Peroxisome Biogenesis Disorder 6B

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0013937 peroxisome biogenesis disorder 6B

The dismech entry and the MONDO class denote the same entity: the milder, non-classic band of PEX10-related peroxisome biogenesis disorder. The severe band is MONDO:0013936 and is curated separately.

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic PEX10 variants, and specifically genotypes leaving residual peroxin-10 function on at least one allele. Reported patients in the ataxic form are compound heterozygotes combining a missense allele with a second, often truncating, allele.

Autosomal recessive inheritance

Show evidence (2 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.

PMID:28320181 SUPPORT Human Clinical

"All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10."

A worked biallelic genotype in the ataxic form, and the recessive segregation across three affected siblings.

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Subtypes

2

PEX10-related cerebellar ataxia (childhood-onset ataxic form)

Childhood-onset, slowly progressive cerebellar ataxia with axonal polyneuropathy, cognitive impairment and cerebellar atrophy, in patients of otherwise normal or only mildly impaired intellect who reach adult life. This is the presentation that dominates the reported PBD6B literature, and it is the one published explicitly under the PBD6B label.

Show evidence (2 references)

PMID:30640048 SUPPORT Human Clinical

"We identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene."

The sentence that ties the ataxic presentation to the PBD6B label specifically, rather than to PEX10 disease in general. It is the basis for curating the ataxic form inside this entry rather than as a separate concept.

PMID:35038753 SUPPORT Human Clinical

"A literature search yielded 14 similar patients from nine families with PEX10-related cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years of age."

The size and age of onset of the reported population of this subtype. Fourteen patients from nine families is the whole published series, and the reader should have that denominator in mind for every frequency quoted in this entry.

Neonatal adrenoleukodystrophy / infantile Refsum disease presentation

The older phenotype labels for the intermediate band of the Zellweger spectrum: progressive peroxisomal failure with sensory loss, liver dysfunction and developmental delay, but without the congenital malformations of classic Zellweger syndrome. This is the presentation the founding PEX10 genotype-phenotype survey described in its one mildly affected patient.

Show evidence (2 references)

PMID:10862081 SUPPORT Human Clinical

"In contrast, a more mildly affected PEX10-deficient neonatal adrenoleukodystrophy patient expressed a PEX10 allele with a missense mutation, H290Q, affecting the C-terminal zinc-binding domain of the PEX10 product."

The one PEX10 patient carrying the neonatal adrenoleukodystrophy label in the survey that separated the severe from the mild band, and the allele that patient carried. The abstract does not state the patient's sex and neither does this entry.

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 characterisation of the band these older labels describe. Quoted from the spectrum resource rather than from a PEX10 source because no PEX10-specific series describes this presentation in comparable detail.

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Discussions and Knowledge Gaps

2

How often is every standard peroxisomal test - plasma very-long-chain fatty acids and cultured-fibroblast assays - normal in a patient who nevertheless has biallelic PEX10 variants and disease?

KNOWLEDGE GAP normal_biochemistry_at_the_mild_end

Attached to

pathophysiology#Partial Failure of Peroxisomal Matrix Protein Import biochemical#Very-long-chain fatty acid ratios

Two independent observations say the standard screen can be silent at this end of the allelic series: the absolute very-long-chain fatty acid concentration is normal in several of the reported ataxic patients, and one PEX10 patient with clearly abnormal blood metabolites had normal results across multiple peroxisomal pathways in cultured fibroblasts. Neither observation comes with a denominator for false negatives, because both come from patients who were eventually diagnosed. Nobody has counted the patients in whom the screen was normal and the diagnosis was therefore never made, so the true sensitivity of a peroxisomal screen in unexplained recessive ataxia is unknown. That is the number a clinician deciding whether to sequence needs.

Show evidence (2 references)

PMID:19127411 SUPPORT Human Clinical

"Despite the abnormal metabolites detected in blood (phytanate, bile acid intermediates and pipecolate), analysis of multiple peroxisomal pathways in fibroblasts yielded normal results."

A PEX10 patient in whom the fibroblast assays - the reference method for a biogenesis disorder - were entirely normal.

PMID:35038753 SUPPORT Human Clinical

"Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA levels were in normal limits in several patients."

The blood-side version of the same problem: the analyte most laboratories report was normal in several patients who had the disease.

Is the PEX10 ataxic form part of peroxisome biogenesis disorder 6B, or a third band distinct from both 6A and the neonatal adrenoleukodystrophy presentation?

CONTROVERSY where_the_ataxic_form_belongs

Attached to

disease# has_subtypes#Ataxic form

The literature says both things. One group describes PEX10 as causing three subtypes - Zellweger syndrome, neonatal adrenoleukodystrophy and an ataxic form - which reads as a third band alongside, not inside, the 6B concept; the existing dismech entry for peroxisome biogenesis disorder 6A follows that reading and carries the ataxic form as a differential diagnosis. Against that, a published ataxic patient is labelled peroxisome biogenesis disorder 6B by the authors reporting him, and the OMIM concept that MONDO:0013937 maps to covers the milder PEX10 phenotypes generally. This entry takes the second reading, because the A/B pair is a severity split with only two members and an ataxic form that sat outside both would have no ontology class to live in. The consequence is recorded rather than hidden: the ataxic form is curated here as a subtype, and the peroxisome biogenesis disorder 6A entry's differential row describing it now overlaps this entry.

Show evidence (3 references)

PMID:28320181 SUPPORT Human Clinical

"the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild)"

The three-band reading, which treats the ataxic form as its own subtype.

PMID:30640048 REFUTE Human Clinical

"To describe the clinical and genetic features of a Chinese peroxisome biogenesis disorder 6B patient with PEX10 mutations and review PEX10-related peroxisomal disorders."

The competing reading, in which an ataxic patient simply is a peroxisome biogenesis disorder 6B patient. Recorded as refuting the three-band framing above, because the two cannot both be the right way to file this presentation.

PMID:40267090 REFUTE Human Clinical

"The three patients had similar phenotypes of milder PBDs, which were further genetically determined as PBD6B."

A second, independent group assigning milder PEX10 disease to the PBD6B label directly. Recorded on the same side as the sentence above: it treats PBD6B as the home of milder PEX10 disease generally rather than of one named presentation.

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Pathophysiology

5

Biallelic Hypomorphic PEX10 Genotype

Mechanism confidence: Established

Both PEX10 alleles carry variants, but at least one retains partial peroxin-10 function. In the reported ataxic patients these are missense changes, several of them in or adjacent to the C-terminal RING finger, carried opposite a second allele that may itself be severe. The residual-function threshold, not gene identity, is what separates this entry from PBD6A.

Genetic context PEX10 hgnc:8851 variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Missense alleles predominate. Homozygous missense genotypes are also reported at the mild end, so COMPOUND_HETEROZYGOUS records the commoner reported configuration rather than a requirement.

peroxisomal membrane GO:0005778

Downstream

Partial Loss of Peroxin-10 RING Function The reported mild alleles cluster in and around the C-terminal zinc-binding RING module, the part of the protein that carries its function, but alter rather than remove it.

Show evidence (2 references)

PMID:10862081 SUPPORT Human Clinical

"These results support the hypothesis that severe, loss-of-function mutations in PEX genes cause more severe clinical phenotypes, whereas mildly affected PBD patients have PEX gene mutations that retain residual function."

The residual-function account that defines this entry against PBD6A, stated by the survey that assembled both bands.

PMID:27230853 SUPPORT Human Clinical

"With whole exome sequencing, two mutations in PEX10 were found in the three patients: c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the missense change p.Arg311Gln."

A worked mild-band genotype: two missense alleles, in a family whose disease was slowly progressive and compatible with adult life.

Partial Loss of Peroxin-10 RING Function

Mechanism confidence: Established

Peroxin-10 is a peroxisomal membrane protein whose C-terminal C3HC4 zinc-finger RING motif carries its function. A missense change in that module degrades the activity rather than abolishing it, which is the molecular difference between this entry and the severe band.

peroxisomal membrane GO:0005778

Downstream

Partial Failure of Peroxisomal Matrix Protein Import Degraded RING function leaves matrix-protein import partly rather than wholly defective, which is what produces a cell population with some import-competent peroxisomes and some not.

Show evidence (4 references)

PMID:10862081 SUPPORT INDIRECT In Vitro

"Although these results demonstrate serious flaws in the PEX10 functional complementation assay, they do suggest that the C-terminal zinc-binding domain is critical for PEX10 function."

