 1-2, demers2023pex13preventspexophagy pages 14-15, gaussmann2024modulationofperoxisomal pages 3-4)

Key conclusions and knowledge gaps

PBD11B is an exceptionally rare, recessive PEX13 matrix-import disorder with a continuous phenotype from lethal infantile multisystem disease to progressive childhood neurologic disease. The strongest recent advances are the 2023 demonstration that PEX13 restrains ubiquitinated-PEX5/ROS-driven pexophagy and the 2024 structural definition of the PEX13 FxxxF–SH3–PEX5–PEX14 interaction network. (demers2023pex13preventspexophagy pages 14-15, gaussmann2024modulationofperoxisomal pages 3-4)

The most important database caveats are: (1) published case counts cannot support population prevalence or phenotype percentages; (2) normal VLCFA testing does not exclude PEX13 disease; (3) broad ZSD outcome statistics must not be treated as PEX13-specific; and (4) no intervention has yet demonstrated genotype-specific disease modification. Priority research needs include an international PEX13 registry, standardized longitudinal severity measures, variant-level functional assays, natural-history biomarkers, patient-derived neural/hepatic models, and therapies that restore matrix import without merely increasing nonfunctional peroxisomal membrane structures.

References

  1. (su2024severezellwegerspectrum pages 1-2): Ling Su, Min‐Zhi Peng, Xiao‐Dan Chen, Shuang Wu, and Li Liu. Severe zellweger spectrum disorder due to a novel missense variant in the pex13 gene: a case report and the literature review. Molecular Genetics & Genomic Medicine, Nov 2024. URL: https://doi.org/10.1002/mgg3.2315, doi:10.1002/mgg3.2315. This article has 3 citations and is from a peer-reviewed journal.

  2. (borgia2022genotype–phenotypecorrelationsand pages 1-2): Paola Borgia, Simona Baldassari, Nicoletta Pedemonte, Ebba Alkhunaizi, Gianluca D’Onofrio, Domenico Tortora, Elisa Calì, Paolo Scudieri, Ganna Balagura, Ilaria Musante, Maria Cristina Diana, Marina Pedemonte, Maria Stella Vari, Michele Iacomino, Antonella Riva, Roberto Chimenz, Giuseppe D. Mangano, Mohammad Hasan Mohammadi, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Andrea Accogli, Maria Cristina Schiaffino, Mohamad Maghnie, Miguel Angel Soler, Karl Echiverri, Charles K. Abrams, Pasquale Striano, Sara Fortuna, Reza Maroofian, Henry Houlden, Federico Zara, Chiara Fiorillo, and Vincenzo Salpietro. Genotype–phenotype correlations and disease mechanisms in pex13-related zellweger spectrum disorders. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02415-5, doi:10.1186/s13023-022-02415-5. This article has 8 citations and is from a peer-reviewed journal.

  3. (su2024severezellwegerspectrum pages 4-6): Ling Su, Min‐Zhi Peng, Xiao‐Dan Chen, Shuang Wu, and Li Liu. Severe zellweger spectrum disorder due to a novel missense variant in the pex13 gene: a case report and the literature review. Molecular Genetics & Genomic Medicine, Nov 2024. URL: https://doi.org/10.1002/mgg3.2315, doi:10.1002/mgg3.2315. This article has 3 citations and is from a peer-reviewed journal.

  4. (borgia2022genotype–phenotypecorrelationsand pages 6-9): Paola Borgia, Simona Baldassari, Nicoletta Pedemonte, Ebba Alkhunaizi, Gianluca D’Onofrio, Domenico Tortora, Elisa Calì, Paolo Scudieri, Ganna Balagura, Ilaria Musante, Maria Cristina Diana, Marina Pedemonte, Maria Stella Vari, Michele Iacomino, Antonella Riva, Roberto Chimenz, Giuseppe D. Mangano, Mohammad Hasan Mohammadi, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Andrea Accogli, Maria Cristina Schiaffino, Mohamad Maghnie, Miguel Angel Soler, Karl Echiverri, Charles K. Abrams, Pasquale Striano, Sara Fortuna, Reza Maroofian, Henry Houlden, Federico Zara, Chiara Fiorillo, and Vincenzo Salpietro. Genotype–phenotype correlations and disease mechanisms in pex13-related zellweger spectrum disorders. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02415-5, doi:10.1186/s13023-022-02415-5. This article has 8 citations and is from a peer-reviewed journal.

