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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0013933 peroxisome biogenesis disorder 5B

The dismech entry and the MONDO class denote the same entity: the milder, non-classic band of PEX2-related peroxisome biogenesis disorder. MONDO places both bands under MONDO:0100260 peroxisome biogenesis disorder due to PEX2 defect; the severe band, MONDO:0013932, is not yet curated here.

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic PEX2 variants, and specifically genotypes leaving residual peroxin-2 function on at least one allele. The reported mild-band patients are either homozygous for a C-terminal frameshift that spares most of the protein, or compound heterozygous for a residual-function missense allele opposite a null allele that is itself known from classic Zellweger syndrome.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:20301621 SUPPORT Other

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

The recurrence risk that genetic counselling for this entry turns on, stated for the spectrum as a whole. The quantitative risk is quoted rather than summarised because it is the sentence families are counselled from.

PMID:21392394 SUPPORT Human Clinical

"No mutation was found in P1 and P2 asymptomatic siblings, who had normal peroxisomal parameters in plasma and no neurologic symptoms."

Recessive segregation worked through a sibship: two affected brothers homozygous for the allele, three unaffected siblings without it and biochemically normal.

CGGV:assertion_17bf1c4a-1775-40c6-a499-774c93827343-2020-02-07T170000.000Z SUPPORT Other

ClinGen's Peroxisomal Disorders expert panel records autosomal recessive inheritance for the locus. The assertion is made against the grouping concept MONDO:0019234 rather than against this entry's MONDO:0013933, so it fixes the gene and the mode of inheritance and says nothing about the severity band.

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Subtypes

2

PEX2-related cerebellar ataxia (childhood-onset ataxic form) MONDO:0957443

PEX2 hgnc:9717

Childhood-onset, slowly progressive cerebellar ataxia with cerebellar atrophy on MRI, axonal sensorimotor polyneuropathy and generalised areflexia, in individuals who reach adult life with normal or near-normal intellect. This is the best documented PEX2 mild presentation: two brothers reported in 2011 and an unrelated man reported in 2012 who shares one of their alleles.

Show evidence (4 references)

PMID:21392394 SUPPORT Human Clinical

"Two brothers are described who developed progressive cerebellar ataxia at 3 1/2 and 18 years, respectively."

The founding report of this presentation, and the source of both its age range and its progressive course. Two brothers is the whole of that report, and the reader should hold that denominator against every statement made about this subtype.

PMID:23430938 SUPPORT Human Clinical

"A 51-year-old Italian man was referred to us because of a clinical picture characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset and slowly progressive course."

An unrelated patient with the same presentation, and the one that establishes survival to middle age at this locus.

ORPHA:642965 SUPPORT Other

"A rare genetic, peroxisomal disease characterized by childhood or adolescence onset slowly progressing cerebellar ataxia and severe axonal sensorimotor polyneuropathy due to PEX 2 deficieny."

Orphanet recognises this presentation as a named entity and defines it in terms that match the curated subtype: childhood or adolescent onset, slow progression, cerebellar ataxia with axonal sensorimotor polyneuropathy. Quoted with Orphanet's own typographical errors intact. Marked OTHER because an Orphanet record is a curated database entry rather than a study.

+ 1 more reference

Neonatal adrenoleukodystrophy / infantile Refsum disease presentation

PEX2 hgnc:9717

The older phenotype labels for the intermediate and mild bands of the Zellweger spectrum: progressive peroxisomal failure with sensory loss, liver disease and developmental delay, without the congenital malformations of classic Zellweger syndrome. At the PEX2 locus this presentation rests on individually reported patients - the infantile Refsum disease patient carrying E55K opposite a nonsense allele, and the mildly affected homozygous W223X patient in the four-patient complementation group 10 series - rather than on any assembled cohort.

Show evidence (3 references)

PMID:10528859 SUPPORT Human Clinical

"We identified a mutation in the PEX2 gene in an IRD patient with compound heterozygosity for a missense mutation and the known nonsense mutation detected in ZS patients."

The infantile Refsum disease patient at this locus, and the genotype - one residual-function missense allele opposite an allele already known from the severe band - that defines the mild band.

PMID:14630978 SUPPORT Human Clinical

"Surprisingly, the patient lacking the domain had a mild phenotype, whereas the C247R patient had a severe phenotype."

A second mildly affected PEX2 patient, and the authors' own surprise at the genotype-phenotype result, which is retained rather than smoothed over: the correlation between allele class and severity holds in general but is not mechanical.

PMID:20301621 SUPPORT Other

"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."

The GeneReviews characterisation of the band these older labels name. Quoted from the spectrum resource rather than from a PEX2 source because no PEX2 series describes this presentation in comparable detail; it is therefore a spectrum-general statement, not a PEX2-specific one.

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Discussions and Knowledge Gaps

2

How often is the plasma very-long-chain fatty acid screen normal in a patient who nevertheless carries a biallelic mild PEX2 genotype, and what proportion of mild PEX2 disease is therefore missed by a work-up that stops at that test?

KNOWLEDGE GAP normal_biochemistry_at_the_mild_end

Attached to

pathophysiology#Residual Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis biochemical#Plasma very-long-chain fatty acids

Two of the three reported ataxic patients had nearly normal very-long-chain fatty acids, and one had a fibroblast panel that was normal on every axis except phytanic acid alpha-oxidation. If that is representative, the screening test in routine use has poor sensitivity in exactly the band this entry covers - but three patients cannot establish a rate, and there is no ascertainment-corrected series to compute one from. The reporting authors themselves predicted that systematic metabolite screening would increase the apparent frequency of mild disease, which is a statement that the current denominator is wrong.

Is temperature-sensitive peroxisome assembly a general property of mild peroxisome biogenesis disorder genotypes, or only of a subset that happens to include PEX2 E55K?

CONTROVERSY temperature_sensitivity_is_not_universal

Attached to

pathophysiology#Partial Failure of Peroxisomal Matrix Protein Import

The 2000 study found every infantile Refsum disease cell line it tested to be temperature-sensitive and concluded that the property characterises the milder forms, with PEX2 E55K shown to be its direct cause by transfection. The 2012 PEX2 patient contradicts that generalisation: his peroxisomal mosaicism persisted at both 37 and 40 degrees, and his authors concluded that the assay did not spare them from sequencing. Both observations are in this entry, on the same node, and the entry does not resolve them - the honest reading is that temperature sensitivity is allele-dependent rather than band-dependent.

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Pathophysiology

8

Biallelic PEX2 Genotype With Residual Peroxin-2 Function

Mechanism confidence: Established

Both PEX2 alleles are altered, but the genotype as a whole leaves partial peroxin-2 activity. Two configurations are reported at this end of the series: homozygosity for a frameshift so close to the stop codon that most of the protein survives (c.865_866insA, p.Ser289LysfsX36), and compound heterozygosity for a residual-function missense allele opposite a nonsense allele already known from classic Zellweger syndrome (E55K opposite R119X). The residual-function threshold, not gene identity, is what separates this entry from peroxisome biogenesis disorder 5A.

Genetic context PEX2 hgnc:9717 variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

COMPOUND_HETEROZYGOUS records the configuration of the reported E55K and R119X patients. It is not a requirement of the entry: the two ataxic brothers were apparently homozygous for a single C-terminal frameshift allele, and the mildly affected patient in the complementation group 10 series was homozygous for W223X.

peroxisome organization GO:0007031 ↓ DECREASED

peroxisomal membrane GO:0005778

Downstream

Partial Loss of Peroxin-2 RING Ubiquitin Ligase Function A residual-function PEX2 allele yields a peroxin-2 that reaches the peroxisomal membrane and retains part of its activity, rather than a protein that is absent or non-functional.

Show evidence (3 references)

PMID:10528859 SUPPORT In Vitro

"These data suggest that allelic heterogeneity of the PEX gene affects the peroxisomal protein import and functions and regulates the clinical severity in PBD."

The residual-function account that defines this entry against peroxisome biogenesis disorder 5A, stated by the study that made it at the PEX2 locus itself.

PMID:40621817 SUPPORT BACKGROUND Human Clinical

"In general, clinical severity correlates to lower levels of residual PEX gene activity and much less to which PEX gene is involved (e.g. PEX16 vs PEX2 vs PEX3)"

States the residual-activity rule, and its corollary that the severity band matters more than which peroxin is affected. Graded HUMAN_CLINICAL with quote_role BACKGROUND because the sentence sits in the introduction of a Drosophila study and restates the human clinical correlation established elsewhere.

PMID:21392394 SUPPORT Human Clinical

"Sequencing of candidate PEX genes revealed a homozygous c.865_866insA mutation in the PEX2 gene leading to a frameshift 17 codons upstream of the stop codon."

The homozygous mild-band genotype, and the structural reason it is mild: a frameshift seventeen codons from the end alters the C-terminus rather than removing the protein.

Partial Loss of Peroxin-2 RING Ubiquitin Ligase Function

Mechanism confidence: Established

Peroxin-2 is an integral peroxisomal membrane protein with two transmembrane domains and a cytosolic C-terminal zinc-binding RING finger. Together with peroxin-10 and peroxin-12 it forms the membrane-embedded ubiquitin ligase that ubiquitinates the PTS1 receptor PEX5 so the receptor can be retrotranslocated and reused. Degrading that activity rather than abolishing it is the molecular difference between this entry and the severe band.

ubiquitin-protein transferase activity GO:0004842 ↓ DECREASED

peroxisomal membrane GO:0005778

Downstream

Partial Failure of Peroxisomal Matrix Protein Import Degraded ligase activity slows PEX5 recycling, so matrix-protein import is reduced rather than abolished - the state that produces a mixed population of import-competent and import-incompetent organelles.

Show evidence (4 references)

PMID:14630978 SUPPORT Human Clinical

"PBD patients belonging to complementation group 10 (CG10) have mutations in the PEX2 gene (PXMP3), which codes for a protein (PEX2) that contains two transmembrane domains and a zinc-binding domain considered to be important for its interaction with other proteins of the peroxisomal protein..."

The domain architecture this node asserts, from a PEX2 patient series rather than from a general review.

PMID:21392394 SUPPORT BACKGROUND Human Clinical

"The PEX2, PEX10 and PEX12 genes encode peroxins that are integral peroxisomal membrane proteins with a cytosolic carboxy-terminal RING finger domain that act as ubiquitin ligases required for the ubiquitination of the PTS1-receptor (PEX5) in the peroxisomal membrane"

Names the ligase activity and its substrate. Graded HUMAN_CLINICAL with quote_role BACKGROUND: the sentence is the discussion's framing of established biochemistry rather than a result of the case report it sits in.

PMID:35768507 SUPPORT INDIRECT In Vitro

"Recycling requires receptor modification by a membrane-embedded ubiquitin ligase complex comprising three RING finger domain-containing proteins (Pex2, Pex10 and Pex12)"

The complex peroxin-2's RING domain belongs to, and what it does. INDIRECT because the structure was solved in a fungal system, so the human claim rests on conservation.

+ 1 more reference

Partial Failure of Peroxisomal Matrix Protein Import

Mechanism confidence: Established

Matrix-protein import is reduced but not abolished. In patient fibroblasts this appears as peroxisomal mosaicism - some cells with normal peroxisomes, some with none, some mixed - and as a population of partially functional organelles that import the PTS1 enzymes acyl-CoA oxidase and thiolase while leaving catalase in the cytosol, which the group that described them named catalase-less peroxisomes. In the PEX2 E55K case the defect is temperature-sensitive, recovering at a permissive temperature; in the Italian patient the mosaicism persisted at 40 degrees, so the temperature test does not detect every mild PEX2 genotype. The fibroblast bound below is the cell the defect was assayed in, not a claim about which cell drives the disease: the import machinery is ubiquitous and the tissue that fails clinically is the cerebellum.

fibroblast CL:0000057

protein import into peroxisome matrix GO:0016558 ↓ DECREASED

peroxisomal matrix GO:0005782

Downstream

Residual Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis Because the import defect is partial, the peroxisomal pathways run at reduced rather than absent capacity - and in the ataxic patients several of them measure normal in cultured fibroblasts.

Show evidence (5 references)

PMID:10960480 SUPPORT In Vitro

"Catalase-less peroxisomes were also observed in human fibroblasts from patients with milder forms of peroxisome biogenesis disorder, including the one from which the mutant PEX2 gene was derived."

Establishes that the partially functional organelle characterised in the cell model is present in patient fibroblasts, including the PEX2 patient whose allele was used.

PMID:23430938 SUPPORT In Vitro

"Immunofluorescence microscopy analysis using antibodies raised against catalase, a peroxisomal matrix enzyme, revealed a heterogeneous pattern: some cells showed normal peroxisomes whereas in other cells peroxisomes were absent, and in yet other cells a mixed picture was observed."

Peroxisomal mosaicism observed directly in a PEX2 patient's fibroblasts, which is the cellular claim of this node.

PMID:11330043 SUPPORT In Vitro

"We found that all IRD cell lines and some NALD lines belonging to several different complementation groups are temperature-sensitive in peroxisome assembly; that is, they lacked catalase-positive peroxisomes at 37 degrees C, but do gain the peroxisomes at 30 degrees C."

The temperature-sensitive behaviour of the mild band's import defect, from the study that identified the PEX2 E55K/R119X genotype in an infantile Refsum disease patient.

+ 2 more references

Residual Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis

Mechanism confidence: Established

Beta-oxidation of very-long-chain fatty acids, alpha-oxidation of phytanic acid, beta-oxidation of the C27 bile-acid intermediates and the first steps of plasmalogen synthesis all depend on imported matrix enzymes, so all are affected together - but at this end of the series they are affected partially. In the ataxic brothers fibroblast plasmalogen synthesis, DHAPAT activity and very-long-chain fatty acid oxidation were normal and only phytanic acid alpha-oxidation was slightly abnormal; in the Italian patient DHAPAT activity and C26:0 beta-oxidation were likewise normal. This is the node where this entry diverges most sharply from classic Zellweger syndrome, and it is the reason a fibroblast panel can be reassuring in a patient who has the disease.

very long-chain fatty acid catabolic process GO:0042760 ↓ DECREASED fatty acid alpha-oxidation GO:0001561 ↓ DECREASED ether lipid biosynthetic process GO:0008611 ↓ DECREASED

Downstream

Accumulation of Branched-Chain Fatty Acids and Bile-Acid Intermediates Reduced alpha- and beta-oxidation capacity lets phytanic acid, pristanic acid and the C27 bile-acid intermediates DHCA and THCA rise in plasma, even where the very-long-chain fatty acids do not.

Show evidence (2 references)

PMID:21392394 SUPPORT In Vitro

"showed normal plasmalogen biosynthesis, DHAP-AT activity, oxidation of VLCFAs, and pristanic acid"

The fibroblast result in the ataxic form. Quoted because it is the strongest single statement of how attenuated this node is here; the same paragraph adds that phytanic acid oxidation was only slightly abnormal.

PMID:23430938 SUPPORT In Vitro

"DHAPAT activity and C26:0 beta-oxidation, which are considered the best biochemical markers in predicting life expectancy of patients with PBDs (Gootjes et al. 2002), were normal."

An independent patient with the same result, and the prognostic reading the authors put on it.

Accumulation of Branched-Chain Fatty Acids and Bile-Acid Intermediates

Mechanism confidence: Established

The circulating biochemical lesion. At this end of the spectrum it is attenuated and selective: in the ataxic brothers plasma very-long-chain fatty acids were nearly normal while phytanic and pristanic acid were moderately raised, whereas in the Italian patient very-long-chain fatty acids, branched-chain fatty acids and bile-acid intermediates were all raised and erythrocyte plasmalogens were normal. Which analytes move therefore differs between reported patients, and a single normal analyte carries little exclusionary weight.

very long-chain fatty acid catabolic process GO:0042760 ↓ DECREASED ether lipid biosynthetic process GO:0008611 ↓ DECREASED

Downstream

Cerebellar Neurodegeneration The clinically dominant consequence at this end of the spectrum falls on the cerebellum. The link is an inference from the imaging and neuropathological pattern rather than a demonstrated toxic mechanism in these patients.

Show evidence (2 references)

PMID:21392394 SUPPORT Human Clinical

"Plasma VLCFAs were nearly normal in patients P1 and P2, but a moderate increase in the levels of phytanic and pristanic acids was found, prompting us to suspect a peroxisomal disorder"

The selective, attenuated pattern this node asserts, and the analytes that actually led to the diagnosis in the ataxic form.

PMID:23430938 SUPPORT Human Clinical

"Analysis of plasma peroxisomal parameters revealed increased levels of very long chain fatty acids (VLCFAs), branched-chain fatty acids (pristanic and phytanic acid), and bile acid intermediates, prompting us to suspect a peroxisomal disorder."