Supports the claim while carrying the authors' own caveat about the assay that produced it. Quoted whole rather than trimmed to the supportive clause. Marked INDIRECT because, with the assay called into question by its own authors, the domain claim rests on the mutational pattern rather than on activity measurements.

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)"

Names the complex peroxin-10's RING domain belongs to, and what it does. Quoted rather than paraphrased because the subunit naming is the load-bearing detail. INDIRECT: the structure was solved in a fungal system, so the human claim rests on conservation.

PMID:35768507 SUPPORT INDIRECT In Vitro

"Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel. The three ring finger domains form a cytosolic tower, with ring finger 2 (RF2) positioned above the channel pore."

The architectural reason a missense change in one RING domain degrades rather than abolishes the assembly: each of the three subunits contributes to a shared channel, and the RING domains sit above its pore. INDIRECT for the same reason as above.

+ 1 more reference

Partial Failure of Peroxisomal Matrix Protein Import

Mechanism confidence: Established

Matrix-protein import is reduced but not abolished. In a patient with the ataxic form this appears in fibroblasts as peroxisomal mosaicism - some peroxisomes importing and some not - together with a catalase import deficiency and abnormal organelle morphology. It is the cellular counterpart of the residual-function genotype, and it is why the biochemical signature in blood is attenuated rather than absent. 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 Metabolic Impairment Fewer import-competent peroxisomes means reduced flux through every peroxisomal pathway at once, rather than the abolition seen in the severe band.

Show evidence (2 references)

PMID:35038753 SUPPORT In Vitro

"Immunohistochemistry confirmed pathogenicity in the patients' cultured fibroblasts demonstrating peroxisomal mosaicism with a general catalase import deficiency as well as conspicuous peroxisome morphology as an expression of impaired peroxisomal function."

The direct cellular observation behind this node, in a patient with the ataxic form. Mosaicism rather than uniform failure is what distinguishes the partial defect from the severe band's empty organelle.

PMID:20695019 SUPPORT In Vitro

"Transfection with wild-type PEX10 corrected the fibroblast phenotype."

A rescue experiment in ataxic-form patient cells, which is what makes the cellular defect attributable to the PEX10 lesion rather than merely coincident with it.

Residual Peroxisomal Metabolic Impairment

Mechanism confidence: Established

Peroxisomal beta-oxidation and phytanic acid handling run below normal without failing. The measurable consequences are a raised phytanic acid and raised very-long-chain fatty acid ratios, against absolute very-long-chain fatty acid concentrations that are often within the reference interval - which is the reason this band is missed on a conventional peroxisomal screen.

very long-chain fatty acid catabolic process GO:0042760 ↓ DECREASED

Downstream

Cerebellar Degeneration The cerebellum is the organ that fails first and hardest in this band. No source cited here traces which lost peroxisomal function is responsible, so the intermediates are recorded as unknown rather than implied.

Peripheral axonal polyneuropathy Length-dependent axonal neuropathy accompanies the cerebellar disease in most reported patients.

Cognitive impairment Cognitive impairment is common but not universal, and several reported patients had normal intelligence.

Sensorineural hearing impairment Hearing loss can precede the ataxia and be the presenting complaint, which is how the diagnosis is most often delayed.

Elevated circulating phytanic acid Phytanic acid alpha-oxidation is peroxisomal, so a partial biogenesis defect raises it directly.

Impaired vibratory sensation Large-fibre sensory loss, measured clinically in the founding ataxia report.

Mydriasis Pupillary autonomic involvement, reported as one of three additional characteristic features in an ataxic-form sibship.

Hyperreflexia Pyramidal involvement in the same sibship.

Retinal dystrophy Part of the progressive sensory loss of the intermediate band. Carried from the spectrum resource rather than from a PEX10 series.

Leukodystrophy White matter disease, part of the neurological picture of the intermediate band.

Adrenal insufficiency Adrenal failure develops progressively rather than presenting at diagnosis, which is why the surveillance row schedules ACTH and cortisol from age one.

Nephrolithiasis Renal oxalate stones, the manifestation the annual urine oxalate-to-creatinine ratio on the surveillance row screens for.

Decreased liver function Liver dysfunction is part of the intermediate-band picture and is not reported in the PEX10 ataxic cohort.

Show evidence (1 reference)

PMID:35038753 SUPPORT Human Clinical

"Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA levels were in normal limits in several patients. VLCFA ratios (C24:0/C22:0 and/or C26:0/C22:0), though, were elevated in 11/11 cases."

The quantitative signature of a partial peroxisomal defect across the reported ataxic cohort, and the sentence on which this entry's diagnostic advice rests.

Cerebellar Degeneration

Mechanism confidence: Established

Progressive loss of cerebellar tissue, visible as cerebellar atrophy on MRI in almost every reported patient and clinically as ataxia, intention tremor and nystagmus. It is the defining lesion of this band, and its selectivity - cerebellum first, in a disorder of an organelle present in every cell - is unexplained.

Downstream

Cerebellar atrophy The radiological expression of the tissue loss.

Ataxia The clinical expression of the tissue loss, and the presenting symptom in most patients.

Intention tremor A cerebellar sign reported alongside the atrophy.

Nystagmus An oculomotor cerebellar sign in the same patient.

Show evidence (1 reference)

PMID:35038753 SUPPORT Human Clinical

"In 12/13 patients brain MRI showed cerebellar atrophy."

The imaging frequency across the reported cohort, which is what makes this node the centre of the entry rather than one feature among many.

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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

16

Digestive 1

Decreased liver function HP:0001410

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones"

Names liver dysfunction among the manifestations of the milder band.

Ear 1

Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:35038753 SUPPORT Human Clinical

"In 11/14 patients, the first and main symptom was cerebellar ataxia; in three patients, it was sensorineural hearing impairment."

Records hearing loss as the presenting symptom in three of fourteen patients.

PMID:28784167 SUPPORT Human Clinical

"The patient, an Assyrian girl originating from Iraq, presented with sensorineural hearing impairment at the age of 5 followed by sensorimotor polyneuropathy, cognitive delay, impaired gross and fine motor skills, and tremor and muscle weakness in her teens."

A worked case in which hearing loss came first, with the interval to the neurological features. The paediatric sequence is the reason audiology is on the surveillance schedule for this entry.

Endocrine 1

Adrenal insufficiency HP:0000846

Show evidence (2 references)

PMID:20301621 SUPPORT Other

"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones"

Names adrenal insufficiency among the manifestations of the milder band.

PMID:20301621 SUPPORT Other

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

The surveillance interval, quoted on the phenotype as well as on the treatment row because the timing is the clinically actionable part: screening starts in infancy because the deficit accrues rather than presents.

Eye 3

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:30640048 SUPPORT Human Clinical

"The proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus."

Same sentence; names the nystagmus.

Mydriasis HP:0011499

Show evidence (1 reference)

PMID:28320181 SUPPORT Human Clinical

"Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement."

The single family in which these features are described, which is why the entry records the denominator in the phenotype description.

Retinal dystrophy HP:0000556

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss)"

Names retinal dystrophy as the visual component of the milder band.

Genitourinary 1

Nephrolithiasis HP:0000787

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones"

Names renal oxalate stones among the manifestations of the milder band.

Metabolism 1

Elevated circulating phytanic acid Elevated circulating phytanic acid concentration HP:0010571

Show evidence (1 reference)

PMID:35038753 SUPPORT Human Clinical

"Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA levels were in normal limits in several patients."

Gives the frequency and, in the same sentence, the contrast with the normal absolute VLCFA that makes phytanic acid the more useful screen here.

Nervous System 8

Ataxia HP:0001251

Course: PROGRESSIVE

Show evidence (2 references)

PMID:35038753 SUPPORT Human Clinical

"In 11/14 patients, the first and main symptom was cerebellar ataxia; in three patients, it was sensorineural hearing impairment. Finally, all 14 patients developed ataxia."

Gives both the frequency as a presenting symptom and the eventual universality across the reported cohort.

PMID:27230853 SUPPORT Human Clinical

"Three adult patients are reported belonging to a non-consanguineous French family affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs."

An independent family, and the source of the PROGRESSIVE course recorded on the binding. Quoted in preference to a summary sentence because it also shows that the disease is compatible with adult life.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:35038753 SUPPORT Human Clinical

"In 12/13 patients brain MRI showed cerebellar atrophy."