  5. (krause2006identificationofnovel pages 3-4): Cindy Krause, Hendrik Rosewich, Melissa Thanos, and Jutta Gärtner. Identification of novel mutations in pex2, pex6, pex10, pex12, and pex13 in zellweger spectrum patients. Human Mutation, 27:1157-1157, Nov 2006. URL: https://doi.org/10.1002/humu.9462, doi:10.1002/humu.9462. This article has 61 citations and is from a domain leading peer-reviewed journal.

  6. (krause2013functionalanalysisof pages 1-2): Cindy Krause, Hendrik Rosewich, Andrew Woehler, and Jutta Gärtner. Functional analysis of pex13 mutation in a zellweger syndrome spectrum patient reveals novel homooligomerization of pex13 and its role in human peroxisome biogenesis. Human molecular genetics, 22 19:3844-57, Oct 2013. URL: https://doi.org/10.1093/hmg/ddt238, doi:10.1093/hmg/ddt238. This article has 42 citations and is from a domain leading peer-reviewed journal.

  7. (borgia2022genotype–phenotypecorrelationsand pages 11-13): Paola Borgia, Simona Baldassari, Nicoletta Pedemonte, Ebba Alkhunaizi, Gianluca D’Onofrio, Domenico Tortora, Elisa Calì, Paolo Scudieri, Ganna Balagura, Ilaria Musante, Maria Cristina Diana, Marina Pedemonte, Maria Stella Vari, Michele Iacomino, Antonella Riva, Roberto Chimenz, Giuseppe D. Mangano, Mohammad Hasan Mohammadi, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Andrea Accogli, Maria Cristina Schiaffino, Mohamad Maghnie, Miguel Angel Soler, Karl Echiverri, Charles K. Abrams, Pasquale Striano, Sara Fortuna, Reza Maroofian, Henry Houlden, Federico Zara, Chiara Fiorillo, and Vincenzo Salpietro. Genotype–phenotype correlations and disease mechanisms in pex13-related zellweger spectrum disorders. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02415-5, doi:10.1186/s13023-022-02415-5. This article has 8 citations and is from a peer-reviewed journal.

  8. (gaussmann2024modulationofperoxisomal pages 3-4): Stefan Gaussmann, Rebecca Peschel, Julia Ott, Krzysztof M. Zak, Judit Sastre, Florent Delhommel, Grzegorz M. Popowicz, Job Boekhoven, Wolfgang Schliebs, Ralf Erdmann, and Michael Sattler. Modulation of peroxisomal import by the pex13 sh3 domain and a proximal fxxxf binding motif. Nature Communications, Apr 2024. URL: https://doi.org/10.1038/s41467-024-47605-w, doi:10.1038/s41467-024-47605-w. This article has 16 citations and is from a highest quality peer-reviewed journal.

  9. (gaussmann2024modulationofperoxisomal pages 11-12): Stefan Gaussmann, Rebecca Peschel, Julia Ott, Krzysztof M. Zak, Judit Sastre, Florent Delhommel, Grzegorz M. Popowicz, Job Boekhoven, Wolfgang Schliebs, Ralf Erdmann, and Michael Sattler. Modulation of peroxisomal import by the pex13 sh3 domain and a proximal fxxxf binding motif. Nature Communications, Apr 2024. URL: https://doi.org/10.1038/s41467-024-47605-w, doi:10.1038/s41467-024-47605-w. This article has 16 citations and is from a highest quality peer-reviewed journal.

  10. (gaussmann2024modulationofperoxisomal pages 1-2): Stefan Gaussmann, Rebecca Peschel, Julia Ott, Krzysztof M. Zak, Judit Sastre, Florent Delhommel, Grzegorz M. Popowicz, Job Boekhoven, Wolfgang Schliebs, Ralf Erdmann, and Michael Sattler. Modulation of peroxisomal import by the pex13 sh3 domain and a proximal fxxxf binding motif. Nature Communications, Apr 2024. URL: https://doi.org/10.1038/s41467-024-47605-w, doi:10.1038/s41467-024-47605-w. This article has 16 citations and is from a highest quality peer-reviewed journal.