An unrelated patient in whom the very-long-chain fatty acids were raised, which is why this node describes the pattern as variable between patients rather than as a fixed signature.

Cerebellar Neurodegeneration

Mechanism confidence: Hypothetical

Progressive loss of cerebellar tissue, radiologically atrophy of the vermis and the lateral hemispheres, and in the most affected patient of the cerebellar peduncles and bulbar olives as well. Two features distinguish it from the severe band: it is degenerative rather than malformative - the Sevin brothers had no neuronal migration defect - and it occurs without white-matter signal change, so this is not a leukodystrophy. Marked HYPOTHETICAL because the step from the metabolic lesion to cerebellar cell loss is not established in these patients. The Purkinje cell is recorded as the vulnerable cell type on the strength of the PEX2-null mouse, in which Purkinje dendritic arborization is abnormal; no human PEX2 neuropathology is available, so the cell-level localisation is an inference from the model rather than an observation in these patients.

cerebellar Purkinje cell CL:0000121

cerebellum UBERON:0002037

Downstream

Ataxia The cerebellar atrophy is the substrate of the ataxia that defines this entry's commonest presentation.

Cerebellar atrophy The radiological expression of the same tissue lesion.

Dysarthria Cerebellar dysarthria, reported in patients of both families.

Dysmetria Limb dysmetria, a cerebellar sign of the same lesion.

Nystagmus Gaze-evoked nystagmus, an oculomotor sign of the cerebellar lesion.

Show evidence (3 references)

PMID:21392394 SUPPORT INDIRECT BACKGROUND Model Organism

"Cerebellar defects (cerebellar hypoplasia, altered folial pattern, abnormal Purkinje cell dendritic arborization) are observed in PEX 2 deficient mice"

The only evidence that the cerebellar lesion of PEX2 deficiency is Purkinje-centered, and the basis for conforming this node to the Purkinje degeneration module. Graded MODEL_ORGANISM because the quoted finding is from PEX2-null mice, and BACKGROUND because this human case report is restating a mouse result it did not generate. INDIRECT: a null mouse is a more severe lesion than the residual-function genotype of this entry, and dendritic abnormality is not cell loss.

PMID:21392394 SUPPORT Human Clinical

"At the age of 9 years, a brain MRI showed atrophy of the vermis and lateral hemispheres of the cerebellum that worsened at the age of 14 years, but without signs of demyelination or neuronal migration defects in forebrain and cerebellum"

Establishes all three claims of this node at once: the anatomy, the progression between two scans, and the absence of both demyelination and the migration defect of classic Zellweger syndrome.

PMID:21392394 SUPPORT INDIRECT Human Clinical

"The patients that we describe seem to have progressive cerebellar atrophy rather than malformative cerebellar hypoplasia."

The authors' distinction between a degenerative and a malformative process, carrying their own hedge. INDIRECT because it is an interpretation of serial imaging, not a pathological finding.

Peripheral Axonal Degeneration

Mechanism confidence: Established

Length-dependent axonal degeneration of peripheral nerve, established on nerve conduction studies. It is a second, largely independent site of injury rather than a consequence of the cerebellar lesion, and its severity does not track the ataxia: the Sevin brothers had normal nerve conduction at nine, fourteen and eighteen years, while the older Italian patient had a severe axonal sensorimotor polyneuropathy with pes cavus.

peripheral nervous system UBERON:0000010

Downstream

Peripheral axonal neuropathy The clinical and electrophysiological expression of the axonal lesion.

Areflexia Generalised loss of tendon reflexes. The neuropathy explains it in only one of the three reported PEX2 patients: the Italian adult had generalised areflexia alongside a severe axonal sensorimotor polyneuropathy on nerve conduction studies, whereas both Sevin brothers already had reduced reflexes while their nerve conduction remained normal at nine and fourteen years. In those two the hyporeflexia preceded any demonstrable neuropathy, so this edge is the mechanism in the adult and not an established explanation for the sign wherever it appears in this entry.

Pes cavus The skeletal consequence of long-standing distal denervation, present bilaterally in the one patient in whom the neuropathy was severe.

Show evidence (2 references)

PMID:23430938 SUPPORT Human Clinical

"Nerve conduction studies indicated a severe axonal sensorimotor polyneuropathy."

The electrophysiological basis for calling the neuropathy axonal and sensorimotor, which is what the phenotype binding asserts.

PMID:21392394 REFUTE Human Clinical

"Fundoscopic examination, electroretinogram, EEG, electromyography, peripheral nerve conduction, visual, brainstem auditory and somatosensory evoked potentials, and audiogram were normal at 9 and 14 years."

A negative result recorded as such. In the two ataxic brothers nerve conduction, retinal and auditory testing were all normal into the mid-teens, so neither the neuropathy nor the sensory loss is obligatory in this entry, and their absence does not argue against the diagnosis.

Multisystem Peroxisomal Disease

Mechanism confidence: Established

The organ-level consequences the peroxisomal lesion produces outside the nervous system - liver disease, adrenal insufficiency, renal oxalate stones, enamel and bone involvement. This node is curated at spectrum level rather than at PEX2 level, and the distinction is deliberate: the liver, adrenal, renal, enamel and bone features are not reported in a PEX2 mild-band patient in any source cited here, and the reason they belong in this entry is that GeneReviews describes them for the intermediate and milder band and builds its surveillance schedule around them. The sensory losses are different - hypoacusia and early retinopathy were both observed in the Italian PEX2 adult - so for those two downstream targets the node records an observed phenotype. For the rest, a reader should treat it as the expected organ set to watch for.

Downstream

Hepatic dysfunction Liver involvement, the organ problem the one approved therapy is directed at.

Adrenal insufficiency Adrenocortical failure, which GeneReviews asks to be screened for from age one.

Sensorineural hearing impairment Progressive sensorineural hearing loss, one of the two sensory losses GeneReviews names for this band. In the one PEX2 patient followed long enough it appeared in adult life.

Retinal dystrophy Retinal dystrophy, the second of the two sensory losses, and likewise late at this locus.

Cataract Lens opacity, which the management review groups with retinopathy and glaucoma as the typical ocular involvement of the spectrum. Band-level, like the retinal dystrophy edge above, and not observed in a PEX2 patient in any source cited here.

Amelogenesis imperfecta Enamel defect of the secondary dentition, the most consistently reported non-neurological feature of this band.

Osteopenia Reduced bone mineral density, reported in some individuals in this band.

Hypotonia Hypotonia, typical of this band but absent from the PEX2 ataxic patients, whose early development was normal.

Global developmental delay Developmental delay, typical of this band and absent from the ataxic subtype of this entry.

Calcium oxalate nephrolithiasis Renal oxalate stones, a consequence of failed peroxisomal glyoxylate detoxification, and the surveillance item most easily forgotten in a patient whose presentation is neurological.

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."

GeneReviews' description of the band this entry occupies, and the source of the organ set this node names. It is a statement about the intermediate and milder Zellweger spectrum as a whole rather than about PEX2, which is why the node is curated at spectrum level and why its non-sensory organ involvements carry no observed PEX2 instance.

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Pathograph

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

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Phenotypes

21

Digestive 1

Hepatic dysfunction Decreased liver function HP:0001410

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."

GeneReviews' description of the band this subtype occupies. It is a statement about the intermediate and milder Zellweger spectrum as a whole, not about PEX2, and no PEX2 patient in the sources cited here is reported with this feature - which is why the record is scoped to the NALD-IRD subtype and carries no frequency.

Ear 1

Sensorineural hearing impairment HP:0000407

Course: PROGRESSIVE

Show evidence (2 references)

PMID:23430938 SUPPORT Human Clinical

"Between the third and the fifth decades, bilateral hypoacusia and initial retinopathy were detected."

The only PEX2-specific dating of the sensory loss in this entry, and the basis for calling it late and progressive rather than congenital.

PMID:14630978 SUPPORT Human Clinical

"Common to PBDs are liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness."

The class-level statement, quoted from the paper that reported the mildly affected complementation group 10 patient. It is a statement about peroxisome biogenesis disorders generally, not about this severity band, and is used only to place hearing loss among the expected features.

Endocrine 1

Adrenal insufficiency HP:0000846

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."

GeneReviews' description of the band this subtype occupies. It is a statement about the intermediate and milder Zellweger spectrum as a whole, not about PEX2, and no PEX2 patient in the sources cited here is reported with this feature - which is why the record is scoped to the NALD-IRD subtype and carries no frequency.

Eye 4

Nystagmus HP:0000639

Show evidence (2 references)

PMID:23430938 SUPPORT Human Clinical

"On admission to our Department, neurological examination showed gait ataxia, lateral and vertical gaze-evoked nystagmus, hypoacusia, mild dysarthria, slight dysmetria, generalized areflexia, and bilateral pes cavus."

The oculomotor findings in the adult patient.

PMID:21392394 SUPPORT Human Clinical

"He had truncal ataxia, moderate cerebellar tremor, mild scanning dysarthria, nystagmus, slow saccades without oculo-motor apraxia and hyporeflexia."

The same sign in an unrelated child, with the explicit note that oculomotor apraxia was absent - the older brother's had it, so the sign is inconsistent within one family.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:23430938 SUPPORT Human Clinical

"A 51-year-old Italian man was referred to us because of a clinical picture characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset and slowly progressive course."

Strabismus named among the presenting features.

Retinal dystrophy HP:0000556

Course: PROGRESSIVE

Show evidence (2 references)

PMID:23430938 SUPPORT Human Clinical

"Between the third and the fifth decades, bilateral hypoacusia and initial retinopathy were detected."

The PEX2-specific observation, and the reason the binding carries a progressive course.

PMID:20301621 SUPPORT Other

"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."

GeneReviews' account of sensory loss in the band this entry occupies. Spectrum-general rather than PEX2-specific, and marked OTHER because GeneReviews is an expert synthesis rather than a primary study.

Cataract HP:0000518

Show evidence (1 reference)

PMID:26627182 SUPPORT INDIRECT Other

"Sensorineural deafness and ocular abnormalities like retinopathy, cataracts and glaucoma are typical"

The management review's statement that cataract is a typical ocular finding of the spectrum, which is why it is carried as a surveillance target. The quote is trimmed at a line break in the cached full text; the same sentence goes on to warn that these findings are not always recognised at first presentation. INDIRECT because it is a spectrum-level statement and no PEX2 patient cited here is reported with cataract.

Genitourinary 1

Calcium oxalate nephrolithiasis HP:0008672

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."

GeneReviews' description of the band this subtype occupies. It is a statement about the intermediate and milder Zellweger spectrum as a whole, not about PEX2, and no PEX2 patient in the sources cited here is reported with this feature - which is why the record is scoped to the NALD-IRD subtype and carries no frequency.

Head and Neck 1

Amelogenesis imperfecta HP:0000705

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."

GeneReviews' frequency statement for the band, quoted with its own misspelling intact because a snippet does not correct its source. The frequency is band-level and is not transferred to PEX2 as a rate.

Limbs 1

Pes cavus HP:0001761

Show evidence (1 reference)

PMID:23430938 SUPPORT Human Clinical

"Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and bilateral pes cavus."

The examination finding in the one patient in whom it is reported.

Musculoskeletal 2

Osteopenia HP:0000938

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."

The same sentence, quoted for the weaker of its two frequency claims. Recording both from one sentence keeps the contrast the source draws.

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"While hypotonia and developmental delays are typical, intellect can be normal."

GeneReviews' statement for the intermediate and milder band, quoted whole so the qualifier travels with the claim: hypotonia and delay are typical, and preserved intellect is still compatible with the diagnosis.

Nervous System 9

Ataxia HP:0001251

Course: PROGRESSIVE

Show evidence (2 references)

PMID:21392394 SUPPORT Human Clinical

"Two brothers are described who developed progressive cerebellar ataxia at 3 1/2 and 18 years, respectively."

Both the age range and the progressive course recorded on this binding, in the founding report of the presentation.

PMID:21392394 SUPPORT Human Clinical

"Cerebellar ataxia exacerbated slowly up to the age of 14 years but he was still able to walk without support."

The rate of progression in the younger brother, quoted because "slowly progressive" is a claim the entry makes repeatedly and this is the sentence that measures it.

Cerebellar atrophy HP:0001272

Course: PROGRESSIVE

Show evidence (2 references)

PMID:23430938 SUPPORT Human Clinical

"Brain MRI revealed marked atrophy of the subtentorial regions including cerebellum, cerebellar peduncles, and bulbar olives, and showed moderate atrophy of the supratentorial regions of the brain"

The fullest description of the imaging phenotype, in the oldest reported patient. Note that it extends beyond the cerebellum, which the younger patients' scans did not.

PMID:21392394 SUPPORT Human Clinical

"At the age of 9 years, a brain MRI showed atrophy of the vermis and lateral hemispheres of the cerebellum that worsened at the age of 14 years, but without signs of demyelination or neuronal migration defects in forebrain and cerebellum"

Serial imaging in the same child, which is the basis for the PROGRESSIVE course on this binding rather than an inference from the clinical course.

Dysarthria HP:0001260

Show evidence (2 references)

PMID:21392394 SUPPORT Human Clinical

"His milestones were normal but mild dysarthria was noticed at 2 1/2 years."

The earliest recorded sign in any patient in this entry, and the pediatric point that normal early milestones do not exclude it.

PMID:23430938 SUPPORT Human Clinical

"Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and bilateral pes cavus."

An unrelated adult patient with the same sign.

Dysmetria HP:0001310

Show evidence (1 reference)

PMID:23430938 SUPPORT Human Clinical

"Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and bilateral pes cavus."

The examination finding in the reported adult patient.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:23430938 SUPPORT Human Clinical

"A 51-year-old Italian man was referred to us because of a clinical picture characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset and slowly progressive course."

Areflexia named as one of the four cardinal features of the reported presentation.

Peripheral axonal neuropathy HP:0003477

Show evidence (1 reference)

PMID:23430938 SUPPORT Human Clinical

"Nerve conduction studies indicated a severe axonal sensorimotor polyneuropathy."

The electrophysiological finding this binding records.

Cognitive impairment HP:0100543

Show evidence (2 references)

PMID:23430938 REFUTE Human Clinical

"Dysmorphic features, cognitive impairment, and seizures were absent."

A recorded negative in the oldest reported patient. Marked REFUTE because it contradicts the claim that cognitive impairment is a feature of this entry, which is what this phenotype record exists to settle.

PMID:21392394 REFUTE Human Clinical

"He had truncal ataxia, moderate cerebellar tremor, mild scanning dysarthria, nystagmus, slow saccades without oculo-motor apraxia and hyporeflexia. His total ataxia score evaluated by the International Cooperative Ataxia Rating Scale (ICARS) was 17/100. He had no other neurological symptoms and..."

Cognitive function explicitly preserved over five years of follow-up in the younger brother, despite his ataxia score doubling. Quoted at length because the contrast between the two trajectories in one patient is the point.

Leukodystrophy HP:0002415

Show evidence (1 reference)

PMID:20301621 SUPPORT INDIRECT Other

"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."

GeneReviews names leukodystrophy among the neurologic involvements of the intermediate and milder band this subtype occupies. INDIRECT because the statement is about the Zellweger spectrum as a whole and no PEX2 patient cited here has white-matter change - the two reported families are expressly reported without it.

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:20301621 SUPPORT Other

"While hypotonia and developmental delays are typical, intellect can be normal."

The band-level statement. Its second clause is the one that matters for this entry: preserved intellect does not exclude the diagnosis, which is exactly what the PEX2 ataxic patients show.

PMID:14630978 SUPPORT Human Clinical

"Common to PBDs are liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness."

The class-level statement from the paper reporting the mildly affected complementation group 10 patient. It covers peroxisome biogenesis disorders generally, and the word "variable" is the operative one.

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Genetic Associations

1

PEX2

Gene: PEX2 hgnc:9717 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (8 references)

PMID:1546315 SUPPORT In Vitro

"A human complementary DNA has been cloned that complements the disease's symptoms (including defective peroxisome assembly) in fibroblasts from a patient with Zellweger syndrome."

The original identification of the gene, by functional complementation. Quoted from the primary report rather than from a review.

CGGV:assertion_17bf1c4a-1775-40c6-a499-774c93827343-2020-02-07T170000.000Z SUPPORT Other

"In summary, PEX2 is definitively associated with autosomal recessive peroxisomal biogenesis disorder."

ClinGen's Peroxisomal Disorders Gene Curation Expert Panel classifies the relationship as Definitive. The assertion is against the grouping concept MONDO:0019234 peroxisome biogenesis disorder, so it establishes the gene-disease relationship for the locus and not for this severity band.