The imaging frequency across the reported cohort.

Peripheral axonal polyneuropathy Peripheral axonal neuropathy HP:0003477

Show evidence (2 references)

PMID:35038753 SUPPORT Human Clinical

"Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings."

Gives the frequency in the reported cohort.

PMID:20695019 SUPPORT Human Clinical

"We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense."

Names the neuropathy as axonal, which is what the binding asserts, in the founding report of this presentation.

Cognitive impairment HP:0100543

Show evidence (2 references)

PMID:35038753 SUPPORT Human Clinical

"Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings."

Gives the frequency in the reported cohort.

PMID:20695019 SUPPORT Human Clinical

"We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense."

Supports this record's own statement that the finding is not universal: two patients with the disorder had normal intelligence. Graded SUPPORT rather than REFUTE because it does not contradict the feature's existence at 9 of 14, only its obligatory status, which is what a reader needs before using normal intelligence to rule the diagnosis out.

Intention tremor HP:0002080

Show evidence (1 reference)

PMID:30640048 SUPPORT Human Clinical

"The proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus."

Reports the tremor in a patient the authors label peroxisome biogenesis disorder 6B.

Hyperreflexia HP:0001347

Show evidence (2 references)

PMID:28320181 SUPPORT Human Clinical

"3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement"

Names hyperreflexia among the characteristic features of the ataxic form.

PMID:27230853 SUPPORT INDIRECT Human Clinical

"affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs"

An independent family with pyramidal involvement. INDIRECT for the binding rather than the finding: "pyramidal signs" is broader than Hyperreflexia, which is the sign the other source names.

Impaired vibratory sensation HP:0002495

Show evidence (1 reference)

PMID:20695019 SUPPORT Human Clinical

"We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense."

Names the sensory finding in the two index patients.

Leukodystrophy HP:0002415

Show evidence (1 reference)

PMID:20301621 SUPPORT Other

"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones"

Names leukodystrophy among the neurological features of the milder band.

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Genetic Associations

1

PEX10

Gene: PEX10 hgnc:8851 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (6 references)

PMID:9700193 SUPPORT In Vitro

"These results demonstrate that mutation in PEX10 is the genetic cause of complementation group B PBD."

Establishes the gene-disease relationship for the locus, by complementation. Quoted from a primary report rather than taken from the sibling entry.

CGGV:assertion_c0f7f094-ac3b-4309-ad8f-8e604f006485-2019-12-06T050000.000Z SUPPORT Other

ClinGen's Peroxisomal Disorders expert panel classifies the PEX10 gene-disease relationship as Definitive, with autosomal recessive inheritance. The assertion is made against the grouping concept MONDO:0019234 peroxisome biogenesis disorder rather than against this entry's MONDO:0013937, so it establishes the gene and the mode of inheritance for the locus and says nothing about the severity band.

PMID:20695019 SUPPORT Human Clinical

"Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA, and in the adult, c.2T>C (novel) and c.790C>T."

The genotypes in the two patients who founded the ataxic presentation, each a compound heterozygote.

+ 3 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. Management is symptomatic and, for this band, is dominated by the sensory and motor consequences: hearing aids, refractive correction, fat-soluble vitamin supplementation, and rehabilitation for the ataxia and neuropathy.

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 rather than to this entry. The modality is OTHER because the row spans devices, surgery and supplementation, none of which is a behavioural intervention.

Cholic acid supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: cholic acid CHEBI:16359

Platform: Small molecule

Bile acid replacement, given because peroxisomal bile-acid biosynthesis is impaired. It is the one approved therapy for the Zellweger spectrum - Cholbam, approved by the FDA in March 2015 as adjunctive treatment - and the reported benefit is hepatic: improved liver chemistries and reduced toxic bile acid intermediates. Two limits belong on that claim. The evidence is spectrum-wide rather than PEX10-specific, and in the founding PEX10 ataxia report the drug was started alongside dietary phytanic acid restriction with no outcome reported, so nothing here says it alters the cerebellar disease that defines this band.

Mechanism Target:

Residual Peroxisomal Metabolic Impairment — Replaces a product the impaired peroxisomal pathway makes less of; it does not restore matrix-protein import.

Show evidence (3 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."

Establishes the regulatory status of the treatment. INDIRECT for this entry: the approval is for the Zellweger spectrum as a class, and no PEX10-specific or PBD6B-specific approval or trial is cited here.

PMID:34521419 SUPPORT INDIRECT Other

"Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD."

The reported outcome, and its scope. It is a hepatic and biochemical outcome in Zellweger spectrum patients generally; it says nothing about the ataxia or the neuropathy, which is why this entry does not claim a neurological benefit.

PMID:20695019 SUPPORT INDIRECT Human Clinical

"Bile acid supplements and dietary restriction of phytanic acid were started."

Records that the treatment was given in ataxic-form patients specifically. INDIRECT because the sentence reports an intervention, not its effect - that report gives no outcome.

Dietary phytanic acid restriction

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Restriction of dietary phytanic acid, the substrate that accumulates because peroxisomal alpha-oxidation is impaired. As with the bile acid supplement, the founding report records that it was started and not what it achieved.

Mechanism Target:

Elevated circulating phytanic acid — Acts on the substrate rather than on the enzyme deficiency, by lowering the load the impaired alpha-oxidation pathway has to clear.

Show evidence (1 reference)

PMID:20695019 SUPPORT INDIRECT Human Clinical

"Bile acid supplements and dietary restriction of phytanic acid were started."

Same sentence, for the dietary arm. INDIRECT for the same reason: an intervention is recorded, an outcome is not.

Multisystem surveillance

Annual audiology and ophthalmology; annual liver function, coagulation and liver imaging; head MRI for white matter change; developmental and educational review; ACTH and cortisol from age one and annually; six-monthly dental examination; annual urine oxalate-to-creatinine ratio. For a child presenting with isolated ataxia the audiology and ophthalmology arms matter most, because sensory loss is the manifestation that accrues silently.

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"

Specifies the core surveillance intervals.

PMID:20301621 SUPPORT Other

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

Adrenal surveillance is scheduled from infancy because insufficiency develops progressively rather than presenting at diagnosis.

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Biochemical Markers

1

Very-long-chain fatty acid ratios

Context: The C24:0/C22:0 and C26:0/C22:0 ratios, rather than the absolute very-long-chain fatty acid concentrations, are what is abnormal at this end of the spectrum.

Show evidence (2 references)

PMID:35038753 SUPPORT Human Clinical

"VLCFA ratios (C24:0/C22:0 and/or C26:0/C22:0), though, were elevated in 11/11 cases."

The ratios were abnormal in every patient in whom they were measured, which is what makes them the analyte to ask for.

PMID:35038753 SUPPORT DIRECT Human Clinical

"Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA levels were in normal limits in several patients."

Supports this record's claim that the ratios rather than the absolute concentrations are the abnormal quantity: the absolute values were within reference limits in several patients who had the disease, so a normal absolute value carries no exclusionary weight at this end of the spectrum.

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Diagnosis

2

Targeted peroxisomal metabolic screen

Plasma phytanic acid together with the very-long-chain fatty acid ratios, requested specifically rather than as part of a generic panel, in a child with unexplained recessive ataxia and cerebellar atrophy.

Show evidence (1 reference)

PMID:35038753 SUPPORT Human Clinical

"We suggest including measurement of phytanic acid and VLCFA ratios in metabolic screening tests in unexplained autosomal recessive ataxias with cerebellar atrophy, especially when there is an early onset and symptoms are mild."

The authors' own diagnostic recommendation, scoped to exactly the clinical situation this entry describes.

PEX gene sequencing

Molecular confirmation by identifying biallelic PEX10 variants. At this end of the spectrum it is not merely confirmatory: biochemical and fibroblast studies can be normal, so sequencing may be the only route to the diagnosis.

Show evidence (2 references)

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."

States the confirmatory test and the gene set it covers.

PMID:19127411 SUPPORT Human Clinical

"This case highlights that molecular analysis may be essential to the diagnosis of patients at the milder end of the ZSD spectrum."

The authors' conclusion from a PEX10 patient whose fibroblast studies were entirely normal, which is the specific reason sequencing is not optional here.

📈

Progression

1

Childhood onset, slow progression, survival into adult life

This is the prognostic fact that separates the entry from PBD6A, where death usually occurs in the first year. First symptoms in the reported ataxic cohort appear between about three and eight years of age, progression is slow, and affected individuals reach adulthood - the founding report describes an adult patient, and an independent family contributed three adults.