  11. (su2024severezellwegerspectrum pages 2-4): Ling Su, Min‐Zhi Peng, Xiao‐Dan Chen, Shuang Wu, and Li Liu. Severe zellweger spectrum disorder due to a novel missense variant in the pex13 gene: a case report and the literature review. Molecular Genetics & Genomic Medicine, Nov 2024. URL: https://doi.org/10.1002/mgg3.2315, doi:10.1002/mgg3.2315. This article has 3 citations and is from a peer-reviewed journal.

  12. (borgia2022genotype–phenotypecorrelationsand pages 2-4): Paola Borgia, Simona Baldassari, Nicoletta Pedemonte, Ebba Alkhunaizi, Gianluca D’Onofrio, Domenico Tortora, Elisa Calì, Paolo Scudieri, Ganna Balagura, Ilaria Musante, Maria Cristina Diana, Marina Pedemonte, Maria Stella Vari, Michele Iacomino, Antonella Riva, Roberto Chimenz, Giuseppe D. Mangano, Mohammad Hasan Mohammadi, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Andrea Accogli, Maria Cristina Schiaffino, Mohamad Maghnie, Miguel Angel Soler, Karl Echiverri, Charles K. Abrams, Pasquale Striano, Sara Fortuna, Reza Maroofian, Henry Houlden, Federico Zara, Chiara Fiorillo, and Vincenzo Salpietro. Genotype–phenotype correlations and disease mechanisms in pex13-related zellweger spectrum disorders. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02415-5, doi:10.1186/s13023-022-02415-5. This article has 8 citations and is from a peer-reviewed journal.

  13. (bose2022characterizationofseverity pages 1-2): Mousumi Bose, Christine Yergeau, Yasmin D’Souza, David D. Cuthbertson, Melisa J. Lopez, Alyssa K. Smolen, and Nancy E. Braverman. Characterization of severity in zellweger spectrum disorder by clinical findings: a scoping review, meta-analysis and medical chart review. Jun 2022. URL: https://doi.org/10.3390/cells11121891, doi:10.3390/cells11121891. This article has 49 citations.

  14. (borgia2022genotype–phenotypecorrelationsand pages 13-15): Paola Borgia, Simona Baldassari, Nicoletta Pedemonte, Ebba Alkhunaizi, Gianluca D’Onofrio, Domenico Tortora, Elisa Calì, Paolo Scudieri, Ganna Balagura, Ilaria Musante, Maria Cristina Diana, Marina Pedemonte, Maria Stella Vari, Michele Iacomino, Antonella Riva, Roberto Chimenz, Giuseppe D. Mangano, Mohammad Hasan Mohammadi, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Andrea Accogli, Maria Cristina Schiaffino, Mohamad Maghnie, Miguel Angel Soler, Karl Echiverri, Charles K. Abrams, Pasquale Striano, Sara Fortuna, Reza Maroofian, Henry Houlden, Federico Zara, Chiara Fiorillo, and Vincenzo Salpietro. Genotype–phenotype correlations and disease mechanisms in pex13-related zellweger spectrum disorders. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02415-5, doi:10.1186/s13023-022-02415-5. This article has 8 citations and is from a peer-reviewed journal.

  15. (bose2022characterizationofseverity pages 12-13): Mousumi Bose, Christine Yergeau, Yasmin D’Souza, David D. Cuthbertson, Melisa J. Lopez, Alyssa K. Smolen, and Nancy E. Braverman. Characterization of severity in zellweger spectrum disorder by clinical findings: a scoping review, meta-analysis and medical chart review. Jun 2022. URL: https://doi.org/10.3390/cells11121891, doi:10.3390/cells11121891. This article has 49 citations.

  16. (bose2022characterizationofseverity pages 9-10): Mousumi Bose, Christine Yergeau, Yasmin D’Souza, David D. Cuthbertson, Melisa J. Lopez, Alyssa K. Smolen, and Nancy E. Braverman. Characterization of severity in zellweger spectrum disorder by clinical findings: a scoping review, meta-analysis and medical chart review. Jun 2022. URL: https://doi.org/10.3390/cells11121891, doi:10.3390/cells11121891. This article has 49 citations.