PMID:11330043 SUPPORT Human Clinical

"We identified heterozygous mutations E55K/R119Stop in the PEX2 gene of an IRD patient of complementation group F."

The genotype of the infantile Refsum disease patient, and the complementation group assignment PEX2 disease was first reached through. Quoted from the companion report by the same group because it states both facts in one sentence.

+ 5 more references

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Medical Actions

4

Symptomatic and supportive management

Action: Supportive Care NCIT:C15747

Platform: Other

There is no disease-modifying therapy. For this band management is dominated by the motor and sensory consequences - rehabilitation for the ataxia and neuropathy, hearing aids, refractive correction, fat-soluble vitamin supplementation - rather than by the neonatal problems that dominate the severe band.

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"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 for the spectrum. The list is spectrum-wide; gastrostomy in particular belongs to the severe band and not to this entry. The modality is OTHER because the row spans devices, surgery and supplementation.

Cholic acid supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: cholic acid CHEBI:16359

Platform: Small molecule

Bile-acid replacement, given because peroxisomal bile-acid synthesis is impaired and the C27 intermediates that accumulate are hepatotoxic. It is the only approved therapy for the Zellweger spectrum. Two limits belong on the claim: the evidence is spectrum-wide rather than PEX2-specific, and it is directed at liver disease, which is not what dominates the reported PEX2 mild-band patients - so nothing here says it alters the cerebellar disease that defines this entry.

Show evidence (2 references)

PMID:34521419 SUPPORT INDIRECT Other

"Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders."

The regulatory status of the one approved therapy. INDIRECT for this entry: the approval is for the spectrum, and no outcome in a PEX2 mild-band patient is reported anywhere in the sources cited here.

PMID:34521419 SUPPORT INDIRECT Other

"This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population."

The target of the therapy - liver disease - and the reviewers' own acknowledgement that the supporting clinical data are limited. Quoted rather than summarised so the caveat travels with the claim.

Multidisciplinary surveillance

Platform: Other

Scheduled monitoring rather than treatment, and the part of management that matters most in a slowly progressive disorder where the sensory losses arrive decades after the ataxia. For a child diagnosed in this band the practical core is annual audiology and ophthalmology, liver function and liver imaging, an annual urine oxalate-to-creatinine ratio, adrenal function from the first year, six-monthly dental review, and developmental and educational follow-up.

Show evidence (2 references)

PMID:20301621 SUPPORT Other

"Annual audiology and ophthalmologic evaluations; annual monitoring of liver function and coagulation factors, and ultrasound and/or fibroscan to evaluate liver architecture; monitor for changes in seizure activity; head MRI to evaluate for white matter changes that may explain changes in..."

The GeneReviews surveillance schedule for the spectrum, which is the only sourced schedule available for this entry. It is written for the spectrum as a whole, so parts of it - seizure monitoring in particular - address problems not reported in the PEX2 mild band.

PMID:20301621 SUPPORT Other

"Dental examinations every six months. Annual urine oxalate-to-creatinine ratio with consideration of kidney imaging when performing liver imaging."

The two surveillance items most easily forgotten in a patient whose presentation is neurological: the enamel defect of the secondary dentition and renal oxalate stones.

Dietary phytanic acid restriction

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Restriction of dietary phytanic acid, on the reasoning that phytanic acid is exclusively of dietary origin and is one of the two branched-chain species that accumulate in this entry. The Zellweger spectrum management literature does not recommend it generally: it is reserved for extremely high phytanic acid levels and is explicitly advised against when levels are only moderately raised, because maintaining caloric intake matters more. The PEX2 patients cited here are reported only as having increased branched-chain fatty acids, with no statement that phytanic acid reaches the extreme level at which the review indicates restriction, and no outcome of this intervention is reported in any of them. For this entry it is therefore a conditional option rather than a therapy of demonstrated benefit.

Show evidence (1 reference)

PMID:26627182 SUPPORT INDIRECT Other

"A phytanic acid restricted diet is only necessary when levels of phytanic acid are extremely high and is not recommended when levels are moderately increased"

The Zellweger spectrum management review's actual statement on phytanic acid restriction, which both establishes the intervention as a recognised option and supplies the threshold that keeps it conditional. INDIRECT because it is stated for the spectrum rather than for PEX2, and OTHER because the source is an expert management review rather than a study.

🔬

Biochemical Markers

3

Plasma branched-chain fatty acids

Context: Phytanic and pristanic acid are the analytes that led to the diagnosis in the ataxic form, and they moved when the very-long-chain fatty acids did not.

Show evidence (1 reference)

PMID:21392394 SUPPORT Human Clinical

"Plasma VLCFAs were nearly normal in patients P1 and P2, but a moderate increase in the levels of phytanic and pristanic acids was found, prompting us to suspect a peroxisomal disorder"

The abnormality that opened the diagnosis, and the normal result that would have closed it if the branched-chain fatty acids had not been measured.

Plasma very-long-chain fatty acids

Context: The screening test for the Zellweger spectrum, and the one that is unreliable at this end of it. Nearly normal in the two ataxic brothers, raised in the unrelated adult patient.

Show evidence (1 reference)

PMID:23430938 SUPPORT Human Clinical

"Analysis of plasma peroxisomal parameters revealed increased levels of very long chain fatty acids (VLCFAs), branched-chain fatty acids (pristanic and phytanic acid), and bile acid intermediates, prompting us to suspect a peroxisomal disorder."

The patient in whom the very-long-chain fatty acids were raised, quoted alongside the contrary result in the brothers so the record shows both.

Cultured fibroblast peroxisomal assays

Context: The confirmatory panel - plasmalogen synthesis, DHAPAT activity, very-long-chain fatty acid and pristanic acid beta-oxidation, phytanic acid alpha-oxidation - which at this end of the spectrum can be almost entirely normal in a patient who has the disease.

Show evidence (1 reference)

PMID:21392394 SUPPORT In Vitro

"Taken together, those analyses pointed towards a mild peroxisomal defect, but did not clearly indicate at which level."

The authors' reading of a near-normal fibroblast panel, and the reason they went on to sequence three candidate peroxin genes rather than stopping.

🔬

Diagnosis

2

Targeted plasma peroxisomal metabolite panel

Plasma very-long-chain fatty acids with phytanic acid, pristanic acid and the C27 bile-acid intermediates DHCA and THCA. Cheap, widely available, and the step that identified the disorder in every reported patient in this entry - but only because the branched-chain species were requested alongside the very-long-chain fatty acids.

Show evidence (1 reference)

PMID:21392394 SUPPORT Human Clinical

"Systematic screening for such PEX gene defect can easily and reliably be performed by the simple measurement of peroxisomal metabolites in plasma and will probably increase the frequency of PBD patients with mild phenotypes such as ARCA."

The authors' proposal for how this diagnosis is reached, and their prediction that the mild band is under-ascertained.

PEX gene sequencing

Sequencing of the peroxin genes, which is what confirms the diagnosis. In both reported families the metabolite profile pointed to a peroxisomal defect without localising it, and the biochemical assays could not narrow it further, so molecular testing was not a confirmation of a biochemical answer but the source of the answer.

Show evidence (3 references)

PMID:21392394 SUPPORT Human Clinical

"Genetic screening of PEX2 and other PEX genes involved in peroxisomal biogenesis is warranted in children and adults with ARCA."

The recommendation this record implements, stated for both children and adults - the age range this entry spans.

PMID:23430938 SUPPORT Human Clinical

"Peroxisomal mosaicism with a mixed population of fibroblasts with and without peroxisomes persisted at 40°C, making systematic sequencing of the different PEX genes necessary."

Why the cell-biological work-up did not substitute for sequencing in this patient: the temperature-shift assay that identifies many mild genotypes did not resolve his.

PMID:20301621 SUPPORT Other

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

GeneReviews' diagnostic criterion for the spectrum, which is what makes biallelic PEX variant identification the confirmatory test rather than a supporting one. Quoted because it states the role this record plays; OTHER because GeneReviews is an expert consensus chapter rather than a study.

📈

Progression

1

Childhood or adolescent onset, slow progression, survival to middle age

The prognostic fact that separates this entry from peroxisome biogenesis disorder 5A, where infants typically die in the first year. In the ataxic form first symptoms appear between about two and a half and eighteen years, progression is slow, and the oldest reported patient was ambulant and independent at fifty-one. That trajectory is drawn from three patients in two families and should be read as the reported experience, not as a prognosis that can be quoted to a family.

Show evidence (3 references)

PMID:23430938 SUPPORT Human Clinical

"The patient, born at term with normal birth weight and Apgar scores, developed normally until 3 years of age, when unsteady walking and frequent falls were noticed."

The pediatric onset in the oldest reported patient, and the normal neonatal course that precedes it - which is the observation that keeps this entry out of the neonatal band.

PMID:23430938 SUPPORT Human Clinical

"Motor disturbances progressed very slowly during childhood and adolescence without impairing his daily activities."

The rate of progression through the childhood years, in the one patient followed to middle age.

PMID:21392394 SUPPORT Human Clinical

"His older brother (P2) had normal neurologic examination at 14 years, but at the age of 18 years he started to develop cerebellar signs with impaired gait, dysmetria, ataxia of the trunk, dysarthria, hyporeflexia and slow saccades with oculomotor apraxia."

The other end of the onset range, in a sibling with the same genotype - a fourteen-year difference in age at onset within one family, which is why this entry does not offer an expected age of onset.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No numeric prevalence is available for this entry, and none is asserted. The ataxic form rests on two brothers and one unrelated man; the neonatal adrenoleukodystrophy / infantile Refsum presentation on individually reported patients. No source cited here gives a rate, a denominator, or PEX2's share of the Zellweger spectrum. The PEX Gene Screen reports that the relative frequencies of the different PEX gene defects matched earlier complementation data, but publishes no PEX2 figure that could be quoted.

Show evidence (1 reference)

PMID:15542397 NO_EVIDENCE Human Clinical

"The proportion of patients with different PEX gene defects correlated with frequencies previously identified by complementation analysis."

Cited to record what the largest molecular series of the spectrum does and does not say. It reports that the gene-level proportions were as expected without giving a figure for PEX2, and it does not split its patients into severity bands at all, so it bears on neither the frequency nor the prevalence of this entry.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Peroxisome Biogenesis Disorder 5B:

Peroxisome biogenesis disorder 5A (Zellweger)

Overlapping Features The severe band at the same locus. Separated not by gene but by residual peroxin-2 function, and in practice by congenital malformations and death in the first year of life. It is not curated in this repository.

Distinguishing Features

Congenital malformations - neuronal migration defect, renal cysts, epiphyseal stippling
Neonatal hypotonia, poor feeding and distinctive facies
Death in the first year without developmental progress
Absent rather than mosaic peroxisomal matrix-protein import in fibroblasts

Show evidence (2 references)

PMID:20301621 SUPPORT Other

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

The clinical outcome that separates the two bands.

PMID:10528859 SUPPORT In Vitro

"The nonsense mutation severely affects these peroxisomal functions as well as the protein import."

The cellular counterpart of the clinical split, measured at this locus: the allele that produces the severe band abolishes what the mild allele preserves in part.

Other autosomal recessive cerebellar ataxias

Overlapping Features The clinical differential this entry is actually met in. A child or adult with progressive ataxia, cerebellar atrophy and reduced reflexes is worked up for Friedreich ataxia, ataxia telangiectasia and the ataxias with oculomotor apraxia; a peroxisomal biogenesis disorder is not on the first list and is missed unless the branched-chain fatty acids are requested. Both reported families were tested for Friedreich ataxia and oculomotor apraxia type 1 before the peroxisomal work-up.

Distinguishing Features

Raised plasma phytanic and pristanic acid, with the pristanic/phytanic ratio above one
Raised C27 bile-acid intermediates DHCA and THCA
Plasma very-long-chain fatty acids may be near normal
Biallelic PEX2 variants on sequencing

Show evidence (1 reference)

PMID:21392394 SUPPORT Human Clinical

"Molecular studies of frataxin and aprataxin genes ruled out Friedrich ataxia and cerebellar ataxia with oculomotor apraxia 1 (AOA1)."

The specific alternatives excluded before this diagnosis was reached, in the founding report.

Alpha-methylacyl-CoA racemase deficiency

Overlapping Features The trap this entry's biochemical profile sets. A raised pristanic acid with a raised pristanic/phytanic ratio and normal very-long-chain fatty acids is the classic AMACR picture, and it was the first diagnosis considered in the two ataxic brothers.

Distinguishing Features

Distinguished by R- and S-isomer analysis of DHCA and THCA
Distinguished by AMACR enzyme activity in fibroblasts
Traces of DHCA and THCA also exclude adult Refsum disease

Show evidence (1 reference)

PMID:21392394 SUPPORT Human Clinical

"This was ruled out by the measurement of R- and S- isomers of DHCA and THCA in plasma and AMACR activity in fibroblasts from P1."

The tests that resolved the misdirection. The preceding sentence in the same paragraph, which states that the raised pristanic and phytanic acids with normal very-long-chain fatty acids first suggested AMACR deficiency, carries a bracketed citation and is therefore paraphrased in this record's description rather than quoted.

Zellweger spectrum disorders of other complementation groups

Overlapping Features The other twelve ZSD-PEX genes produce overlapping phenotypes across the same severity range, and mild bands with cerebellar ataxia are described at PEX10, PEX12 and PEX16 as well as here. The distinction is molecular and does not change management.

Distinguishing Features

Different causal PEX gene on sequencing
Clinically and biochemically overlapping at the same point on the severity range
PEX16 mild disease additionally reported with spastic paraparesis, leukodystrophy and cataract

Show evidence (2 references)

PMID:21392394 SUPPORT Human Clinical

"However, these patients displayed additional neurological symptoms including axonal motor neuropathy and decreased vibration sense in PEX10- mutated patients and spastic paraparesia, leukodystrophy peripheral neuropathy and cataracts in patients with PEX16 mutation."

The features that were used to tell the neighbouring mild bands apart at the time. The preceding sentence, which reports that mild cerebellar-ataxia phenotypes had just been shown at PEX10 and PEX16, carries a bracketed citation and is not quoted. Note that the distinction drawn here - an isolated ataxia at PEX2 against an ataxia-plus at PEX10 - does not survive the later PEX2 patient, who had a severe neuropathy.

PMID:20301621 SUPPORT Other

"the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype"

The current gene-agnostic framing, which is why the differential between complementation groups is molecular rather than clinical.

🔬

Clinical Trials

1

NCT06190626 NOT_APPLICABLE

Longitudinal observational natural-history study of the retinal degeneration of Zellweger spectrum disorder, set up to define its course, to work out which tests best track progression, and to produce prognostic information about vision loss. It enrolls at spectrum level rather than by complementation group, so it is relevant to this entry through the retinal dystrophy the milder band carries rather than through PEX2 specifically. NOT_APPLICABLE because it is observational and follows no FDA phase.

Target Phenotypes: Retinal dystrophy HP:0000556

Show evidence (1 reference)

clinicaltrials:NCT06190626 SUPPORT Human Clinical

"The goal of this observational study is to define the course of the retinal degeneration in a ZSD patient cohort."

The registered objective, which is what makes this study relevant to the retinal dystrophy this entry records for the intermediate and milder band.

{ }

Source YAML

click to show

name: Peroxisome Biogenesis Disorder 5B
creation_date: "2026-09-26T00:00:00Z"
category: Mendelian
description: >-
  Peroxisome biogenesis disorder 5B is the milder, non-Zellweger band of the PEX2 allelic
  series. The gene and the lesion are the same as in peroxisome biogenesis disorder 5A;
  what separates the two is how much peroxin-2 function the genotype leaves. Peroxin-2 is
  an integral peroxisomal membrane protein whose cytosolic C-terminal RING finger works
  with peroxin-10 and peroxin-12 as the ubiquitin ligase that recycles the PTS1 receptor
  PEX5, so a genotype retaining partial peroxin-2 activity leaves matrix-protein import
  reduced rather than abolished, and with it very-long-chain fatty acid beta-oxidation,
  branched-chain fatty acid oxidation, bile-acid synthesis and plasmalogen synthesis.

  The cellular correlate of that partial import defect has been worked out at this locus
  specifically, and it is what makes PEX2 a useful model of the mild band. Fibroblasts from
  mildly affected patients carry peroxisomal mosaicism - some cells with import-competent
  peroxisomes, some without - and a population of partially functional organelles that
  import the PTS1 enzymes but not catalase, named catalase-less peroxisomes by the group
  that characterised them. The PEX2 E55K allele found in an infantile Refsum disease
  patient reproduces that behaviour when transfected into a PEX2-null cell line, and it is
  temperature-sensitive: the peroxisomes are absent at 37 degrees and recovered at 30.