Show evidence (2 references)

PMID:35038753 SUPPORT Human Clinical

"A literature search yielded 14 similar patients from nine families with PEX10-related cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years of age."

States the age of onset across the reported cohort.

PMID:27230853 SUPPORT Human Clinical

"The age at onset was in childhood or in adolescence (3-15 years)."

An independent family's onset range, which extends the upper bound into adolescence and is reported in adults.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No numeric prevalence is available for this entry. The reported population of the ataxic form is fourteen patients from nine families assembled by literature review; the neonatal adrenoleukodystrophy presentation at this locus rests on a single patient in the founding genotype-phenotype survey. No source cited here gives a rate, a denominator, or PEX10's share of the Zellweger spectrum, so none is asserted.

Show evidence (1 reference)

PMID:35038753 SUPPORT Human Clinical

"A literature search yielded 14 similar patients from nine families with PEX10-related cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years of age."

Quoted for the denominator. Fourteen patients is the entire reported ataxic-form population, which is why this entry asserts a qualitative band rather than a rate.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Peroxisome Biogenesis Disorder 6B:

Peroxisome biogenesis disorder 6A (Zellweger)

Overlapping Features The severe band at the same locus. Separated not by gene but by residual peroxin-10 function, and in practice by the presence of congenital malformations and death in the first year.

Distinguishing Features

Congenital malformations - neuronal migration defect, renal cysts, epiphyseal stippling
Truncating alleles on both sides rather than a retained-function missense allele
Death in the first year of life without developmental progress

Show evidence (2 references)

PMID:10862081 SUPPORT Human Clinical

"All four PEX10-deficient Zellweger Syndrome (ZS) patients were found to have nonsense, frameshift, or splice site mutations that remove large portions of the PEX10 coding region."

The mutational class of the severe band, contrasted in the same survey with the missense allele of the mild band.

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.

Other autosomal recessive cerebellar ataxias

Overlapping Features The clinical differential this entry is actually met in: a child or young adult with progressive ataxia, cerebellar atrophy and an axonal neuropathy. A peroxisomal biogenesis disorder is not the first consideration and is missed unless the specific analytes are requested.

Distinguishing Features

Raised phytanic acid and raised very-long-chain fatty acid ratios
Absolute very-long-chain fatty acid concentrations may be normal
Biallelic PEX10 variants on sequencing

Show evidence (1 reference)

PMID:20695019 SUPPORT Human Clinical

"Peroxisomal biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia."

The authors' own statement of where this entry sits in a clinical differential.

Zellweger spectrum disorders of other complementation groups

Overlapping Features The other twelve ZSD-PEX genes produce overlapping phenotypes across the same severity range. The distinction is molecular, and it does not change management.

Distinguishing Features

Different causal PEX gene on sequencing
Clinically and biochemically overlapping at the same point on the severity range

Show evidence (1 reference)

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"

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

{ }

Source YAML

click to show

name: Peroxisome Biogenesis Disorder 6B
creation_date: "2026-09-25T00:00:00Z"
category: Mendelian
description: >-
  Peroxisome biogenesis disorder 6B is the mild end of the PEX10 allelic series: the same
  gene and the same lesion as peroxisome biogenesis disorder 6A, separated from it by how
  much peroxin-10 function the genotype leaves rather than by a different mechanism. The
  survey that founded the split found the two groups carrying systematically different
  kinds of allele - every PEX10 patient with the classic Zellweger phenotype carried
  nonsense, frameshift or splice variants removing large parts of the coding region, while
  the one mildly affected patient in that survey carried a missense variant in the
  C-terminal zinc-binding domain.

  What lands in this entry is therefore everything PEX10 does short of classic Zellweger
  syndrome, and in the reported literature that is dominated by one picture: a
  childhood-onset, slowly progressive cerebellar ataxia with axonal polyneuropathy and
  cognitive impairment, in patients who survive into adult life. The largest assembly of
  these patients is a literature review of fourteen individuals from nine families, most
  with first symptoms between three and eight years of age, all of whom eventually
  developed ataxia. That picture is explicitly labelled peroxisome biogenesis disorder 6B
  in the literature. The older neonatal adrenoleukodystrophy presentation sits at the
  other end of the same entry and is the one the founding genotype-phenotype survey
  described.

  The diagnostically consequential fact about this band is biochemical and it runs against
  how the Zellweger spectrum is usually screened. Absolute plasma very-long-chain fatty
  acid concentrations can be entirely normal here, while the C24:0/C22:0 and C26:0/C22:0
  ratios are raised; in the fourteen-patient review the ratios were elevated in every one
  of the eleven patients in whom they were measured, and phytanic acid was elevated in
  eight of twelve. Cultured fibroblasts can also mislead: one PEX10 patient with clearly
  abnormal blood metabolites had entirely normal results across multiple peroxisomal
  pathways in fibroblasts. A normal peroxisomal screen at this end of the spectrum does
  not exclude the diagnosis, and the route to it is molecular.