  17. (NCT06190626 chunk 1): Nancy Braverman. Longitudinal Prospective Natural History Study of Retinopathy in Zellweger Spectrum Disorder. McGill University Health Centre/Research Institute of the McGill University Health Centre. 2023. ClinicalTrials.gov Identifier: NCT06190626

  18. (bose2022characterizationofseverity pages 2-3): Mousumi Bose, Christine Yergeau, Yasmin D’Souza, David D. Cuthbertson, Melisa J. Lopez, Alyssa K. Smolen, and Nancy E. Braverman. Characterization of severity in zellweger spectrum disorder by clinical findings: a scoping review, meta-analysis and medical chart review. Jun 2022. URL: https://doi.org/10.3390/cells11121891, doi:10.3390/cells11121891. This article has 49 citations.

  19. (jiang2025modellingperoxisomaldisorders pages 11-13): Chenxing S. Jiang and Michael Schrader. Modelling peroxisomal disorders in zebrafish. Jan 2025. URL: https://doi.org/10.3390/cells14020147, doi:10.3390/cells14020147. This article has 4 citations.

  20. (bose2022characterizationofseverity pages 10-12): Mousumi Bose, Christine Yergeau, Yasmin D’Souza, David D. Cuthbertson, Melisa J. Lopez, Alyssa K. Smolen, and Nancy E. Braverman. Characterization of severity in zellweger spectrum disorder by clinical findings: a scoping review, meta-analysis and medical chart review. Jun 2022. URL: https://doi.org/10.3390/cells11121891, doi:10.3390/cells11121891. This article has 49 citations.

  21. (NCT03440905 chunk 1): Proxy-Reported Symptoms and Quality of Life Survey in Zellweger Spectrum Disorders. University of South Florida. 2018. ClinicalTrials.gov Identifier: NCT03440905

  22. (demers2023pex13preventspexophagy pages 14-15): Nicholas D. Demers, Victoria Riccio, Doo Sin Jo, Sushil Bhandari, Kelsey B. Law, Weifang Liao, Choy Kim, G. Angus McQuibban, Seong-Kyu Choe, Dong-Hyung Cho, and Peter K. Kim. Pex13 prevents pexophagy by regulating ubiquitinated pex5 and peroxisomal ros. Jan 2023. URL: https://doi.org/10.1080/15548627.2022.2160566, doi:10.1080/15548627.2022.2160566. This article has 66 citations and is from a domain leading peer-reviewed journal.

  23. (demers2023pex13preventspexophagy pages 6-7): Nicholas D. Demers, Victoria Riccio, Doo Sin Jo, Sushil Bhandari, Kelsey B. Law, Weifang Liao, Choy Kim, G. Angus McQuibban, Seong-Kyu Choe, Dong-Hyung Cho, and Peter K. Kim. Pex13 prevents pexophagy by regulating ubiquitinated pex5 and peroxisomal ros. Jan 2023. URL: https://doi.org/10.1080/15548627.2022.2160566, doi:10.1080/15548627.2022.2160566. This article has 66 citations and is from a domain leading peer-reviewed journal.

  24. (maxwell2003pex13inactivationin pages 6-8): Megan Maxwell, Jonas Bjorkman, Tam Nguyen, Peter Sharp, John Finnie, Carol Paterson, Ian Tonks, Barbara C. Paton, Graham F. Kay, and Denis I. Crane. Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a zellweger syndrome phenotype. Molecular and Cellular Biology, 23:5947-5957, Aug 2003. URL: https://doi.org/10.1128/mcb.23.16.5947-5957.2003, doi:10.1128/mcb.23.16.5947-5957.2003. This article has 134 citations and is from a domain leading peer-reviewed journal.

  25. (bose2022characterizationofseverity pages 16-17): Mousumi Bose, Christine Yergeau, Yasmin D’Souza, David D. Cuthbertson, Melisa J. Lopez, Alyssa K. Smolen, and Nancy E. Braverman. Characterization of severity in zellweger spectrum disorder by clinical findings: a scoping review, meta-analysis and medical chart review. Jun 2022. URL: https://doi.org/10.3390/cells11121891, doi:10.3390/cells11121891. This article has 49 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 31
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 0
Terms whose name is worth a second look 1

Terms whose name is worth a second look

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

  • GO:0005778 (1 mention) - the report calls it "GO cellular component: peroxisomal membrane"; GO calls it peroxisomal membrane**

Every term resolved, and every label the report gave matched.