  Clinically this entry holds everything PEX2 does short of classic Zellweger syndrome, and
  the published patients fall into two groups that are not equally evidenced. The better
  documented is a childhood-onset, slowly progressive cerebellar ataxia with cerebellar
  atrophy, axonal sensorimotor polyneuropathy and areflexia, in patients who reach adult
  life - two brothers with onset at three and a half and eighteen years, and an Italian man
  still ambulant and cognitively intact at fifty-one. The other is the older neonatal
  adrenoleukodystrophy and infantile Refsum disease presentation, which at this locus rests
  on a small number of individually reported patients.

  The diagnostically consequential fact is biochemical. In the ataxic patients plasma
  very-long-chain fatty acids were nearly normal and it was a moderate rise in phytanic and
  pristanic acid that prompted the peroxisomal work-up; fibroblast beta-oxidation,
  plasmalogen synthesis and DHAPAT activity were normal. A normal very-long-chain fatty
  acid screen therefore does not exclude this diagnosis, and the route to it is sequencing.
synonyms:
- PBD5B
- peroxisome biogenesis disorder type 5B
- PEX2-related neonatal adrenoleukodystrophy
- PEX2-related infantile Refsum disease
- PEX2-related cerebellar ataxia
- attenuated PEX2-related Zellweger spectrum disorder
disease_term:
  preferred_term: peroxisome biogenesis disorder 5B
  term:
    id: MONDO:0013933
    label: peroxisome biogenesis disorder 5B
parents:
- Peroxisome Biogenesis Disorder
- Zellweger Spectrum Disorders
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      An autosomal recessive Mendelian disorder of organelle assembly, reached historically
      through complementation grouping - group F in the Japanese series, CG10 in the North
      American one - and then through identification of the gene.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Also an inborn error of metabolism. At this end of the allelic series the biochemical
      signature is attenuated rather than absent, which is what makes it easy to miss.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013933
      label: peroxisome biogenesis disorder 5B
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The dismech entry and the MONDO class denote the same entity: the milder, non-classic
      band of PEX2-related peroxisome biogenesis disorder. MONDO places both bands under
      MONDO:0100260 peroxisome biogenesis disorder due to PEX2 defect; the severe band,
      MONDO:0013932, is not yet curated here.
references:
- reference: PMID:20301621
  title: "Zellweger Spectrum Disorder."
  tags:
  - GeneReviews
- reference: PMID:1546315
  title: "A human gene responsible for Zellweger syndrome that affects peroxisome assembly."
- reference: PMID:10528859
  title: "Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders."
- reference: PMID:10960480
  title: "Catalase-less peroxisomes. Implication in the milder forms of peroxisome biogenesis disorder."
- reference: PMID:11330043
  title: "Temperature sensitivity in peroxisome assembly processes characterizes milder forms of peroxisome biogenesis disorders."
- reference: PMID:14630978
  title: "Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder."
- reference: PMID:10652207
  title: "Molecular mechanism of detectable catalase-containing particles, peroxisomes, in fibroblasts from a PEX2-defective patient."
- reference: PMID:21392394
  title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
- reference: PMID:23430938
  title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
- reference: PMID:40621817
  title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
- reference: PMID:35768507
  title: "A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel."
- reference: PMID:26750748
  title: "Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines."
- reference: PMID:26627182
  title: "Zellweger spectrum disorders: clinical overview and management approach."
- reference: PMID:34521419
  title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
- reference: PMID:15542397
  title: "The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum."
- reference: ORPHA:642965
  title: "Autosomal recessive ataxia due to PEX2 deficiency"
- reference: CGGV:assertion_17bf1c4a-1775-40c6-a499-774c93827343-2020-02-07T170000.000Z
  title: "PEX2 / peroxisome biogenesis disorder (Definitive)"
has_subtypes:
- name: Ataxic form
  display_name: PEX2-related cerebellar ataxia (childhood-onset ataxic form)
  subtype_term:
    preferred_term: autosomal recessive ataxia due to PEX2 deficiency
    term:
      id: MONDO:0957443
      label: autosomal recessive ataxia due to PEX2 deficiency
  description: >-
    Childhood-onset, slowly progressive cerebellar ataxia with cerebellar atrophy on MRI,
    axonal sensorimotor polyneuropathy and generalised areflexia, in individuals who reach
    adult life with normal or near-normal intellect. This is the best documented PEX2 mild
    presentation: two brothers reported in 2011 and an unrelated man reported in 2012 who
    shares one of their alleles.
  genes:
  - preferred_term: PEX2
    term:
      id: hgnc:9717
      label: PEX2
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two brothers are described who developed progressive cerebellar ataxia at 3 1/2 and 18 years, respectively."
    explanation: >-
      The founding report of this presentation, and the source of both its age range and
      its progressive course. Two brothers is the whole of that report, and the reader
      should hold that denominator against every statement made about this subtype.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 51-year-old Italian man was referred to us because of a clinical picture
      characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset
      and slowly progressive course.
    explanation: >-
      An unrelated patient with the same presentation, and the one that establishes
      survival to middle age at this locus.
  - reference: ORPHA:642965
    reference_title: "Autosomal recessive ataxia due to PEX2 deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare genetic, peroxisomal disease characterized by childhood or adolescence onset
      slowly progressing cerebellar ataxia and severe axonal sensorimotor polyneuropathy due
      to PEX 2 deficieny.
    explanation: >-
      Orphanet recognises this presentation as a named entity and defines it in terms that
      match the curated subtype: childhood or adolescent onset, slow progression, cerebellar
      ataxia with axonal sensorimotor polyneuropathy. Quoted with Orphanet's own typographical
      errors intact. Marked OTHER because an Orphanet record is a curated database entry
      rather than a study.
  - reference: ORPHA:642965
    reference_title: "Autosomal recessive ataxia due to PEX2 deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients develop marked brain atrophy including cerebellum, cerebellar peduncles, and
      bulbar olives. Gait disturbance, moderate truncal ataxia, moderate cerebellar tremor,
      mild dysarthria, areflexia, strabismus, hypoacusia and nystagmus were also reported.
    explanation: >-
      Orphanet's own feature list for the subtype, which is the independent check on the
      phenotype set curated here. It names every clinical feature this entry records for the
      ataxic form, and adds none this entry omits.
- name: NALD-IRD
  display_name: Neonatal adrenoleukodystrophy / infantile Refsum disease presentation
  description: >-
    The older phenotype labels for the intermediate and mild bands of the Zellweger
    spectrum: progressive peroxisomal failure with sensory loss, liver disease and
    developmental delay, without the congenital malformations of classic Zellweger syndrome.
    At the PEX2 locus this presentation rests on individually reported patients - the
    infantile Refsum disease patient carrying E55K opposite a nonsense allele, and the
    mildly affected homozygous W223X patient in the four-patient complementation group 10
    series - rather than on any assembled cohort.
  genes:
  - preferred_term: PEX2
    term:
      id: hgnc:9717
      label: PEX2
  evidence:
  - reference: PMID:10528859
    reference_title: "Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a mutation in the PEX2 gene in an IRD patient with compound
      heterozygosity for a missense mutation and the known nonsense mutation detected in ZS
      patients.
    explanation: >-
      The infantile Refsum disease patient at this locus, and the genotype - one
      residual-function missense allele opposite an allele already known from the severe
      band - that defines the mild band.
  - reference: PMID:14630978
    reference_title: "Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, the patient lacking the domain had a mild phenotype, whereas the C247R patient had a severe phenotype."
    explanation: >-
      A second mildly affected PEX2 patient, and the authors' own surprise at the
      genotype-phenotype result, which is retained rather than smoothed over: the
      correlation between allele class and severity holds in general but is not mechanical.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations, but
      rather progressive peroxisome dysfunction variably manifest as sensory loss
      (secondary to retinal dystrophy and sensorineural hearing loss), neurologic
      involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal
      insufficiency, and renal oxalate stones.
    explanation: >-
      The GeneReviews characterisation of the band these older labels name. Quoted from the
      spectrum resource rather than from a PEX2 source because no PEX2 series describes this
      presentation in comparable detail; it is therefore a spectrum-general statement, not a
      PEX2-specific one.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No numeric prevalence is available for this entry, and none is asserted. The ataxic form
    rests on two brothers and one unrelated man; the neonatal adrenoleukodystrophy /
    infantile Refsum presentation on individually reported patients. No source cited here
    gives a rate, a denominator, or PEX2's share of the Zellweger spectrum. The PEX Gene
    Screen reports that the relative frequencies of the different PEX gene defects matched
    earlier complementation data, but publishes no PEX2 figure that could be quoted.
  evidence:
  - reference: PMID:15542397
    reference_title: "The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "The proportion of patients with different PEX gene defects correlated with frequencies previously identified by complementation analysis."
    explanation: >-
      Cited to record what the largest molecular series of the spectrum does and does not
      say. It reports that the gene-level proportions were as expected without giving a
      figure for PEX2, and it does not split its patients into severity bands at all, so it
      bears on neither the frequency nor the prevalence of this entry.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PEX2 variants, and specifically genotypes leaving residual peroxin-2 function
    on at least one allele. The reported mild-band patients are either homozygous for a
    C-terminal frameshift that spares most of the protein, or compound heterozygous for a
    residual-function missense allele opposite a null allele that is itself known from
    classic Zellweger syndrome.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At conception, each sib of an individual with biallelic ZSD-causing pathogenic
      variants has a 25% chance of being affected, a 50% chance of being an asymptomatic
      carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: >-
      The recurrence risk that genetic counselling for this entry turns on, stated for the
      spectrum as a whole. The quantitative risk is quoted rather than summarised because
      it is the sentence families are counselled from.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No mutation was found in P1 and P2 asymptomatic siblings, who had normal peroxisomal
      parameters in plasma and no neurologic symptoms.
    explanation: >-
      Recessive segregation worked through a sibship: two affected brothers homozygous for
      the allele, three unaffected siblings without it and biochemically normal.
  - reference: CGGV:assertion_17bf1c4a-1775-40c6-a499-774c93827343-2020-02-07T170000.000Z
    reference_title: "PEX2 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX2 | HGNC:9717 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: >-
      ClinGen's Peroxisomal Disorders expert panel records autosomal recessive inheritance
      for the locus. The assertion is made against the grouping concept MONDO:0019234
      rather than against this entry's MONDO:0013933, so it fixes the gene and the mode of
      inheritance and says nothing about the severity band.
pathophysiology:
- name: Biallelic PEX2 Genotype With Residual Peroxin-2 Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: "peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect"
  description: >-
    Both PEX2 alleles are altered, but the genotype as a whole leaves partial peroxin-2
    activity. Two configurations are reported at this end of the series: homozygosity for a
    frameshift so close to the stop codon that most of the protein survives
    (c.865_866insA, p.Ser289LysfsX36), and compound heterozygosity for a residual-function
    missense allele opposite a nonsense allele already known from classic Zellweger
    syndrome (E55K opposite R119X). The residual-function threshold, not gene identity, is
    what separates this entry from peroxisome biogenesis disorder 5A.
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    gene:
      preferred_term: PEX2
      term:
        id: hgnc:9717
        label: PEX2
    description: >-
      COMPOUND_HETEROZYGOUS records the configuration of the reported E55K and R119X
      patients. It is not a requirement of the entry: the two ataxic brothers were
      apparently homozygous for a single C-terminal frameshift allele, and the mildly
      affected patient in the complementation group 10 series was homozygous for W223X.
  biological_processes:
  - preferred_term: peroxisome organization
    modifier: DECREASED
    term:
      id: GO:0007031
      label: peroxisome organization
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  evidence:
  - reference: PMID:10528859
    reference_title: "Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data suggest that allelic heterogeneity of the PEX gene affects the peroxisomal
      protein import and functions and regulates the clinical severity in PBD.
    explanation: >-
      The residual-function account that defines this entry against peroxisome biogenesis
      disorder 5A, stated by the study that made it at the PEX2 locus itself.
  - reference: PMID:40621817
    reference_title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      In general, clinical severity correlates to lower levels of residual PEX gene
      activity and much less to which PEX gene is involved (e.g. PEX16 vs PEX2 vs PEX3)
    explanation: >-
      States the residual-activity rule, and its corollary that the severity band matters
      more than which peroxin is affected. Graded HUMAN_CLINICAL with quote_role BACKGROUND
      because the sentence sits in the introduction of a Drosophila study and restates the
      human clinical correlation established elsewhere.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of candidate PEX genes revealed a homozygous c.865_866insA mutation in the
      PEX2 gene leading to a frameshift 17 codons upstream of the stop codon.
    explanation: >-
      The homozygous mild-band genotype, and the structural reason it is mild: a frameshift
      seventeen codons from the end alters the C-terminus rather than removing the protein.
  downstream:
  - target: Partial Loss of Peroxin-2 RING Ubiquitin Ligase Function
    description: >-
      A residual-function PEX2 allele yields a peroxin-2 that reaches the peroxisomal
      membrane and retains part of its activity, rather than a protein that is absent or
      non-functional.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21392394
      reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The fact that peroxisomes in the patient's fibroblasts were normally present and
        contained catalase suggests that the mutated PEX2 is localized correctly in the
        peroxisomal membrane and still is partly active.
      explanation: >-
        The authors' inference that the mild allele yields a partly active, correctly
        localised protein. Their own "suggests" is preserved and the item is marked
        INDIRECT, because the claim is read off organelle morphology rather than from an
        activity measurement.
- name: Partial Loss of Peroxin-2 RING Ubiquitin Ligase Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Peroxin-2 is an integral peroxisomal membrane protein with two transmembrane domains
    and a cytosolic C-terminal zinc-binding RING finger. Together with peroxin-10 and
    peroxin-12 it forms the membrane-embedded ubiquitin ligase that ubiquitinates the PTS1
    receptor PEX5 so the receptor can be retrotranslocated and reused. Degrading that
    activity rather than abolishing it is the molecular difference between this entry and
    the severe band.
  molecular_functions:
  - preferred_term: ubiquitin-protein transferase activity
    modifier: DECREASED
    term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  evidence:
  - reference: PMID:14630978
    reference_title: "Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PBD patients belonging to complementation group 10 (CG10) have mutations in the PEX2
      gene (PXMP3), which codes for a protein (PEX2) that contains two transmembrane domains
      and a zinc-binding domain considered to be important for its interaction with other
      proteins of the peroxisomal protein import machinery.
    explanation: >-
      The domain architecture this node asserts, from a PEX2 patient series rather than from
      a general review.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The PEX2, PEX10 and PEX12 genes encode peroxins that are integral peroxisomal membrane
      proteins with a cytosolic carboxy-terminal RING finger domain that act as ubiquitin
      ligases required for the ubiquitination of the PTS1-receptor (PEX5) in the peroxisomal
      membrane
    explanation: >-
      Names the ligase activity and its substrate. Graded HUMAN_CLINICAL with quote_role
      BACKGROUND: the sentence is the discussion's framing of established biochemistry
      rather than a result of the case report it sits in.
  - reference: PMID:35768507
    reference_title: "A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Recycling requires receptor modification by a membrane-embedded ubiquitin ligase
      complex comprising three RING finger domain-containing proteins (Pex2, Pex10 and
      Pex12)
    explanation: >-
      The complex peroxin-2's RING domain belongs to, and what it does. INDIRECT because the
      structure was solved in a fungal system, so the human claim rests on conservation.
  - reference: PMID:10652207
    reference_title: "Molecular mechanism of detectable catalase-containing particles, peroxisomes, in fibroblasts from a PEX2-defective patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, a defect in the C-terminal portion of Pex2p exposed to the cytosol
      containing a RING finger motif caused the mild phenotype, residual enzyme activities,
      and mosaic detectable peroxisomes in fibroblasts from the patient.
    explanation: >-
      The single sentence that ties the defining claims of this entry together at the PEX2
      locus: a C-terminal RING-region lesion, a mild clinical phenotype, residual enzyme
      activity, and peroxisomal mosaicism. It is also the structural account of why the
      c.865_866insA frameshift seventeen codons from the stop codon lands in this band.
  downstream:
  - target: Partial Failure of Peroxisomal Matrix Protein Import
    description: >-
      Degraded ligase activity slows PEX5 recycling, so matrix-protein import is reduced
      rather than abolished - the state that produces a mixed population of import-competent
      and import-incompetent organelles.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10528859
      reference_title: "Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we noted the E55K mutation had mosaic activities of peroxisomal protein import
        machinery and residual activities of peroxisomal functions, including
        dihydroxyacetone phosphate acyltransferase and beta oxidation of very long chain
        fatty acids
      explanation: >-
        The transfection experiment that ties a specific mild PEX2 allele to mosaic import
        and residual pathway activity, which is exactly what this edge asserts.
- name: Partial Failure of Peroxisomal Matrix Protein Import
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Matrix-protein import is reduced but not abolished. In patient fibroblasts this appears
    as peroxisomal mosaicism - some cells with normal peroxisomes, some with none, some
    mixed - and as a population of partially functional organelles that import the PTS1
    enzymes acyl-CoA oxidase and thiolase while leaving catalase in the cytosol, which the
    group that described them named catalase-less peroxisomes. In the PEX2 E55K case the
    defect is temperature-sensitive, recovering at a permissive temperature; in the Italian
    patient the mosaicism persisted at 40 degrees, so the temperature test does not detect
    every mild PEX2 genotype. The fibroblast bound below is the cell the defect was assayed
    in, not a claim about which cell drives the disease: the import machinery is ubiquitous
    and the tissue that fails clinically is the cerebellum.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: protein import into peroxisome matrix
    modifier: DECREASED
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
  cellular_components:
  - preferred_term: peroxisomal matrix
    term:
      id: GO:0005782
      label: peroxisomal matrix
  evidence:
  - reference: PMID:10960480
    reference_title: "Catalase-less peroxisomes. Implication in the milder forms of peroxisome biogenesis disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Catalase-less peroxisomes were also observed in human fibroblasts from patients with
      milder forms of peroxisome biogenesis disorder, including the one from which the
      mutant PEX2 gene was derived.
    explanation: >-
      Establishes that the partially functional organelle characterised in the cell model is
      present in patient fibroblasts, including the PEX2 patient whose allele was used.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluorescence microscopy analysis using antibodies raised against catalase, a
      peroxisomal matrix enzyme, revealed a heterogeneous pattern: some cells showed normal
      peroxisomes whereas in other cells peroxisomes were absent, and in yet other cells a
      mixed picture was observed.
    explanation: >-
      Peroxisomal mosaicism observed directly in a PEX2 patient's fibroblasts, which is the
      cellular claim of this node.
  - reference: PMID:11330043
    reference_title: "Temperature sensitivity in peroxisome assembly processes characterizes milder forms of peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that all IRD cell lines and some NALD lines belonging to several different
      complementation groups are temperature-sensitive in peroxisome assembly; that is, they
      lacked catalase-positive peroxisomes at 37 degrees C, but do gain the peroxisomes at
      30 degrees C.
    explanation: >-
      The temperature-sensitive behaviour of the mild band's import defect, from the study
      that identified the PEX2 E55K/R119X genotype in an infantile Refsum disease patient.
  - reference: PMID:10652207