  The gene-agnostic downstream cascade shared by the whole spectrum is curated on the
  Zellweger Spectrum Disorders entry, and the severe PEX10 band is curated as peroxisome
  biogenesis disorder 6A. What is carried here is what is PEX10-specific and specific to
  the attenuated band.
synonyms:
- PBD6B
- peroxisome biogenesis disorder type 6B
- PEX10-related neonatal adrenoleukodystrophy
- PEX10-related cerebellar ataxia
- attenuated PEX10-related Zellweger spectrum disorder
disease_term:
  preferred_term: peroxisome biogenesis disorder 6B
  term:
    id: MONDO:0013937
    label: peroxisome biogenesis disorder 6B
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 through
      complementation grouping and then gene identification.
  - 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:0013937
      label: peroxisome biogenesis disorder 6B
    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 PEX10-related peroxisome biogenesis disorder. The severe band is
      MONDO:0013936 and is curated separately.
references:
- reference: PMID:20301621
  title: "Zellweger Spectrum Disorder."
  tags:
  - GeneReviews
- reference: PMID:10862081
  title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
- reference: PMID:20695019
  title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
- reference: PMID:27230853
  title: "Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia."
- reference: PMID:28320181
  title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
- reference: PMID:30640048
  title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
- reference: PMID:35038753
  title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
- reference: PMID:28784167
  title: "Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report."
- reference: PMID:19127411
  title: "A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts."
- reference: PMID:9683594
  title: "Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders."
- reference: PMID:9700193
  title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
- reference: PMID:26750748
  title: "Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines."
- reference: PMID:34521419
  title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
- reference: PMID:35768507
  title: "A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel."
- reference: PMID:40267090
  title: "Identification of novel compound heterozygous variants in the PEX10 gene in a Han-Chinese family with PEX10-related peroxisome biogenesis disorders."
- reference: CGGV:assertion_c0f7f094-ac3b-4309-ad8f-8e604f006485-2019-12-06T050000.000Z
  title: "PEX10 / peroxisome biogenesis disorder (Definitive)"
has_subtypes:
- name: Ataxic form
  display_name: PEX10-related cerebellar ataxia (childhood-onset ataxic form)
  description: >-
    Childhood-onset, slowly progressive cerebellar ataxia with axonal polyneuropathy,
    cognitive impairment and cerebellar atrophy, in patients of otherwise normal or only
    mildly impaired intellect who reach adult life. This is the presentation that dominates
    the reported PBD6B literature, and it is the one published explicitly under the PBD6B
    label.
  evidence:
  - reference: PMID:30640048
    reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene."
    explanation: >-
      The sentence that ties the ataxic presentation to the PBD6B label specifically, rather
      than to PEX10 disease in general. It is the basis for curating the ataxic form inside
      this entry rather than as a separate concept.
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A literature search yielded 14 similar patients from nine families with PEX10-related
      cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years
      of age.
    explanation: >-
      The size and age of onset of the reported population of this subtype. Fourteen
      patients from nine families is the whole published series, and the reader should
      have that denominator in mind for every frequency quoted in this entry.
- name: NALD-IRD
  display_name: Neonatal adrenoleukodystrophy / infantile Refsum disease presentation
  description: >-
    The older phenotype labels for the intermediate band of the Zellweger spectrum:
    progressive peroxisomal failure with sensory loss, liver dysfunction and developmental
    delay, but without the congenital malformations of classic Zellweger syndrome. This is
    the presentation the founding PEX10 genotype-phenotype survey described in its one
    mildly affected patient.
  evidence:
  - reference: PMID:10862081
    reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, a more mildly affected PEX10-deficient neonatal adrenoleukodystrophy
      patient expressed a PEX10 allele with a missense mutation, H290Q, affecting the
      C-terminal zinc-binding domain of the PEX10 product.
    explanation: >-
      The one PEX10 patient carrying the neonatal adrenoleukodystrophy label in the survey
      that separated the severe from the mild band, and the allele that patient carried. The
      abstract does not state the patient's sex and neither does this entry.
  - 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 characterisation of the band these older labels describe. Quoted from the
      spectrum resource rather than from a PEX10 source because no PEX10-specific series
      describes this presentation in comparable detail.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No numeric prevalence is available for this entry. The reported population of the
    ataxic form is fourteen patients from nine families assembled by literature review;
    the neonatal adrenoleukodystrophy presentation at this locus rests on a single patient
    in the founding genotype-phenotype survey. No source cited here gives a rate, a
    denominator, or PEX10's share of the Zellweger spectrum, so none is asserted.
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A literature search yielded 14 similar patients from nine families with PEX10-related
      cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years
      of age.
    explanation: >-
      Quoted for the denominator. Fourteen patients is the entire reported ataxic-form
      population, which is why this entry asserts a qualitative band rather than a rate.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PEX10 variants, and specifically genotypes leaving residual peroxin-10
    function on at least one allele. Reported patients in the ataxic form are compound
    heterozygotes combining a missense allele with a second, often truncating, allele.
  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.
  - reference: PMID:28320181
    reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C
      (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located
      in the RING finger domain of PEX10.
    explanation: >-
      A worked biallelic genotype in the ataxic form, and the recessive segregation across
      three affected siblings.
pathophysiology:
- name: Biallelic Hypomorphic PEX10 Genotype
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Both PEX10 alleles carry variants, but at least one retains partial peroxin-10
    function. In the reported ataxic patients these are missense changes, several of them
    in or adjacent to the C-terminal RING finger, carried opposite a second allele that may
    itself be severe. The residual-function threshold, not gene identity, is what separates
    this entry from PBD6A.
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    gene:
      preferred_term: PEX10
      term:
        id: hgnc:8851
        label: PEX10
    description: >-
      Missense alleles predominate. Homozygous missense genotypes are also reported at the
      mild end, so COMPOUND_HETEROZYGOUS records the commoner reported configuration rather
      than a requirement.
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  evidence:
  - reference: PMID:10862081
    reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results support the hypothesis that severe, loss-of-function mutations in PEX
      genes cause more severe clinical phenotypes, whereas mildly affected PBD patients
      have PEX gene mutations that retain residual function.
    explanation: >-
      The residual-function account that defines this entry against PBD6A, stated by the
      survey that assembled both bands.
  - reference: PMID:27230853
    reference_title: "Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With whole exome sequencing, two mutations in PEX10 were found in the three patients:
      c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the
      missense change p.Arg311Gln.
    explanation: >-
      A worked mild-band genotype: two missense alleles, in a family whose disease was
      slowly progressive and compatible with adult life.
  downstream:
  - target: Partial Loss of Peroxin-10 RING Function
    description: >-
      The reported mild alleles cluster in and around the C-terminal zinc-binding RING
      module, the part of the protein that carries its function, but alter rather than
      remove it.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28320181
      reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING
        finger domain of PEX10
      explanation: >-
        Places a mild-band allele inside the RING finger domain, which is what this edge
        asserts.
- name: Partial Loss of Peroxin-10 RING Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Peroxin-10 is a peroxisomal membrane protein whose C-terminal C3HC4 zinc-finger RING
    motif carries its function. A missense change in that module degrades the activity
    rather than abolishing it, which is the molecular difference between this entry and the
    severe band.
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  evidence:
  - reference: PMID:10862081
    reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Although these results demonstrate serious flaws in the PEX10 functional
      complementation assay, they do suggest that the C-terminal zinc-binding domain is
      critical for PEX10 function.
    explanation: >-
      Supports the claim while carrying the authors' own caveat about the assay that
      produced it. Quoted whole rather than trimmed to the supportive clause. Marked
      INDIRECT because, with the assay called into question by its own authors, the domain
      claim rests on the mutational pattern rather than on activity measurements.
  - 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: >-
      Names the complex peroxin-10's RING domain belongs to, and what it does. Quoted
      rather than paraphrased because the subunit naming is the load-bearing detail.
      INDIRECT: the structure was solved in a fungal system, so the human claim rests on
      conservation.
  - reference: PMID:35768507
    reference_title: "A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Each subunit of the complex contributes five transmembrane segments that co-assemble
      into an open channel. The three ring finger domains form a cytosolic tower, with ring
      finger 2 (RF2) positioned above the channel pore.
    explanation: >-
      The architectural reason a missense change in one RING domain degrades rather than
      abolishes the assembly: each of the three subunits contributes to a shared channel,
      and the RING domains sit above its pore. INDIRECT for the same reason as above.
  - reference: PMID:9700193
    reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "This implies that the C-terminal part, including the RING finger, is required for biological function of Pex10p."
    explanation: >-
      Localises peroxin-10's biological function to the domain the mild alleles alter. The
      authors' own "This implies" is preserved: the inference is theirs, drawn from a
      frameshift immediately upstream of the motif rather than from a missense allele, which
      is why this is marked INDIRECT for a missense-driven node.
  downstream:
  - target: Partial Failure of Peroxisomal Matrix Protein Import
    description: >-