    reference_title: "Molecular mechanism of detectable catalase-containing particles, peroxisomes, in fibroblasts from a PEX2-defective patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Some of the fibroblasts from the patient with the del642G mutation contained numerous
      catalase-containing particles, whereas no fibroblasts containing such particles were
      found in the patient with the del550C mutation.
    explanation: >-
      The cell-by-cell contrast between a mild and a severe PEX2 allele in the same study:
      catalase-containing particles in some fibroblasts of the C-terminal-lesion patient and
      in none of the other. This is the observation the word mosaicism names.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "The mosaicism was observed both at 37°C and at 40°C."
    explanation: >-
      Cited against the generality of the temperature-sensitive claim rather than against the
      node. In this PEX2 patient the mosaicism did not resolve with temperature, so a
      negative temperature-shift assay does not exclude a mild PEX2 genotype - which is why
      the same report concludes that sequencing the PEX genes was necessary.
  downstream:
  - target: Residual Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis
    description: >-
      Because the import defect is partial, the peroxisomal pathways run at reduced rather
      than absent capacity - and in the ataxic patients several of them measure normal in
      cultured fibroblasts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10528859
      reference_title: "Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The nonsense mutation severely affects these peroxisomal functions as well as the
        protein import.
      explanation: >-
        The contrast that makes this edge quantitative rather than qualitative: in the same
        assay the null allele abolished the functions the mild allele preserved in part.
- name: Residual Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: "peroxisomal_metabolic_failure#Failure of Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis"
  description: >-
    Beta-oxidation of very-long-chain fatty acids, alpha-oxidation of phytanic acid,
    beta-oxidation of the C27 bile-acid intermediates and the first steps of plasmalogen
    synthesis all depend on imported matrix enzymes, so all are affected together - but at
    this end of the series they are affected partially. In the ataxic brothers fibroblast
    plasmalogen synthesis, DHAPAT activity and very-long-chain fatty acid oxidation were
    normal and only phytanic acid alpha-oxidation was slightly abnormal; in the Italian
    patient DHAPAT activity and C26:0 beta-oxidation were likewise normal. This is the node
    where this entry diverges most sharply from classic Zellweger syndrome, and it is the
    reason a fibroblast panel can be reassuring in a patient who has the disease.
  biological_processes:
  - preferred_term: very long-chain fatty acid catabolic process
    modifier: DECREASED
    term:
      id: GO:0042760
      label: very long-chain fatty acid catabolic process
  - preferred_term: fatty acid alpha-oxidation
    modifier: DECREASED
    term:
      id: GO:0001561
      label: fatty acid alpha-oxidation
  - preferred_term: ether lipid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      showed normal plasmalogen biosynthesis, DHAP-AT activity, oxidation of VLCFAs, and
      pristanic acid
    explanation: >-
      The fibroblast result in the ataxic form. Quoted because it is the strongest single
      statement of how attenuated this node is here; the same paragraph adds that phytanic
      acid oxidation was only slightly abnormal.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DHAPAT activity and C26:0 beta-oxidation, which are considered the best biochemical
      markers in predicting life expectancy of patients with PBDs (Gootjes et al. 2002), were
      normal.
    explanation: >-
      An independent patient with the same result, and the prognostic reading the authors
      put on it.
  downstream:
  - target: Accumulation of Branched-Chain Fatty Acids and Bile-Acid Intermediates
    description: >-
      Reduced alpha- and beta-oxidation capacity lets phytanic acid, pristanic acid and the
      C27 bile-acid intermediates DHCA and THCA rise in plasma, even where the
      very-long-chain fatty acids do not.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21392394
      reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Further studies showed a moderate increase of bile acid intermediates (DHCA and
        THCA) in plasma and normal levels of pipecolic acid in plasma and CSF
      explanation: >-
        The accumulating species measured in patients of the ataxic form, and the one that
        did not accumulate.
- name: Accumulation of Branched-Chain Fatty Acids and Bile-Acid Intermediates
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  conforms_to: "peroxisomal_metabolic_failure#Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency"
  description: >-
    The circulating biochemical lesion. At this end of the spectrum it is attenuated and
    selective: in the ataxic brothers plasma very-long-chain fatty acids were nearly normal
    while phytanic and pristanic acid were moderately raised, whereas in the Italian patient
    very-long-chain fatty acids, branched-chain fatty acids and bile-acid intermediates were
    all raised and erythrocyte plasmalogens were normal. Which analytes move therefore
    differs between reported patients, and a single normal analyte carries little
    exclusionary weight.
  chemical_entities:
  - preferred_term: phytanic acid
    modifier: INCREASED
    term:
      id: CHEBI:16285
      label: phytanic acid
  - preferred_term: pristanic acid
    modifier: INCREASED
    term:
      id: CHEBI:51340
      label: pristanic acid
  biological_processes:
  - preferred_term: very long-chain fatty acid catabolic process
    modifier: DECREASED
    term:
      id: GO:0042760
      label: very long-chain fatty acid catabolic process
  - preferred_term: ether lipid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma VLCFAs were nearly normal in patients P1 and P2, but a moderate increase in the
      levels of phytanic and pristanic acids was found, prompting us to suspect a peroxisomal
      disorder
    explanation: >-
      The selective, attenuated pattern this node asserts, and the analytes that actually led
      to the diagnosis in the ataxic form.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of plasma peroxisomal parameters revealed increased levels of very long chain
      fatty acids (VLCFAs), branched-chain fatty acids (pristanic and phytanic acid), and
      bile acid intermediates, prompting us to suspect a peroxisomal disorder.
    explanation: >-
      An unrelated patient in whom the very-long-chain fatty acids were raised, which is why
      this node describes the pattern as variable between patients rather than as a fixed
      signature.
  downstream:
  - target: Cerebellar Neurodegeneration
    description: >-
      The clinically dominant consequence at this end of the spectrum falls on the
      cerebellum. The link is an inference from the imaging and neuropathological pattern
      rather than a demonstrated toxic mechanism in these patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In our patient, the moderate impairment in peroxisome biogenesis affects
        predominantly neuronal cells in the cerebellum.
      explanation: >-
        The authors' own statement of the tissue selectivity this edge asserts. Marked
        INDIRECT because it is read off the imaging and the clinical picture; the step from
        the accumulating metabolites to Purkinje-cell loss is not demonstrated in these
        patients, and the Sevin report says in as many words that how the defect selectively
        injures cerebellar neurons is unknown.
- name: Cerebellar Neurodegeneration
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  description: >-
    Progressive loss of cerebellar tissue, radiologically atrophy of the vermis and the
    lateral hemispheres, and in the most affected patient of the cerebellar peduncles and
    bulbar olives as well. Two features distinguish it from the severe band: it is
    degenerative rather than malformative - the Sevin brothers had no neuronal migration
    defect - and it occurs without white-matter signal change, so this is not a
    leukodystrophy. Marked HYPOTHETICAL because the step from the metabolic lesion to
    cerebellar cell loss is not established in these patients. The Purkinje cell is recorded
    as the vulnerable cell type on the strength of the PEX2-null mouse, in which Purkinje
    dendritic arborization is abnormal; no human PEX2 neuropathology is available, so the
    cell-level localisation is an inference from the model rather than an observation in
    these patients.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: BACKGROUND
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cerebellar defects (cerebellar hypoplasia, altered folial pattern, abnormal Purkinje
      cell dendritic arborization) are observed in PEX 2 deficient mice
    explanation: >-
      The only evidence that the cerebellar lesion of PEX2 deficiency is Purkinje-centered,
      and the basis for conforming this node to the Purkinje degeneration module. Graded
      MODEL_ORGANISM because the quoted finding is from PEX2-null mice, and BACKGROUND
      because this human case report is restating a mouse result it did not generate.
      INDIRECT: a null mouse is a more severe lesion than the residual-function genotype of
      this entry, and dendritic abnormality is not cell loss.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 9 years, a brain MRI showed atrophy of the vermis and lateral hemispheres
      of the cerebellum that worsened at the age of 14 years, but without signs of
      demyelination or neuronal migration defects in forebrain and cerebellum
    explanation: >-
      Establishes all three claims of this node at once: the anatomy, the progression between
      two scans, and the absence of both demyelination and the migration defect of classic
      Zellweger syndrome.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients that we describe seem to have progressive cerebellar atrophy rather than
      malformative cerebellar hypoplasia.
    explanation: >-
      The authors' distinction between a degenerative and a malformative process, carrying
      their own hedge. INDIRECT because it is an interpretation of serial imaging, not a
      pathological finding.
  downstream:
  - target: Ataxia
    description: >-
      The cerebellar atrophy is the substrate of the ataxia that defines this entry's
      commonest presentation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The moderate impairment in peroxisome biogenesis seems to affect predominantly
        neuronal cells in cerebellum, leading to cerebellar atrophy.
      explanation: >-
        Ties the cerebellar tissue lesion to the clinical syndrome in a PEX2 patient. The
        authors' "seems to" is preserved.
  - target: Cerebellar atrophy
    description: The radiological expression of the same tissue lesion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain MRI showed marked cerebellar atrophy and absence of white matter involvement."
      explanation: >-
        The imaging finding in a PEX2 patient, together with the negative that keeps this
        entry out of the leukodystrophies.
  - target: Dysarthria
    description: Cerebellar dysarthria, reported in patients of both families.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and
        bilateral pes cavus.
      explanation: The cerebellar examination findings in the reported adult patient.
  - target: Dysmetria
    description: Limb dysmetria, a cerebellar sign of the same lesion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and
        bilateral pes cavus.
      explanation: >-
        Records the dysmetria alongside the other cerebellar signs in the patient with marked
        cerebellar atrophy on MRI.
  - target: Nystagmus
    description: Gaze-evoked nystagmus, an oculomotor sign of the cerebellar lesion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        On admission to our Department, neurological examination showed gait ataxia, lateral
        and vertical gaze-evoked nystagmus, hypoacusia, mild dysarthria, slight dysmetria,
        generalized areflexia, and bilateral pes cavus.
      explanation: >-
        Names the nystagmus as gaze-evoked, which is what places it with the cerebellar
        lesion rather than with the retinopathy.
- name: Peripheral Axonal Degeneration
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    Length-dependent axonal degeneration of peripheral nerve, established on nerve
    conduction studies. It is a second, largely independent site of injury rather than a
    consequence of the cerebellar lesion, and its severity does not track the ataxia: the
    Sevin brothers had normal nerve conduction at nine, fourteen and eighteen years, while
    the older Italian patient had a severe axonal sensorimotor polyneuropathy with pes cavus.
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies indicated a severe axonal sensorimotor polyneuropathy."
    explanation: >-
      The electrophysiological basis for calling the neuropathy axonal and sensorimotor,
      which is what the phenotype binding asserts.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fundoscopic examination, electroretinogram, EEG, electromyography, peripheral nerve
      conduction, visual, brainstem auditory and somatosensory evoked potentials, and
      audiogram were normal at 9 and 14 years.
    explanation: >-
      A negative result recorded as such. In the two ataxic brothers nerve conduction,
      retinal and auditory testing were all normal into the mid-teens, so neither the
      neuropathy nor the sensory loss is obligatory in this entry, and their absence does
      not argue against the diagnosis.
  downstream:
  - target: Peripheral axonal neuropathy
    description: The clinical and electrophysiological expression of the axonal lesion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Electromyography and nerve conduction studies indicated a severe axonal sensorimotor
        polyneuropathy.
      explanation: The examination and electrophysiology behind this phenotype.
  - target: Areflexia
    description: >-
      Generalised loss of tendon reflexes. The neuropathy explains it in only one of the three
      reported PEX2 patients: the Italian adult had generalised areflexia alongside a severe
      axonal sensorimotor polyneuropathy on nerve conduction studies, whereas both Sevin
      brothers already had reduced reflexes while their nerve conduction remained normal at
      nine and fourteen years. In those two the hyporeflexia preceded any demonstrable
      neuropathy, so this edge is the mechanism in the adult and not an established
      explanation for the sign wherever it appears in this entry.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        On admission to our Department, neurological examination showed gait ataxia, lateral
        and vertical gaze-evoked nystagmus, hypoacusia, mild dysarthria, slight dysmetria,
        generalized areflexia, and bilateral pes cavus. Electromyography and nerve conduction
        studies indicated a severe axonal sensorimotor polyneuropathy.
      explanation: >-
        Puts the generalised areflexia and the axonal sensorimotor polyneuropathy in the same
        patient on the same examination, which is the closest the sources come to the causal
        step. INDIRECT because co-occurrence in one patient does not establish that the
        neuropathy produced the areflexia, and because the separately reported Sevin brothers
        had reduced reflexes with normal nerve conduction.
  - target: Pes cavus
    description: >-
      The skeletal consequence of long-standing distal denervation, present bilaterally in
      the one patient in whom the neuropathy was severe.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23430938
      reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and
        bilateral pes cavus.
      explanation: >-
        Records the pes cavus alongside the areflexia in the same patient. INDIRECT because
        the source states the co-occurrence, not the causal step from denervation to foot
        deformity.
- name: Multisystem Peroxisomal Disease
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  conforms_to: "peroxisomal_metabolic_failure#Multisystem Peroxisomal Disease"
  description: >-
    The organ-level consequences the peroxisomal lesion produces outside the nervous system -
    liver disease, adrenal insufficiency, renal oxalate stones, enamel and bone involvement.
    This node is curated at spectrum level rather than at PEX2 level, and the distinction is
    deliberate: the liver, adrenal, renal, enamel and bone features are not reported in a PEX2
    mild-band patient in any source cited here, and the reason they belong in this entry is
    that GeneReviews describes them for the intermediate and milder band and builds its
    surveillance schedule around them. The sensory losses are different - hypoacusia and early
    retinopathy were both observed in the Italian PEX2 adult - so for those two downstream
    targets the node records an observed phenotype. For the rest, a reader should treat it as
    the expected organ set to watch for.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations, but
      rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
      to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
      polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
      renal oxalate stones.
    explanation: >-
      GeneReviews' description of the band this entry occupies, and the source of the organ
      set this node names. It is a statement about the intermediate and milder Zellweger
      spectrum as a whole rather than about PEX2, which is why the node is curated at spectrum
      level and why its non-sensory organ involvements carry no observed PEX2 instance.
  downstream:
  - target: Hepatic dysfunction
    description: Liver involvement, the organ problem the one approved therapy is directed at.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34521419
      reference_title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        In the absence of functional peroxisomes, bile acid synthesis is disrupted, and
        multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle,
        eyes, ears, and nervous system.
      explanation: >-
        Names disrupted bile-acid synthesis as the step between the peroxisomal lesion and
        multisystem disease including the liver. INDIRECT, and stated for absent peroxisomes
        rather than for the partial import defect of this entry.
  - target: Adrenal insufficiency
    description: Adrenocortical failure, which GeneReviews asks to be screened for from age one.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "ACTH and cortisol levels by age one year and annually thereafter."
      explanation: >-
        The surveillance interval, quoted because it is the actionable form of this claim.
        INDIRECT: it establishes that the risk is expected in this band, not that any PEX2
        patient has developed it.
  - target: Sensorineural hearing impairment
    description: >-
      Progressive sensorineural hearing loss, one of the two sensory losses GeneReviews names
      for this band. In the one PEX2 patient followed long enough it appeared in adult life.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Individuals with intermediate/milder ZSD do not have congenital malformations, but
        rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
        to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
        polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
        renal oxalate stones.
      explanation: >-
        Attributes the sensory loss of this band to progressive peroxisome dysfunction.
        INDIRECT: the mechanism between the metabolic lesion and cochlear failure is not
        stated, and the sentence is spectrum-level rather than PEX2-specific.
  - target: Retinal dystrophy
    description: >-
      Retinal dystrophy, the second of the two sensory losses, and likewise late at this locus.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Individuals with intermediate/milder ZSD do not have congenital malformations, but
        rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
        to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
        polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
        renal oxalate stones.
      explanation: >-
        The same sentence, for the retinal half of the sensory loss. INDIRECT for the same
        reasons.
  - target: Cataract
    description: >-
      Lens opacity, which the management review groups with retinopathy and glaucoma as the
      typical ocular involvement of the spectrum. Band-level, like the retinal dystrophy edge
      above, and not observed in a PEX2 patient in any source cited here.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26627182
      reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Sensorineural deafness and ocular abnormalities like retinopathy, cataracts and glaucoma
        are typical
      explanation: >-
        Places cataract among the typical ocular findings of the Zellweger spectrum, alongside
        the retinopathy and deafness this node already carries edges for. INDIRECT because the
        statement is about the spectrum rather than about PEX2, and because no intermediate step
        between the peroxisomal lesion and the lens is given.
  - target: Amelogenesis imperfecta
    description: >-
      Enamel defect of the secondary dentition, the most consistently reported non-neurological
      feature of this band.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
      explanation: >-
        Places the enamel defect in this band and gives its frequency there. INDIRECT: no
        mechanism linking the peroxisomal lesion to amelogenesis is stated, and no PEX2
        patient is reported with it.
  - target: Osteopenia
    description: Reduced bone mineral density, reported in some individuals in this band.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
      explanation: >-
        The weaker of the two frequency claims in that sentence, recorded so the contrast the
        source draws is preserved on the edge as well as on the phenotype.
  - target: Hypotonia
    description: >-
      Hypotonia, typical of this band but absent from the PEX2 ataxic patients, whose early
      development was normal.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "While hypotonia and developmental delays are typical, intellect can be normal."
      explanation: >-
        The band-level expectation. INDIRECT, and quoted with its qualifier so the edge does
        not read as a claim that every patient in this entry is hypotonic.
  - target: Global developmental delay
    description: >-
      Developmental delay, typical of this band and absent from the ataxic subtype of this entry.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "While hypotonia and developmental delays are typical, intellect can be normal."
      explanation: >-
        The same band-level sentence, whose second clause is the one that matters here:
        preserved intellect does not exclude the diagnosis.
  - target: Calcium oxalate nephrolithiasis
    description: >-
      Renal oxalate stones, a consequence of failed peroxisomal glyoxylate detoxification, and
      the surveillance item most easily forgotten in a patient whose presentation is neurological.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Annual urine oxalate-to-creatinine ratio with consideration of kidney imaging when
        performing liver imaging.
      explanation: >-
        The surveillance item for this complication. INDIRECT for the same reason as the
        adrenal edge: it records an expected risk in the band rather than an observed PEX2
        finding.

phenotypes:
- category: Neurologic
  name: Ataxia
  subtype: Ataxic form
  description: >-
    Cerebellar ataxia, the presenting and dominant feature of this entry's better documented
    subtype. Onset is in childhood in two of the three reported patients - three and a half
    years in one brother, three years in the Italian patient - and in adolescence in the
    third, at eighteen. Progression is slow enough that the brothers were walking unaided at
    fourteen and the Italian patient was ambulant at fifty-one.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two brothers are described who developed progressive cerebellar ataxia at 3 1/2 and 18 years, respectively."
    explanation: >-
      Both the age range and the progressive course recorded on this binding, in the founding
      report of the presentation.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebellar ataxia exacerbated slowly up to the age of 14 years but he was still able to
      walk without support.
    explanation: >-
      The rate of progression in the younger brother, quoted because "slowly progressive" is
      a claim the entry makes repeatedly and this is the sentence that measures it.
- category: Neurologic
  name: Cerebellar atrophy
  subtype: Ataxic form
  description: >-
    Cerebellar atrophy on MRI, in the reported patients involving the vermis and the lateral
    hemispheres and, in the oldest, the cerebellar peduncles and bulbar olives. White matter
    is spared, which is the imaging finding that separates this entry from the
    leukodystrophic presentations of the spectrum.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed marked atrophy of the subtentorial regions including cerebellum,
      cerebellar peduncles, and bulbar olives, and showed moderate atrophy of the
      supratentorial regions of the brain
    explanation: >-
      The fullest description of the imaging phenotype, in the oldest reported patient. Note
      that it extends beyond the cerebellum, which the younger patients' scans did not.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 9 years, a brain MRI showed atrophy of the vermis and lateral hemispheres
      of the cerebellum that worsened at the age of 14 years, but without signs of
      demyelination or neuronal migration defects in forebrain and cerebellum
    explanation: >-
      Serial imaging in the same child, which is the basis for the PROGRESSIVE course on this
      binding rather than an inference from the clinical course.
- category: Neurologic
  name: Dysarthria
  subtype: Ataxic form
  description: >-
    Cerebellar dysarthria. In the younger brother it was the first noticed sign, at about
    two and a half years, a year before the gait disturbance.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His milestones were normal but mild dysarthria was noticed at 2 1/2 years."
    explanation: >-
      The earliest recorded sign in any patient in this entry, and the pediatric point that
      normal early milestones do not exclude it.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and
      bilateral pes cavus.
    explanation: An unrelated adult patient with the same sign.
- category: Neurologic
  name: Dysmetria
  subtype: Ataxic form
  description: Limb dysmetria, part of the cerebellar syndrome in both reported families.
  phenotype_term:
    preferred_term: Dysmetria
    term:
      id: HP:0001310
      label: Dysmetria
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and
      bilateral pes cavus.
    explanation: The examination finding in the reported adult patient.
- category: Neurologic
  name: Nystagmus
  subtype: Ataxic form
  description: >-
    Gaze-evoked nystagmus in the adult patient, and nystagmus with slow saccades in the
    younger of the two brothers. Reported with oculomotor apraxia in the older brother,
    which is a differential-diagnostic trap because it points towards the ataxias with
    oculomotor apraxia.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On admission to our Department, neurological examination showed gait ataxia, lateral
      and vertical gaze-evoked nystagmus, hypoacusia, mild dysarthria, slight dysmetria,
      generalized areflexia, and bilateral pes cavus.
    explanation: The oculomotor findings in the adult patient.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had truncal ataxia, moderate cerebellar tremor, mild scanning dysarthria,
      nystagmus, slow saccades without oculo-motor apraxia and hyporeflexia.
    explanation: >-
      The same sign in an unrelated child, with the explicit note that oculomotor apraxia was
      absent - the older brother's had it, so the sign is inconsistent within one family.
- category: Neurologic
  name: Areflexia
  subtype: Ataxic form
  description: >-
    Generalised loss of tendon reflexes in the adult patient; hyporeflexia rather than
    areflexia in the two brothers. The combination of cerebellar ataxia with reduced reflexes
    is the clinical signature the reporting authors propose as the trigger for peroxisomal
    testing.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 51-year-old Italian man was referred to us because of a clinical picture
      characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset
      and slowly progressive course.
    explanation: >-
      Areflexia named as one of the four cardinal features of the reported presentation.
- category: Neurologic
  name: Peripheral axonal neuropathy
  subtype: Ataxic form
  description: >-
    Axonal sensorimotor polyneuropathy on nerve conduction studies. It is not obligatory and
    it appears late: nerve conduction was normal in both brothers at nine, fourteen and
    eighteen years, and severe in the patient studied at fifty-one.
  phenotype_term:
    preferred_term: Axonal sensorimotor polyneuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies indicated a severe axonal sensorimotor polyneuropathy."
    explanation: The electrophysiological finding this binding records.
- category: Musculoskeletal
  name: Pes cavus
  subtype: Ataxic form
  description: Bilateral pes cavus in the adult patient with the severe axonal neuropathy.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and
      bilateral pes cavus.
    explanation: The examination finding in the one patient in whom it is reported.
- category: Ophthalmologic
  name: Strabismus
  subtype: Ataxic form
  description: Strabismus, one of the four presenting features in the reported adult patient.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 51-year-old Italian man was referred to us because of a clinical picture
      characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset
      and slowly progressive course.
    explanation: Strabismus named among the presenting features.
- category: Otologic
  name: Sensorineural hearing impairment
  description: >-
    Sensorineural hearing loss, which at this end of the spectrum is late and acquired rather
    than congenital: audiometry and brainstem auditory evoked potentials were normal in both
    brothers into the mid-teens, and hearing loss appeared in the Italian patient between the
    third and fifth decades. It is deliberately left unscoped by subtype, because it belongs
    both to the ataxic form on the strength of that patient and to the neonatal
    adrenoleukodystrophy / infantile Refsum presentation on the strength of the
    spectrum-general literature.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Between the third and the fifth decades, bilateral hypoacusia and initial retinopathy were detected."
    explanation: >-
      The only PEX2-specific dating of the sensory loss in this entry, and the basis for
      calling it late and progressive rather than congenital.
  - reference: PMID:14630978
    reference_title: "Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common to PBDs are liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness."
    explanation: >-
      The class-level statement, quoted from the paper that reported the mildly affected
      complementation group 10 patient. It is a statement about peroxisome biogenesis
      disorders generally, not about this severity band, and is used only to place hearing
      loss among the expected features.
- category: Ophthalmologic
  name: Retinal dystrophy
  description: >-
    Retinopathy, also late in the ataxic form: fundoscopy and electroretinography were normal
    in both brothers at nine and fourteen years, and retinopathy was first detected in the
    Italian patient between the third and fifth decades. Like the hearing loss, it is left
    unscoped by subtype.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Between the third and the fifth decades, bilateral hypoacusia and initial retinopathy were detected."
    explanation: >-
      The PEX2-specific observation, and the reason the binding carries a progressive course.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations, but
      rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
      to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
      polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
      renal oxalate stones.
    explanation: >-
      GeneReviews' account of sensory loss in the band this entry occupies. Spectrum-general
      rather than PEX2-specific, and marked OTHER because GeneReviews is an expert synthesis
      rather than a primary study.
- category: Neurologic
  name: Cognitive impairment
  description: >-
    Cognition is normal or near-normal across the reported PEX2 mild-band patients, and this
    record exists to say so rather than to assert a deficit. Full-scale IQ was 75 and 80 in
    the two brothers - the lower end of the normal range - and the adult patient had no
    cognitive impairment at fifty-one. A clinician using preserved intellect to exclude a
    peroxisome biogenesis disorder would be wrong; that is the diagnostic point.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic features, cognitive impairment, and seizures were absent."
    explanation: >-
      A recorded negative in the oldest reported patient. Marked REFUTE because it
      contradicts the claim that cognitive impairment is a feature of this entry, which is
      what this phenotype record exists to settle.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had truncal ataxia, moderate cerebellar tremor, mild scanning dysarthria, nystagmus,
      slow saccades without oculo-motor apraxia and hyporeflexia. His total ataxia score
      evaluated by the International Cooperative Ataxia Rating Scale (ICARS) was 17/100. He
      had no other neurological symptoms and his physical examination was normal. Cerebellar
      ataxia exacerbated slowly up to the age of 14 years but he was still able to walk
      without support. The ICARS score was 33/100. No other neurological signs were present
      and cognitive function remained normal.
    explanation: >-
      Cognitive function explicitly preserved over five years of follow-up in the younger
      brother, despite his ataxia score doubling. Quoted at length because the contrast
      between the two trajectories in one patient is the point.
- category: Hepatic
  name: Hepatic dysfunction
  subtype: NALD-IRD
  description: >-
    Liver disease, which across the Zellweger spectrum ranges from raised transaminases and
    coagulopathy to fibrosis and cirrhosis. It is not reported in any of the three PEX2
    mild-band patients curated here - liver enzymes were explicitly normal in the younger of
    the two ataxic brothers - so this record states an expected complication of the band
    rather than an observed PEX2 feature.
  phenotype_term:
    preferred_term: Liver dysfunction
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations, but
      rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
      to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
      polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
      renal oxalate stones.
    explanation: >-
      GeneReviews' description of the band this subtype occupies. It is a statement about the
      intermediate and milder Zellweger spectrum as a whole, not about PEX2, and no PEX2
      patient in the sources cited here is reported with this feature - which is why the
      record is scoped to the NALD-IRD subtype and carries no frequency.
- category: Endocrine
  name: Adrenal insufficiency
  subtype: NALD-IRD
  description: >-
    Adrenocortical insufficiency. As with the liver disease, this is the band-level
    expectation that drives surveillance - annual ACTH and cortisol from the first year of
    life - and not an observed finding in any PEX2 mild-band patient cited here.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations, but
      rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
      to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
      polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
      renal oxalate stones.
    explanation: >-
      GeneReviews' description of the band this subtype occupies. It is a statement about the
      intermediate and milder Zellweger spectrum as a whole, not about PEX2, and no PEX2
      patient in the sources cited here is reported with this feature - which is why the
      record is scoped to the NALD-IRD subtype and carries no frequency.
- category: Renal
  name: Calcium oxalate nephrolithiasis
  subtype: NALD-IRD
  description: >-
    Renal stones of calcium oxalate, reflecting loss of the peroxisomal glyoxylate
    detoxification that is also lost in primary hyperoxaluria type 1. Band-level rather than
    PEX2-observed; it is the reason an annual urine oxalate-to-creatinine ratio belongs in the
    surveillance schedule of a child with this diagnosis.
  phenotype_term:
    preferred_term: Renal oxalate stones
    term:
      id: HP:0008672
      label: Calcium oxalate nephrolithiasis
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations, but
      rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
      to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
      polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
      renal oxalate stones.
    explanation: >-
      GeneReviews' description of the band this subtype occupies. It is a statement about the
      intermediate and milder Zellweger spectrum as a whole, not about PEX2, and no PEX2
      patient in the sources cited here is reported with this feature - which is why the
      record is scoped to the NALD-IRD subtype and carries no frequency.
- category: Neurologic
  name: Leukodystrophy
  subtype: NALD-IRD
  description: >-
    Progressive white-matter disease, one of the three neurologic involvements GeneReviews
    names for the intermediate and milder band. It is scoped to the NALD-IRD subtype on
    purpose and is the feature that most sharply separates the two subtypes of this entry: the
    ataxic form is defined in part by its absence, with both reported PEX2 families showing
    cerebellar atrophy and explicitly normal white matter on MRI. Band-level rather than
    PEX2-observed.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital malformations, but
      rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary
      to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia,
      polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and
      renal oxalate stones.
    explanation: >-
      GeneReviews names leukodystrophy among the neurologic involvements of the intermediate
      and milder band this subtype occupies. INDIRECT because the statement is about the
      Zellweger spectrum as a whole and no PEX2 patient cited here has white-matter change -
      the two reported families are expressly reported without it.
- category: Ophthalmologic
  name: Cataract
  subtype: NALD-IRD
  description: >-
    Lens opacity, one of the ocular abnormalities the Zellweger spectrum management literature
    groups with retinopathy and glaucoma as typical and often missed at first presentation.
    Band-level rather than PEX2-observed; it is recorded because it is part of the
    ophthalmologic examination a child with this diagnosis is entered into surveillance for.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Sensorineural deafness and ocular abnormalities like retinopathy, cataracts and glaucoma
      are typical
    explanation: >-
      The management review's statement that cataract is a typical ocular finding of the
      spectrum, which is why it is carried as a surveillance target. The quote is trimmed at a
      line break in the cached full text; the same sentence goes on to warn that these findings
      are not always recognised at first presentation. INDIRECT because it is a spectrum-level
      statement and no PEX2 patient cited here is reported with cataract.
- category: Dental
  name: Amelogenesis imperfecta
  subtype: NALD-IRD
  description: >-
    Defective enamel of the secondary dentition, which GeneReviews reports in almost all
    individuals in this band. It is the one feature of the multisystem set that is described
    as near-universal rather than variable, and it is the reason six-monthly dental review sits
    in the surveillance schedule. Not reported in any PEX2 patient cited here.
  phenotype_term:
    preferred_term: Amelogenesis imperfecta of the secondary dentition
    term:
      id: HP:0000705
      label: Amelogenesis imperfecta
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
    explanation: >-
      GeneReviews' frequency statement for the band, quoted with its own misspelling intact
      because a snippet does not correct its source. The frequency is band-level and is not
      transferred to PEX2 as a rate.
- category: Musculoskeletal
  name: Osteopenia
  subtype: NALD-IRD
  description: >-
    Reduced bone mineral density, reported in some individuals in this band. GeneReviews
    contrasts it explicitly with the enamel defect - "some" against "almost all" - so the two
    are not equally expected. Not reported in any PEX2 patient cited here.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
    explanation: >-
      The same sentence, quoted for the weaker of its two frequency claims. Recording both
      from one sentence keeps the contrast the source draws.
- category: Neurologic
  name: Hypotonia
  subtype: NALD-IRD
  description: >-
    Hypotonia, which GeneReviews calls typical for the band together with developmental delay.
    It is absent from the PEX2 ataxic patients, whose early milestones were normal, which is
    the distinction between the two subtypes of this entry.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While hypotonia and developmental delays are typical, intellect can be normal."
    explanation: >-
      GeneReviews' statement for the intermediate and milder band, quoted whole so the
      qualifier travels with the claim: hypotonia and delay are typical, and preserved
      intellect is still compatible with the diagnosis.
- category: Neurodevelopmental
  name: Global developmental delay
  subtype: NALD-IRD
  description: >-
    Developmental delay, typical of the band but not of the ataxic subtype of this entry,
    whose patients had normal milestones and full-scale IQs in or near the normal range.
    Recorded so the two subtypes are not read as one.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While hypotonia and developmental delays are typical, intellect can be normal."
    explanation: >-
      The band-level statement. Its second clause is the one that matters for this entry:
      preserved intellect does not exclude the diagnosis, which is exactly what the PEX2
      ataxic patients show.
  - reference: PMID:14630978
    reference_title: "Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common to PBDs are liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness."
    explanation: >-
      The class-level statement from the paper reporting the mildly affected complementation
      group 10 patient. It covers peroxisome biogenesis disorders generally, and the word
      "variable" is the operative one.