      Degraded RING function leaves matrix-protein import partly rather than wholly
      defective, which is what produces a cell population with some import-competent
      peroxisomes and some not.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9683594
      reference_title: "Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        PEX10-deficient PBD100 cells contain many peroxisomes and import peroxisomal
        membrane proteins but do not import peroxisomal matrix proteins, indicating that
        loss of PEX10 has its most pronounced effect on peroxisomal matrix-protein import.
      explanation: >-
        Establishes that the consequence of losing peroxin-10 is specifically a
        matrix-import defect. Marked INDIRECT because the cell line quoted is a severe-band
        Zellweger line with a complete defect; what this entry asserts is the partial form
        of the same defect.
- name: Partial Failure of Peroxisomal Matrix Protein Import
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Matrix-protein import is reduced but not abolished. In a patient with the ataxic form
    this appears in fibroblasts as peroxisomal mosaicism - some peroxisomes importing and
    some not - together with a catalase import deficiency and abnormal organelle
    morphology. It is the cellular counterpart of the residual-function genotype, and it is
    why the biochemical signature in blood is attenuated rather than absent. 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:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunohistochemistry confirmed pathogenicity in the patients' cultured fibroblasts
      demonstrating peroxisomal mosaicism with a general catalase import deficiency as well
      as conspicuous peroxisome morphology as an expression of impaired peroxisomal
      function.
    explanation: >-
      The direct cellular observation behind this node, in a patient with the ataxic form.
      Mosaicism rather than uniform failure is what distinguishes the partial defect from
      the severe band's empty organelle.
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection with wild-type PEX10 corrected the fibroblast phenotype."
    explanation: >-
      A rescue experiment in ataxic-form patient cells, which is what makes the cellular
      defect attributable to the PEX10 lesion rather than merely coincident with it.
  downstream:
  - target: Residual Peroxisomal Metabolic Impairment
    description: >-
      Fewer import-competent peroxisomes means reduced flux through every peroxisomal
      pathway at once, rather than the abolition seen in the severe band.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27230853
      reference_title: "Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Biochemical blood analyses suggested a mild peroxisomal defect."
      explanation: >-
        The whole-organism biochemical reading of the cellular defect in ataxic-form
        patients: present, and mild.
- name: Residual Peroxisomal Metabolic Impairment
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Peroxisomal beta-oxidation and phytanic acid handling run below normal without failing.
    The measurable consequences are a raised phytanic acid and raised very-long-chain fatty
    acid ratios, against absolute very-long-chain fatty acid concentrations that are often
    within the reference interval - which is the reason this band is missed on a
    conventional peroxisomal screen.
  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
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA
      levels were in normal limits in several patients. VLCFA ratios (C24:0/C22:0 and/or
      C26:0/C22:0), though, were elevated in 11/11 cases.
    explanation: >-
      The quantitative signature of a partial peroxisomal defect across the reported ataxic
      cohort, and the sentence on which this entry's diagnostic advice rests.
  downstream:
  - target: Cerebellar Degeneration
    description: >-
      The cerebellum is the organ that fails first and hardest in this band. No source cited
      here traces which lost peroxisomal function is responsible, so the intermediates are
      recorded as unknown rather than implied.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20695019
      reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients had marked cerebellar atrophy."
      explanation: >-
        Establishes the cerebellar lesion in patients whose peroxisomal defect was
        demonstrated. INDIRECT: the association is shown, the route is not.
  - target: Peripheral axonal polyneuropathy
    description: >-
      Length-dependent axonal neuropathy accompanies the cerebellar disease in most reported
      patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35038753
      reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings."
      explanation: Gives the frequency of the neuropathy in the reported cohort.
  - target: Cognitive impairment
    description: >-
      Cognitive impairment is common but not universal, and several reported patients had
      normal intelligence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35038753
      reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings."
      explanation: Gives the frequency of cognitive impairment in the reported cohort.
  - target: Sensorineural hearing impairment
    description: >-
      Hearing loss can precede the ataxia and be the presenting complaint, which is how the
      diagnosis is most often delayed.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35038753
      reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 11/14 patients, the first and main symptom was cerebellar ataxia; in three
        patients, it was sensorineural hearing impairment.
      explanation: >-
        Records hearing loss as the presenting symptom in three of fourteen reported
        patients.
  - target: Elevated circulating phytanic acid
    description: >-
      Phytanic acid alpha-oxidation is peroxisomal, so a partial biogenesis defect raises it
      directly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35038753
      reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Metabolic screening tests aiming to detect potentially treatable ataxias showed an
        increased value (fourfold upper limit of normal) for phytanic acid and elevated
        very-long-chain fatty acid (VLCFA) ratios (C24:0/C22:0 and C26:0/C22:0), while
        absolute concentrations of VLCFA were normal.
      explanation: >-
        The measured biochemical consequence in an index patient, with the normal absolute
        VLCFA that makes the case instructive.
  - target: Impaired vibratory sensation
    description: Large-fibre sensory loss, measured clinically in the founding ataxia report.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20695019
      reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a child and an adult of normal intelligence with progressive ataxia,
        axonal motor neuropathy, and decreased vibration sense.
      explanation: Names the sensory finding in the two index patients.
  - target: Mydriasis
    description: >-
      Pupillary autonomic involvement, reported as one of three additional characteristic
      features in an ataxic-form sibship.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28320181
      reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The present cases suggest that these PEX10 mutations involve not only cerebellar but
        also more multiple nervous systems including pupillary autonomic, pyramidal and
        extrapyramidal systems.
      explanation: >-
        The authors' own reading of why the pupillary and pyramidal findings belong to the
        same lesion. Their hedge ("suggest") is why this edge carries unknown intermediates.
  - target: Hyperreflexia
    description: Pyramidal involvement in the same sibship.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28320181
      reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The present cases suggest that these PEX10 mutations involve not only cerebellar but
        also more multiple nervous systems including pupillary autonomic, pyramidal and
        extrapyramidal systems.
      explanation: Same sentence; names the pyramidal system among those involved.
  - target: Retinal dystrophy
    description: >-
      Part of the progressive sensory loss of the intermediate band. Carried from the
      spectrum resource rather than from a PEX10 series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        progressive peroxisome dysfunction variably manifest as sensory loss (secondary to
        retinal dystrophy and sensorineural hearing loss)
      explanation: >-
        States the route from progressive peroxisomal dysfunction to the retinal lesion,
        across the milder band of the spectrum.
  - target: Leukodystrophy
    description: >-
      White matter disease, part of the neurological picture of the intermediate band.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
        dysfunction, adrenal insufficiency, and renal oxalate stones
      explanation: Names leukodystrophy among the neurological features of the milder band.
  - target: Adrenal insufficiency
    description: >-
      Adrenal failure develops progressively rather than presenting at diagnosis, which is
      why the surveillance row schedules ACTH and cortisol 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: >-
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
        dysfunction, adrenal insufficiency, and renal oxalate stones
      explanation: Names adrenal insufficiency among the manifestations of the milder band.
  - target: Nephrolithiasis
    description: >-
      Renal oxalate stones, the manifestation the annual urine oxalate-to-creatinine ratio
      on the surveillance row screens for.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
        dysfunction, adrenal insufficiency, and renal oxalate stones
      explanation: Names renal oxalate stones among the manifestations of the milder band.
  - target: Decreased liver function
    description: >-
      Liver dysfunction is part of the intermediate-band picture and is not reported in the
      PEX10 ataxic cohort.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301621
      reference_title: "Zellweger Spectrum Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
        dysfunction, adrenal insufficiency, and renal oxalate stones
      explanation: Names liver dysfunction among the manifestations of the milder band.
- name: Cerebellar Degeneration
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Progressive loss of cerebellar tissue, visible as cerebellar atrophy on MRI in almost
    every reported patient and clinically as ataxia, intention tremor and nystagmus. It is
    the defining lesion of this band, and its selectivity - cerebellum first, in a disorder
    of an organelle present in every cell - is unexplained.
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 12/13 patients brain MRI showed cerebellar atrophy."
    explanation: >-
      The imaging frequency across the reported cohort, which is what makes this node the
      centre of the entry rather than one feature among many.
  downstream:
  - target: Cerebellar atrophy
    description: The radiological expression of the tissue loss.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30640048
      reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cerebral MRI showed cerebellar atrophy."
      explanation: The imaging finding in a patient reported explicitly as PBD6B.
  - target: Ataxia
    description: The clinical expression of the tissue loss, and the presenting symptom in most patients.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35038753
      reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Finally, all 14 patients developed ataxia."
      explanation: Every reported patient of this subtype developed the symptom.
  - target: Intention tremor
    causal_link_type: DIRECT