progression:
- phase: Childhood or adolescent onset, slow progression, survival to middle age
  notes: >-
    The prognostic fact that separates this entry from peroxisome biogenesis disorder 5A,
    where infants typically die in the first year. In the ataxic form first symptoms appear
    between about two and a half and eighteen years, progression is slow, and the oldest
    reported patient was ambulant and independent at fifty-one. That trajectory is drawn from
    three patients in two families and should be read as the reported experience, not as a
    prognosis that can be quoted to a family.
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, born at term with normal birth weight and Apgar scores, developed normally
      until 3 years of age, when unsteady walking and frequent falls were noticed.
    explanation: >-
      The pediatric onset in the oldest reported patient, and the normal neonatal course that
      precedes it - which is the observation that keeps this entry out of the neonatal band.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Motor disturbances progressed very slowly during childhood and adolescence without
      impairing his daily activities.
    explanation: >-
      The rate of progression through the childhood years, in the one patient followed to
      middle age.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His older brother (P2) had normal neurologic examination at 14 years, but at the age of
      18 years he started to develop cerebellar signs with impaired gait, dysmetria, ataxia of
      the trunk, dysarthria, hyporeflexia and slow saccades with oculomotor apraxia.
    explanation: >-
      The other end of the onset range, in a sibling with the same genotype - a fourteen-year
      difference in age at onset within one family, which is why this entry does not offer an
      expected age of onset.
genetic:
- name: PEX2
  gene_term:
    preferred_term: PEX2
    term:
      id: hgnc:9717
      label: PEX2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  review_notes: >-
    PEX2, formerly PXMP3 and originally named peroxisome assembly factor-1, was the first
    human peroxin gene identified, cloned by functional complementation of Zellweger
    fibroblasts in 1992. It defines complementation group F in the Japanese series and
    complementation group 10 in the North American one. The alleles reported in this mild
    band are p.Glu55Lys opposite p.Arg119X in an infantile Refsum disease patient,
    c.865_866insA (p.Ser289LysfsX36) homozygous in two ataxic brothers and opposite
    p.Arg119X in an unrelated ataxic adult, and homozygous p.Trp223X in a mildly affected
    patient of the complementation group 10 series. The last of those is a nonsense allele
    at the mild end, which is why this entry does not claim that allele class alone predicts
    the band.
  evidence:
  - reference: PMID:1546315
    reference_title: "A human gene responsible for Zellweger syndrome that affects peroxisome assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A human complementary DNA has been cloned that complements the disease's symptoms
      (including defective peroxisome assembly) in fibroblasts from a patient with Zellweger
      syndrome.
    explanation: >-
      The original identification of the gene, by functional complementation. Quoted from the
      primary report rather than from a review.
  - reference: CGGV:assertion_17bf1c4a-1775-40c6-a499-774c93827343-2020-02-07T170000.000Z
    reference_title: "PEX2 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In summary, PEX2 is definitively associated with autosomal recessive peroxisomal biogenesis disorder."
    explanation: >-
      ClinGen's Peroxisomal Disorders Gene Curation Expert Panel classifies the relationship
      as Definitive. The assertion is against the grouping concept MONDO:0019234 peroxisome
      biogenesis disorder, so it establishes the gene-disease relationship for the locus and
      not for this severity band.
  - reference: PMID:11330043
    reference_title: "Temperature sensitivity in peroxisome assembly processes characterizes milder forms of peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified heterozygous mutations E55K/R119Stop in the PEX2 gene of an IRD patient
      of complementation group F.
    explanation: >-
      The genotype of the infantile Refsum disease patient, and the complementation group
      assignment PEX2 disease was first reached through. Quoted from the companion report by
      the same group because it states both facts in one sentence.
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, because the c.865_866insA mutation introduces a frameshift 17 codons upstream
      of the stop codon, resulting in a PEX2 protein with an altered C-terminus
      (p.Ser289LysfsX36), it is very unlikely that it could be a non-pathogenic variation
      occurring in the normal population.
    explanation: >-
      The variant that recurs across both reported ataxic families, with the authors' own
      pathogenicity reasoning. Their hedge about the untested paternal allele is recorded in
      the entry notes rather than dropped.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the PXMP3 (PEX2) gene (reference sequence NM_000318.2) identified
      two heterozygous mutations
    explanation: >-
      The compound heterozygous configuration in the unrelated adult patient. The two alleles
      are the Zellweger nonsense variant p.Arg119X and the same C-terminal frameshift carried
      by the two brothers; the published sentence naming them carries a typographical degree
      sign in the cDNA position, so the shorter clause is quoted and the alleles are named in
      review_notes instead.
  - reference: PMID:10652207
    reference_title: "Molecular mechanism of detectable catalase-containing particles, peroxisomes, in fibroblasts from a PEX2-defective patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that the two putative membrane-spanning segments in Pex2p are important
      domains for peroxisome assembly and import and that a defect in one of these domains
      severely affects PBD patients.
    explanation: >-
      The other half of the domain rule, stated as the authors' proposal: a lesion in a
      membrane-spanning segment is severe, where one in the cytosolic C-terminal region is
      mild. Their "We propose" is preserved.
  - reference: PMID:14630978
    reference_title: "Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The third patient had a homozygous mutation leading to the absence of the zinc-binding
      domain (W223X) and the fourth patient had a homozygous mutation leading to the change of
      the second cysteine residue of the zinc-binding domain (C247R).
    explanation: >-
      The two homozygous zinc-binding-domain genotypes whose severities ran opposite to
      expectation - the truncating allele mild, the missense allele severe - which is the
      evidence against reading allele class as a severity rule.
  - reference: PMID:40621817
    reference_title: "Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We identified a severity spectrum for PEX2 and PEX16 alleles, with some missense
      mutations exhibiting severity comparable to truncations. Alleles linked to mild PBD
      showed partial rescue, while variants associated with atypical ataxia could fully
      rescue.
    explanation: >-
      A functional ordering of the specific PEX2 alleles curated here, assayed by humanised
      Drosophila rescue. MODEL_ORGANISM: the measurement is in flies expressing the human
      alleles, and it supports the residual-function account rather than establishing it in
      patients.
biochemical:
- name: Plasma branched-chain fatty acids
  context: >-
    Phytanic and pristanic acid are the analytes that led to the diagnosis in the ataxic
    form, and they moved when the very-long-chain fatty acids did not.
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma VLCFAs were nearly normal in patients P1 and P2, but a moderate increase in the
      levels of phytanic and pristanic acids was found, prompting us to suspect a peroxisomal
      disorder
    explanation: >-
      The abnormality that opened the diagnosis, and the normal result that would have closed
      it if the branched-chain fatty acids had not been measured.
  notes: >-
    A raised pristanic acid with a pristanic/phytanic ratio above one first suggested
    alpha-methylacyl-CoA racemase deficiency in the ataxic brothers, and had to be excluded
    by isomer analysis and enzyme assay before the peroxin genes were sequenced. That is a
    real diagnostic detour, not a theoretical one.
- name: Plasma very-long-chain fatty acids
  context: >-
    The screening test for the Zellweger spectrum, and the one that is unreliable at this end
    of it. Nearly normal in the two ataxic brothers, raised in the unrelated adult patient.
  evidence:
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of plasma peroxisomal parameters revealed increased levels of very long chain
      fatty acids (VLCFAs), branched-chain fatty acids (pristanic and phytanic acid), and bile
      acid intermediates, prompting us to suspect a peroxisomal disorder.
    explanation: >-
      The patient in whom the very-long-chain fatty acids were raised, quoted alongside the
      contrary result in the brothers so the record shows both.
  notes: >-
    A normal plasma very-long-chain fatty acid concentration does not exclude a mild PEX2
    genotype: it was nearly normal in both reported ataxic brothers. Request phytanic acid,
    pristanic acid and the C27 bile-acid intermediates alongside it, and do not treat a normal
    screen as an answer.
- name: Cultured fibroblast peroxisomal assays
  context: >-
    The confirmatory panel - plasmalogen synthesis, DHAPAT activity, very-long-chain fatty
    acid and pristanic acid beta-oxidation, phytanic acid alpha-oxidation - which at this end
    of the spectrum can be almost entirely normal in a patient who has the disease.
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Taken together, those analyses pointed towards a mild peroxisomal defect, but did not
      clearly indicate at which level.
    explanation: >-
      The authors' reading of a near-normal fibroblast panel, and the reason they went on to
      sequence three candidate peroxin genes rather than stopping.
  notes: >-
    The corollary for practice: in a patient with unexplained recessive cerebellar ataxia and
    a suggestive plasma profile, a normal fibroblast panel is not an exclusion, and sequencing
    is the route to the diagnosis.
diagnosis:
- name: Targeted plasma peroxisomal metabolite panel
  description: >-
    Plasma very-long-chain fatty acids with phytanic acid, pristanic acid and the C27
    bile-acid intermediates DHCA and THCA. Cheap, widely available, and the step that
    identified the disorder in every reported patient in this entry - but only because the
    branched-chain species were requested alongside the very-long-chain fatty acids.
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systematic screening for such PEX gene defect can easily and reliably be performed by
      the simple measurement of peroxisomal metabolites in plasma and will probably increase
      the frequency of PBD patients with mild phenotypes such as ARCA.
    explanation: >-
      The authors' proposal for how this diagnosis is reached, and their prediction that the
      mild band is under-ascertained.
- name: PEX gene sequencing
  description: >-
    Sequencing of the peroxin genes, which is what confirms the diagnosis. In both reported
    families the metabolite profile pointed to a peroxisomal defect without localising it, and
    the biochemical assays could not narrow it further, so molecular testing was not a
    confirmation of a biochemical answer but the source of the answer.
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic screening of PEX2 and other PEX genes involved in peroxisomal biogenesis is
      warranted in children and adults with ARCA.
    explanation: >-
      The recommendation this record implements, stated for both children and adults - the
      age range this entry spans.
  - reference: PMID:23430938
    reference_title: "Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peroxisomal mosaicism with a mixed population of fibroblasts with and without peroxisomes
      persisted at 40°C, making systematic sequencing of the different PEX genes necessary.
    explanation: >-
      Why the cell-biological work-up did not substitute for sequencing in this patient: the
      temperature-shift assay that identifies many mild genotypes did not resolve his.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of ZSD is established in a proband with the suggestive clinical and
      biochemical findings above by identification of biallelic pathogenic variants in one of
      the 13 known ZSD-PEX genes.
    explanation: >-
      GeneReviews' diagnostic criterion for the spectrum, which is what makes biallelic PEX
      variant identification the confirmatory test rather than a supporting one. Quoted
      because it states the role this record plays; OTHER because GeneReviews is an expert
      consensus chapter rather than a study.
treatments:
- name: Symptomatic and supportive management
  description: >-
    There is no disease-modifying therapy. For this band management is dominated by the motor
    and sensory consequences - rehabilitation for the ataxia and neuropathy, hearing aids,
    refractive correction, fat-soluble vitamin supplementation - rather than by the neonatal
    problems that dominate the severe band.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    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 for the spectrum. The list is spectrum-wide;
      gastrostomy in particular belongs to the severe band and not to this entry. The modality
      is OTHER because the row spans devices, surgery and supplementation.
- name: Cholic acid supplementation
  description: >-
    Bile-acid replacement, given because peroxisomal bile-acid synthesis is impaired and the
    C27 intermediates that accumulate are hepatotoxic. It is the only approved therapy for the
    Zellweger spectrum. Two limits belong on the claim: the evidence is spectrum-wide rather
    than PEX2-specific, and it is directed at liver disease, which is not what dominates the
    reported PEX2 mild-band patients - so nothing here says it alters the cerebellar disease
    that defines this entry.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:34521419
    reference_title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015,
      is currently the only therapy approved as adjunctive treatment for patients with ZSDs and
      single enzyme bile acid synthesis disorders.
    explanation: >-
      The regulatory status of the one approved therapy. INDIRECT for this entry: the approval
      is for the spectrum, and no outcome in a PEX2 mild-band patient is reported anywhere in
      the sources cited here.
  - reference: PMID:34521419
    reference_title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      This review will focus on the use of CA therapy in the treatment of liver disease
      associated with ZSDs, including recommendations for initiating and maintaining CA therapy
      and the limitations of available clinical data supporting its use in this patient
      population.
    explanation: >-
      The target of the therapy - liver disease - and the reviewers' own acknowledgement that
      the supporting clinical data are limited. Quoted rather than summarised so the caveat
      travels with the claim.
- name: Multidisciplinary surveillance
  description: >-
    Scheduled monitoring rather than treatment, and the part of management that matters most
    in a slowly progressive disorder where the sensory losses arrive decades after the ataxia.
    For a child diagnosed in this band the practical core is annual audiology and
    ophthalmology, liver function and liver imaging, an annual urine oxalate-to-creatinine
    ratio, adrenal function from the first year, six-monthly dental review, and developmental
    and educational follow-up.
  treatment_term:
    preferred_term: multisystem surveillance schedule
  therapeutic_modality: OTHER
  notes: >-
    Deliberately left unbound; the meaning is carried in preferred_term. TreatmentActionTerm
    is rooted at NCIT:C25218 Clinical Intervention or Procedure. Searching NCIT through the
    OLS search API for "surveillance" and for "monitoring" returns NCIT:C15719 Surveillance,
    NCIT:C53607 Patient Monitoring and NCIT:C61256 Monitoring; asking the local NCIT build
    for each one's is-a ancestors returns no NCIT:C25218 among them, so none is a legal value
    for this slot. NCIT:C15419 Disease Screening is reachable from that root and is what this
    repository uses for screening treatments elsewhere, but it names screening an unselected
    population for an undiagnosed disease, which is not what this record describes - here the
    diagnosis is already made and the schedule looks for its complications.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Annual audiology and ophthalmologic evaluations; annual monitoring of liver function and
      coagulation factors, and ultrasound and/or fibroscan to evaluate liver architecture;
      monitor for changes in seizure activity; head MRI to evaluate for white matter changes
      that may explain changes in cognitive and/or motor ability; monitor developmental
      progress and educational needs; ACTH and cortisol levels by age one year and annually
      thereafter.
    explanation: >-
      The GeneReviews surveillance schedule for the spectrum, which is the only sourced
      schedule available for this entry. It is written for the spectrum as a whole, so parts of
      it - seizure monitoring in particular - address problems not reported in the PEX2 mild
      band.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dental examinations every six months. Annual urine oxalate-to-creatinine ratio with
      consideration of kidney imaging when performing liver imaging.
    explanation: >-
      The two surveillance items most easily forgotten in a patient whose presentation is
      neurological: the enamel defect of the secondary dentition and renal oxalate stones.
- name: Dietary phytanic acid restriction
  description: >-
    Restriction of dietary phytanic acid, on the reasoning that phytanic acid is exclusively
    of dietary origin and is one of the two branched-chain species that accumulate in this
    entry. The Zellweger spectrum management literature does not recommend it generally: it
    is reserved for extremely high phytanic acid levels and is explicitly advised against
    when levels are only moderately raised, because maintaining caloric intake matters more.
    The PEX2 patients cited here are reported only as having increased branched-chain fatty
    acids, with no statement that phytanic acid reaches the extreme level at which the review
    indicates restriction, and no outcome of this intervention is reported in any of them. For
    this entry it is therefore a conditional option rather than a therapy of demonstrated
    benefit.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:26627182
    reference_title: "Zellweger spectrum disorders: clinical overview and management approach."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      A phytanic acid restricted diet is only necessary when levels of phytanic acid are
      extremely high and is not recommended when levels are moderately increased
    explanation: >-
      The Zellweger spectrum management review's actual statement on phytanic acid
      restriction, which both establishes the intervention as a recognised option and
      supplies the threshold that keeps it conditional. INDIRECT because it is stated for the
      spectrum rather than for PEX2, and OTHER because the source is an expert management
      review rather than a study.
clinical_trials:
- name: NCT06190626
  phase: NOT_APPLICABLE
  description: >-
    Longitudinal observational natural-history study of the retinal degeneration of Zellweger
    spectrum disorder, set up to define its course, to work out which tests best track
    progression, and to produce prognostic information about vision loss. It enrolls at
    spectrum level rather than by complementation group, so it is relevant to this entry
    through the retinal dystrophy the milder band carries rather than through PEX2
    specifically. NOT_APPLICABLE because it is observational and follows no FDA phase.
  target_phenotypes:
  - preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  notes: >-
    Recruitment status is absent because it is not sourceable from the cached record: the
    ClinicalTrials.gov entry for this study holds only its summary text, with no
    overall-status field, so no value is asserted.
  evidence:
  - reference: clinicaltrials:NCT06190626
    reference_title: "Longitudinal Prospective Natural History Study of Retinopathy in Zellweger Spectrum Disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this observational study is to define the course of the retinal degeneration
      in a ZSD patient cohort.
    explanation: >-
      The registered objective, which is what makes this study relevant to the retinal
      dystrophy this entry records for the intermediate and milder band.
differential_diagnoses:
- name: Peroxisome biogenesis disorder 5A (Zellweger)
  description: >-
    The severe band at the same locus. Separated not by gene but by residual peroxin-2
    function, and in practice by congenital malformations and death in the first year of life.
    It is not curated in this repository.
  distinguishing_features:
  - Congenital malformations - neuronal migration defect, renal cysts, epiphyseal stippling
  - Neonatal hypotonia, poor feeding and distinctive facies
  - Death in the first year without developmental progress
  - Absent rather than mosaic peroxisomal matrix-protein import in fibroblasts
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Infants with severe ZSD are significantly impaired and typically die during the first
      year of life, usually having made no developmental progress.
    explanation: The clinical outcome that separates the two bands.
  - reference: PMID:10528859
    reference_title: "Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The nonsense mutation severely affects these peroxisomal functions as well as the protein
      import.
    explanation: >-
      The cellular counterpart of the clinical split, measured at this locus: the allele that
      produces the severe band abolishes what the mild allele preserves in part.
- name: Other autosomal recessive cerebellar ataxias
  description: >-
    The clinical differential this entry is actually met in. A child or adult with progressive
    ataxia, cerebellar atrophy and reduced reflexes is worked up for Friedreich ataxia, ataxia
    telangiectasia and the ataxias with oculomotor apraxia; a peroxisomal biogenesis disorder
    is not on the first list and is missed unless the branched-chain fatty acids are requested.
    Both reported families were tested for Friedreich ataxia and oculomotor apraxia type 1
    before the peroxisomal work-up.
  distinguishing_features:
  - Raised plasma phytanic and pristanic acid, with the pristanic/phytanic ratio above one
  - Raised C27 bile-acid intermediates DHCA and THCA
  - Plasma very-long-chain fatty acids may be near normal
  - Biallelic PEX2 variants on sequencing
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular studies of frataxin and aprataxin genes ruled out Friedrich ataxia and
      cerebellar ataxia with oculomotor apraxia 1 (AOA1).
    explanation: >-
      The specific alternatives excluded before this diagnosis was reached, in the founding
      report.
- name: Alpha-methylacyl-CoA racemase deficiency
  description: >-
    The trap this entry's biochemical profile sets. A raised pristanic acid with a raised
    pristanic/phytanic ratio and normal very-long-chain fatty acids is the classic AMACR
    picture, and it was the first diagnosis considered in the two ataxic brothers.
  distinguishing_features:
  - Distinguished by R- and S-isomer analysis of DHCA and THCA
  - Distinguished by AMACR enzyme activity in fibroblasts
  - Traces of DHCA and THCA also exclude adult Refsum disease
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was ruled out by the measurement of R- and S- isomers of DHCA and THCA in plasma
      and AMACR activity in fibroblasts from P1.
    explanation: >-
      The tests that resolved the misdirection. The preceding sentence in the same paragraph,
      which states that the raised pristanic and phytanic acids with normal very-long-chain
      fatty acids first suggested AMACR deficiency, carries a bracketed citation and is
      therefore paraphrased in this record's description rather than quoted.
- name: Zellweger spectrum disorders of other complementation groups
  description: >-
    The other twelve ZSD-PEX genes produce overlapping phenotypes across the same severity
    range, and mild bands with cerebellar ataxia are described at PEX10, PEX12 and PEX16 as
    well as here. The distinction is molecular and does not change management.
  distinguishing_features:
  - Different causal PEX gene on sequencing
  - Clinically and biochemically overlapping at the same point on the severity range
  - PEX16 mild disease additionally reported with spastic paraparesis, leukodystrophy and cataract
  evidence:
  - reference: PMID:21392394
    reference_title: "Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, these patients displayed additional neurological symptoms including axonal
      motor neuropathy and decreased vibration sense in PEX10- mutated patients and spastic
      paraparesia, leukodystrophy peripheral neuropathy and cataracts in patients with PEX16
      mutation.
    explanation: >-
      The features that were used to tell the neighbouring mild bands apart at the time. The
      preceding sentence, which reports that mild cerebellar-ataxia phenotypes had just been
      shown at PEX10 and PEX16, carries a bracketed citation and is not quoted. Note that the distinction drawn here - an isolated ataxia at PEX2 against an
      ataxia-plus at PEX10 - does not survive the later PEX2 patient, who had a severe
      neuropathy.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the term "ZSD" is now used to refer to all individuals with a defect in one of the
      ZSD-PEX genes regardless of phenotype
    explanation: >-
      The current gene-agnostic framing, which is why the differential between complementation
      groups is molecular rather than clinical.
discussions:
- discussion_id: normal_biochemistry_at_the_mild_end
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Residual Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis
  - biochemical#Plasma very-long-chain fatty acids
  prompt: >-
    How often is the plasma very-long-chain fatty acid screen normal in a patient who
    nevertheless carries a biallelic mild PEX2 genotype, and what proportion of mild PEX2
    disease is therefore missed by a work-up that stops at that test?
  rationale: >-
    Two of the three reported ataxic patients had nearly normal very-long-chain fatty acids,
    and one had a fibroblast panel that was normal on every axis except phytanic acid
    alpha-oxidation. If that is representative, the screening test in routine use has poor
    sensitivity in exactly the band this entry covers - but three patients cannot establish a
    rate, and there is no ascertainment-corrected series to compute one from. The reporting
    authors themselves predicted that systematic metabolite screening would increase the
    apparent frequency of mild disease, which is a statement that the current denominator is
    wrong.
- discussion_id: temperature_sensitivity_is_not_universal
  kind: CONTROVERSY
  attaches_to:
  - pathophysiology#Partial Failure of Peroxisomal Matrix Protein Import
  prompt: >-
    Is temperature-sensitive peroxisome assembly a general property of mild peroxisome
    biogenesis disorder genotypes, or only of a subset that happens to include PEX2 E55K?
  rationale: >-
    The 2000 study found every infantile Refsum disease cell line it tested to be
    temperature-sensitive and concluded that the property characterises the milder forms, with
    PEX2 E55K shown to be its direct cause by transfection. The 2012 PEX2 patient contradicts
    that generalisation: his peroxisomal mosaicism persisted at both 37 and 40 degrees, and his
    authors concluded that the assay did not spare them from sequencing. Both observations are
    in this entry, on the same node, and the entry does not resolve them - the honest reading
    is that temperature sensitivity is allele-dependent rather than band-dependent.
notes: >-
  Lump/split decision: DISEASE, curated as the mild band of the PEX2 allelic series at
  MONDO:0013933, rather than as a has_subtypes row on a PEX2 parent entry or on the Zellweger
  spectrum entry. The basis is precedent plus ontology, and both are stated here rather than
  assumed. Eleven numbered peroxisome biogenesis disorder entries already exist in kb/, and
  two A/B pairs are curated at exactly this granularity as separate Disease entries - 4A/4B
  and 11A/11B - which are the direct analogue of the 5A/5B pair. Peroxisome_Biogenesis_Disorder_1B,
  _2B, _6B and _8B are likewise separate entries. The ontology agrees: MONDO gives 5A
  (MONDO:0013932) and 5B (MONDO:0013933) separate identifiers under the shared PEX2 parent
  MONDO:0100260. Note the asymmetry this leaves: there is no peroxisome biogenesis disorder 5A
  entry in this repository, so the differential row naming it points at a concept the KB does
  not yet hold. The stub is retired accordingly.