    description: A cerebellar sign reported alongside the atrophy.
    evidence:
    - reference: PMID:30640048
      reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The proband is a 7-year-old boy with mild mental retardation and gait instability,
        intention tremor and nystagmus.
      explanation: Names the tremor in a PBD6B-labelled patient with cerebellar atrophy.
  - target: Nystagmus
    causal_link_type: DIRECT
    description: An oculomotor cerebellar sign in the same patient.
    evidence:
    - reference: PMID:30640048
      reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The proband is a 7-year-old boy with mild mental retardation and gait instability,
        intention tremor and nystagmus.
      explanation: Same sentence; names the nystagmus.
phenotypes:
- category: Neurologic
  name: Ataxia
  subtype: Ataxic form
  description: >-
    Cerebellar ataxia, in most patients the first and dominant symptom, beginning between
    about three and eight years of age and progressing slowly. Every reported patient of
    the ataxic subtype eventually developed it.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 11/14 patients, the first and main symptom was cerebellar ataxia; in three
      patients, it was sensorineural hearing impairment. Finally, all 14 patients developed
      ataxia.
    explanation: >-
      Gives both the frequency as a presenting symptom and the eventual universality across
      the reported cohort.
  - reference: PMID:27230853
    reference_title: "Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three adult patients are reported belonging to a non-consanguineous French family
      affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal
      signs.
    explanation: >-
      An independent family, and the source of the PROGRESSIVE course recorded on the
      binding. Quoted in preference to a summary sentence because it also shows that the
      disease is compatible with adult life.
- category: Neurologic
  name: Cerebellar atrophy
  subtype: Ataxic form
  description: Cerebellar atrophy on brain MRI, present in almost every patient imaged.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 12/13 patients brain MRI showed cerebellar atrophy."
    explanation: The imaging frequency across the reported cohort.
- category: Neurologic
  name: Peripheral axonal polyneuropathy
  description: >-
    Axonal sensorimotor polyneuropathy, present in roughly two thirds of reported ataxic
    patients and confirmed on nerve conduction studies.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings."
    explanation: Gives the frequency in the reported cohort.
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a child and an adult of normal intelligence with progressive ataxia,
      axonal motor neuropathy, and decreased vibration sense.
    explanation: >-
      Names the neuropathy as axonal, which is what the binding asserts, in the founding
      report of this presentation.
- category: Neurologic
  name: Cognitive impairment
  description: >-
    Cognitive impairment in about two thirds of reported ataxic patients, usually mild. It
    is not universal - the founding report describes a child and an adult of normal
    intelligence - which is why this entry does not bind an intellectual-disability term.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings."
    explanation: Gives the frequency in the reported cohort.
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a child and an adult of normal intelligence with progressive ataxia,
      axonal motor neuropathy, and decreased vibration sense.
    explanation: >-
      Supports this record's own statement that the finding is not universal: two patients
      with the disorder had normal intelligence. Graded SUPPORT rather than REFUTE because
      it does not contradict the feature's existence at 9 of 14, only its obligatory status,
      which is what a reader needs before using normal intelligence to rule the diagnosis
      out.
- category: Otologic
  name: Sensorineural hearing impairment
  description: >-
    Sensorineural hearing loss, which in a minority of patients precedes the ataxia and is
    the presenting complaint. In one reported attenuated PEX10 patient it appeared at age
    five, years before the neurological picture declared itself.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 11/14 patients, the first and main symptom was cerebellar ataxia; in three
      patients, it was sensorineural hearing impairment.
    explanation: Records hearing loss as the presenting symptom in three of fourteen patients.
  - reference: PMID:28784167
    reference_title: "Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, an Assyrian girl originating from Iraq, presented with sensorineural
      hearing impairment at the age of 5 followed by sensorimotor polyneuropathy, cognitive
      delay, impaired gross and fine motor skills, and tremor and muscle weakness in her
      teens.
    explanation: >-
      A worked case in which hearing loss came first, with the interval to the neurological
      features. The paediatric sequence is the reason audiology is on the surveillance
      schedule for this entry.
- category: Metabolic
  name: Elevated circulating phytanic acid
  description: >-
    Raised plasma phytanic acid, the alpha-oxidation substrate handled by peroxisomes.
    Elevated in two thirds of the reported ataxic cohort and, with the very-long-chain
    fatty acid ratios, the biochemical signal that points to the diagnosis.
  phenotype_term:
    preferred_term: Elevated circulating phytanic acid concentration
    term:
      id: HP:0010571
      label: Elevated circulating phytanic acid concentration
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA
      levels were in normal limits in several patients.
    explanation: >-
      Gives the frequency and, in the same sentence, the contrast with the normal absolute
      VLCFA that makes phytanic acid the more useful screen here.
- category: Neurologic
  name: Intention tremor
  subtype: Ataxic form
  phenotype_term:
    preferred_term: Intention tremor
    term:
      id: HP:0002080
      label: Intention tremor
  evidence:
  - reference: PMID:30640048
    reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband is a 7-year-old boy with mild mental retardation and gait instability,
      intention tremor and nystagmus.
    explanation: Reports the tremor in a patient the authors label peroxisome biogenesis disorder 6B.
- category: Ophthalmologic
  name: Nystagmus
  subtype: Ataxic form
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:30640048
    reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband is a 7-year-old boy with mild mental retardation and gait instability,
      intention tremor and nystagmus.
    explanation: Same sentence; names the nystagmus.
- category: Ophthalmologic
  name: Mydriasis
  subtype: Ataxic form
  description: >-
    Pupillary dilatation, described together with hyperreflexia and involuntary head
    movement as characteristic additional features in an ataxic-form sibship. Reported in
    one family, so it is a pointer rather than an expected finding.
  phenotype_term:
    preferred_term: Mydriasis
    term:
      id: HP:0011499
      label: Mydriasis
  evidence:
  - reference: PMID:28320181
    reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental
      retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and
      involuntary head movement.
    explanation: >-
      The single family in which these features are described, which is why the entry
      records the denominator in the phenotype description.
- category: Neurologic
  name: Hyperreflexia
  subtype: Ataxic form
  description: >-
    Pyramidal signs, reported both in the ataxic sibship above and, as "pyramidal signs",
    in an independent French family.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:28320181
    reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 additional characteristic features: mydriasis, hyperreflexia and involuntary head
      movement
    explanation: Names hyperreflexia among the characteristic features of the ataxic form.
  - reference: PMID:27230853
    reference_title: "Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal
      signs
    explanation: >-
      An independent family with pyramidal involvement. INDIRECT for the binding rather
      than the finding: "pyramidal signs" is broader than Hyperreflexia, which is the sign
      the other source names.
- category: Neurologic
  name: Impaired vibratory sensation
  description: Reduced vibration sense, the large-fibre sensory component of the neuropathy.
  phenotype_term:
    preferred_term: Impaired vibratory sensation
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  evidence:
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a child and an adult of normal intelligence with progressive ataxia,
      axonal motor neuropathy, and decreased vibration sense.
    explanation: Names the sensory finding in the two index patients.
- category: Ophthalmologic
  name: Retinal dystrophy
  subtype: NALD-IRD
  description: >-
    Progressive retinal dystrophy, part of the sensory loss of the intermediate band.
    Recorded from the spectrum resource: no PEX10-specific series reports it, and it is not
    described in the ataxic cohort.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      progressive peroxisome dysfunction variably manifest as sensory loss (secondary to
      retinal dystrophy and sensorineural hearing loss)
    explanation: Names retinal dystrophy as the visual component of the milder band.
- category: Hepatic
  name: Decreased liver function
  subtype: NALD-IRD
  description: >-
    Liver dysfunction, part of the intermediate-band picture. Recorded from the spectrum
    resource for the same reason as the retinal dystrophy above.
  phenotype_term:
    preferred_term: Decreased liver function
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
      dysfunction, adrenal insufficiency, and renal oxalate stones
    explanation: Names liver dysfunction among the manifestations of the milder band.
- category: Neurologic
  name: Leukodystrophy
  subtype: NALD-IRD
  description: >-
    White matter disease, named by the spectrum resource among the neurological features of
    the intermediate band. It is not reported in the PEX10 ataxic cohort, where the imaging
    finding is cerebellar atrophy.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
      dysfunction, adrenal insufficiency, and renal oxalate stones
    explanation: Names leukodystrophy among the neurological features of the milder band.
- category: Endocrine
  name: Adrenal insufficiency
  subtype: NALD-IRD
  description: >-
    Adrenal insufficiency, which develops progressively rather than presenting at
    diagnosis. It is the reason the surveillance row schedules ACTH and cortisol from age
    one, and it is the manifestation most likely to be missed in a child followed for
    ataxia alone.
  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: >-
      neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
      dysfunction, adrenal insufficiency, and renal oxalate stones
    explanation: Names adrenal insufficiency among the manifestations of the milder band.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACTH and cortisol levels by age one year and annually thereafter."
    explanation: >-
      The surveillance interval, quoted on the phenotype as well as on the treatment row
      because the timing is the clinically actionable part: screening starts in infancy
      because the deficit accrues rather than presents.
- category: Renal
  name: Nephrolithiasis
  subtype: NALD-IRD
  description: >-
    Renal oxalate stones, a manifestation specific to the milder end of the spectrum and
    the target of the annual urine oxalate-to-creatinine ratio on the surveillance row.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver
      dysfunction, adrenal insufficiency, and renal oxalate stones