  Two existing entries already carry PEX2 content, and this entry neither duplicates nor
  supersedes either. Zellweger_Spectrum_Disorders.yaml holds a PEX2-ZSD has_subtypes row
  bound to the shared parent MONDO:0100260, and Peroxisome_Biogenesis_Disorder.yaml describes
  the gene at class level; both state PEX2's place in the RING-finger ubiquitin ligase complex
  generically, across the whole severity range. What is new here is the severity band - the
  mild-band alleles, the residual-function cell biology, and the clinical picture of patients
  who reach adult life. Where this entry restates the generic molecular account it does so from
  primary sources rather than from those entries.

  Which claims are PEX2-specific and which are spectrum-general. This distinction is the one a
  reader of a B-band entry most needs, and it is not left to inference. PEX2-specific and
  drawn from patients with a proven PEX2 genotype: the ataxia, cerebellar atrophy, dysarthria,
  dysmetria, nystagmus, areflexia, axonal polyneuropathy, pes cavus and strabismus; the
  preserved cognition; the onset range and the slow course; the branched-chain fatty acid and
  fibroblast biochemistry; the peroxisomal mosaicism and catalase-less peroxisomes; and every
  genotype named. Spectrum-general, quoted from GeneReviews or from class-level statements and
  labelled as such on each evidence item: the sensory-loss, liver, adrenal and renal-oxalate
  picture of the intermediate band; the recurrence risk; the management and surveillance
  schedule; and the cholic acid approval. Where the two disagree the PEX2 source is preferred
  and the disagreement is recorded - most visibly on the leukodystrophy, which GeneReviews
  lists for the intermediate band and which both PEX2 ataxic reports explicitly exclude on MRI.

  MONDO and Orphanet both recognise the ataxic form as a named entity -
  MONDO:0957443 / ORPHA:642965 "autosomal recessive ataxia due to PEX2 deficiency", whose
  Orphanet synonym is "mild peroxisomal disorder due to PEX2 deficiency" - and it is bound as
  the subtype_term on that has_subtypes row. Worth flagging rather than passing over: MONDO
  files that class under MONDO:0100309 hereditary ataxia, not under MONDO:0013933, so in the
  ontology the ataxic form is a sibling concept reached from the ataxias rather than a child
  of this entry. This entry treats it as a presentation of PEX2 mild-band disease, which is
  how the primary literature treats it - the two case reports that describe these patients
  both frame them as Zellweger spectrum disorder with a mild phenotype, and one of the two
  alleles reported across those patients, p.Arg119X, is a nonsense variant already reported
  in classic Zellweger syndrome. If a
  future reviewer prefers MONDO's reading, the remedy is a separate entry for MONDO:0957443,
  not a change to this one.

  The NALD-IRD row carries no subtype_term, and that is a searched answer rather than an
  omission. Searching MONDO through the OLS search API for "neonatal adrenoleukodystrophy"
  returns two classes, MONDO:0009919 peroxisomal acyl-CoA oxidase deficiency and
  MONDO:0019234 peroxisome biogenesis disorder, which carry the string as a synonym;
  searching for "infantile Refsum disease" returns only MONDO:0019234. Both are the wrong
  concept here - one is a single-enzyme defect at a different locus, the other the
  whole-class grouping - so binding either would assert something false.

  Phenotype frequencies are deliberately absent from this entry, and that is a decision rather
  than an omission. The reported PEX2 mild band is three patients in two families for the
  ataxic form and a small number of individually reported patients for the neonatal
  adrenoleukodystrophy / infantile Refsum presentation. A percentage computed over three
  patients would be a false precision, and importing the frequencies published for the
  Zellweger spectrum - or for the better-studied PEX10 mild band - would attribute to PEX2
  observations that were never made in PEX2 patients. Where a feature's frequency matters
  clinically, the entry states the count instead: the neuropathy was absent in two patients and
  severe in the third, hearing loss and retinopathy were absent into the mid-teens in two and
  appeared in the third's third to fifth decades.

  The pediatric reading. Onset is in childhood in two of the three ataxic patients, and the
  earliest sign in either family was mild dysarthria at about two and a half years, a year
  before the gait disturbance - so the presenting complaint in a child may be speech rather
  than balance. Early milestones were normal in every reported patient, and the neonatal
  period was unremarkable, which is what keeps these children out of a metabolic work-up. The
  sensory losses that define the older labels of this band arrive decades later at this locus,
  which is an argument for instituting the GeneReviews surveillance schedule at diagnosis in a
  child rather than waiting for symptoms. The fourteen-year difference in age at onset between
  two brothers homozygous for the same allele is the caution to give a family: the genotype
  does not predict when.

  Two hedges from the primary sources are carried rather than dropped. The apparent homozygosity
  for c.865_866insA in the two brothers could not be confirmed, because paternal DNA was
  unavailable and a deletion in trans would look identical; the authors say so themselves. And
  the mildly affected homozygous W223X patient in the complementation group 10 series was
  surprising to the authors who reported him, since a nonsense allele removing the zinc-binding
  domain would be expected to be severe - so this entry does not claim that allele class
  predicts the band, only that residual function does.

  No animal model is curated. A Pex2 knockout mouse exists and is well characterised, but it
  is a null allele modelling classic Zellweger syndrome rather than this band, and no
  model carrying a human mild PEX2 allele in a mammal is reported in the sources cited here.
  The humanised Drosophila work is cited as evidence on the gene record instead of as an animal
  model, because what it measures is allele severity by rescue rather than a recapitulation of
  the human phenotype.

  No treatment in this entry has a reported outcome in a PEX2 patient. Cholic acid has an FDA
  approval and a hepatic rationale, both spectrum-wide; dietary phytanic acid restriction has a
  biochemical rationale and no reported result. Every efficacy-bearing treatment evidence item
  is therefore marked INDIRECT, and nothing here claims an effect on the cerebellar disease that
  defines this band.

  Ataxia is bound to HP:0001251, for which "Cerebellar ataxia" is HPO's own exact synonym; the
  course-qualified HP:0002073 Progressive cerebellar ataxia was considered and not taken, on the
  repository convention of carrying course on clinical_course rather than inside the term. The
  cognitive impairment record is bound to HP:0100543 and carries two REFUTE items, because its
  purpose is to record that cognition is preserved - a negative that matters diagnostically -
  rather than to assert a deficit.

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References & Deep Research