    explanation: Names renal oxalate stones among the manifestations of the milder band.
progression:
- phase: Childhood onset, slow progression, survival into adult life
  notes: >-
    This is the prognostic fact that separates the entry from PBD6A, where death usually
    occurs in the first year. First symptoms in the reported ataxic cohort appear between
    about three and eight years of age, progression is slow, and affected individuals reach
    adulthood - the founding report describes an adult patient, and an independent family
    contributed three adults.
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A literature search yielded 14 similar patients from nine families with PEX10-related
      cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years
      of age.
    explanation: States the age of onset across the reported cohort.
  - reference: PMID:27230853
    reference_title: "Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at onset was in childhood or in adolescence (3-15 years)."
    explanation: >-
      An independent family's onset range, which extends the upper bound into adolescence
      and is reported in adults.
genetic:
- name: PEX10
  gene_term:
    preferred_term: PEX10
    term:
      id: hgnc:8851
      label: PEX10
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  review_notes: >-
    Peroxin-10 is a peroxisomal membrane protein with a C-terminal C3HC4 zinc-finger RING
    motif. The alleles reported in this band are predominantly missense and several lie in
    or beside that motif: p.Cys276Phe and p.Arg311Gln in a French family, p.C307Y opposite
    an initiation-codon change in a Japanese sibship, p.G70E with p.L277P in a Chinese
    proband reported as PBD6B, and homozygous p.Leu177Arg in an attenuated case. The
    founding genotype-phenotype survey's mild-band allele was H290Q.
  evidence:
  - reference: PMID:9700193
    reference_title: "Mutations in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results demonstrate that mutation in PEX10 is the genetic cause of complementation group B PBD."
    explanation: >-
      Establishes the gene-disease relationship for the locus, by complementation. Quoted
      from a primary report rather than taken from the sibling entry.
  - reference: CGGV:assertion_c0f7f094-ac3b-4309-ad8f-8e604f006485-2019-12-06T050000.000Z
    reference_title: "PEX10 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PEX10 | HGNC:8851 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive
    explanation: >-
      ClinGen's Peroxisomal Disorders expert panel classifies the PEX10 gene-disease
      relationship as Definitive, with autosomal recessive inheritance. The assertion is
      made against the grouping concept MONDO:0019234 peroxisome biogenesis disorder rather
      than against this entry's MONDO:0013937, so it establishes the gene and the mode of
      inheritance for the locus and says nothing about the severity band.
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA,
      and in the adult, c.2T>C (novel) and c.790C>T.
    explanation: >-
      The genotypes in the two patients who founded the ataxic presentation, each a
      compound heterozygote.
  - reference: PMID:30640048
    reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PEX10 gene test showed compound heterozygous mutations (c.209 G > A, p. G70E and
      c.830 T > C, p. L277 P).
    explanation: >-
      The genotype in the one patient in the literature explicitly labelled peroxisome
      biogenesis disorder 6B, which is the label this entry is scoped to.
  - reference: PMID:40267090
    reference_title: "Identification of novel compound heterozygous variants in the PEX10 gene in a Han-Chinese family with PEX10-related peroxisome biogenesis disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compound heterozygous variants, a novel splicing variant c.113-2A>G and a reported
      substitution c.890T>C (p.Leu297Pro), in the peroxisomal biogenesis factor 10 gene
      (PEX10) were detected.
    explanation: >-
      A second family assigned to this entry's label, and a genotype that shows the
      residual-function requirement is met by one allele rather than two: the splicing
      variant deletes 27 residues in frame while the other allele is missense.
  - reference: PMID:28784167
    reference_title: "Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnosis was confirmed by next generation sequencing analysis, which showed a novel
      homozygous mutation (c.530 T > G (p.Leu177Arg) (NM_153818.1)) in the PEX10 gene
      predicted to be pathogenic.
    explanation: >-
      A homozygous missense genotype at the mild end, which is why the pathophysiology node
      records COMPOUND_HETEROZYGOUS as the commoner configuration rather than a requirement.
biochemical:
- name: Very-long-chain fatty acid ratios
  context: >-
    The C24:0/C22:0 and C26:0/C22:0 ratios, rather than the absolute very-long-chain fatty
    acid concentrations, are what is abnormal at this end of the spectrum.
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VLCFA ratios (C24:0/C22:0 and/or C26:0/C22:0), though, were elevated in 11/11 cases.
    explanation: >-
      The ratios were abnormal in every patient in whom they were measured, which is what
      makes them the analyte to ask for.
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA
      levels were in normal limits in several patients.
    explanation: >-
      Supports this record's claim that the ratios rather than the absolute concentrations
      are the abnormal quantity: the absolute values were within reference limits in several
      patients who had the disease, so a normal absolute value carries no exclusionary
      weight at this end of the spectrum.
  notes: >-
    A normal absolute plasma very-long-chain fatty acid concentration does not exclude
    PEX10 disease at this end of the spectrum; the ratios and phytanic acid are what move.
    Cultured fibroblasts can mislead in the same direction - one PEX10 patient with
    abnormal blood metabolites had normal results across multiple peroxisomal pathways in
    fibroblasts - which is why molecular testing is the route to the diagnosis.
diagnosis:
- name: Targeted peroxisomal metabolic screen
  description: >-
    Plasma phytanic acid together with the very-long-chain fatty acid ratios, requested
    specifically rather than as part of a generic panel, in a child with unexplained
    recessive ataxia and cerebellar atrophy.
  evidence:
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest including measurement of phytanic acid and VLCFA ratios in metabolic
      screening tests in unexplained autosomal recessive ataxias with cerebellar atrophy,
      especially when there is an early onset and symptoms are mild.
    explanation: >-
      The authors' own diagnostic recommendation, scoped to exactly the clinical situation
      this entry describes.
- name: PEX gene sequencing
  description: >-
    Molecular confirmation by identifying biallelic PEX10 variants. At this end of the
    spectrum it is not merely confirmatory: biochemical and fibroblast studies can be
    normal, so sequencing may be the only route to the diagnosis.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of ZSD is established in a proband with the suggestive clinical and
      biochemical findings above by identification of biallelic pathogenic variants in one
      of the 13 known ZSD-PEX genes.
    explanation: States the confirmatory test and the gene set it covers.
  - reference: PMID:19127411
    reference_title: "A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case highlights that molecular analysis may be essential to the diagnosis of
      patients at the milder end of the ZSD spectrum.
    explanation: >-
      The authors' conclusion from a PEX10 patient whose fibroblast studies were entirely
      normal, which is the specific reason sequencing is not optional here.
treatments:
- name: Symptomatic and supportive management
  description: >-
    There is no disease-modifying therapy. Management is symptomatic and, for this band,
    is dominated by the sensory and motor consequences: hearing aids, refractive
    correction, fat-soluble vitamin supplementation, and rehabilitation for the ataxia and
    neuropathy.
  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 rather than to this entry. The
      modality is OTHER because the row spans devices, surgery and supplementation, none of
      which is a behavioural intervention.
- name: Cholic acid supplementation
  description: >-
    Bile acid replacement, given because peroxisomal bile-acid biosynthesis is impaired. It
    is the one approved therapy for the Zellweger spectrum - Cholbam, approved by the FDA in
    March 2015 as adjunctive treatment - and the reported benefit is hepatic: improved liver
    chemistries and reduced toxic bile acid intermediates. Two limits belong on that claim.
    The evidence is spectrum-wide rather than PEX10-specific, and in the founding PEX10
    ataxia report the drug was started alongside dietary phytanic acid restriction with no
    outcome reported, so nothing here says it alters the cerebellar disease that defines
    this band.
  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: >-
      Establishes the regulatory status of the treatment. INDIRECT for this entry: the
      approval is for the Zellweger spectrum as a class, and no PEX10-specific or
      PBD6B-specific approval or trial is cited here.
  - reference: PMID:34521419
    reference_title: "Cholbam® and Zellweger spectrum disorders: treatment implementation and management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been
      shown to improve liver chemistries and reduce toxic bile acid intermediates in the
      majority of patients with ZSD.
    explanation: >-
      The reported outcome, and its scope. It is a hepatic and biochemical outcome in
      Zellweger spectrum patients generally; it says nothing about the ataxia or the
      neuropathy, which is why this entry does not claim a neurological benefit.
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bile acid supplements and dietary restriction of phytanic acid were started."
    explanation: >-
      Records that the treatment was given in ataxic-form patients specifically. INDIRECT
      because the sentence reports an intervention, not its effect - that report gives no
      outcome.
  target_mechanisms:
  - target: Residual Peroxisomal Metabolic Impairment
    description: >-
      Replaces a product the impaired peroxisomal pathway makes less of; it does not restore
      matrix-protein import.
- name: Dietary phytanic acid restriction
  description: >-
    Restriction of dietary phytanic acid, the substrate that accumulates because
    peroxisomal alpha-oxidation is impaired. As with the bile acid supplement, the founding
    report records that it was started and not what it achieved.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bile acid supplements and dietary restriction of phytanic acid were started."
    explanation: >-
      Same sentence, for the dietary arm. INDIRECT for the same reason: an intervention is
      recorded, an outcome is not.
  target_mechanisms:
  - target: Elevated circulating phytanic acid
    description: >-
      Acts on the substrate rather than on the enzyme deficiency, by lowering the load the
      impaired alpha-oxidation pathway has to clear.
- name: Multisystem surveillance
  description: >-
    Annual audiology and ophthalmology; annual liver function, coagulation and liver
    imaging; head MRI for white matter change; developmental and educational review; ACTH
    and cortisol from age one and annually; six-monthly dental examination; annual urine
    oxalate-to-creatinine ratio. For a child presenting with isolated ataxia the audiology
    and ophthalmology arms matter most, because sensory loss is the manifestation that
    accrues silently.
  treatment_term:
    preferred_term: multisystem surveillance schedule
  notes: >-
    Deliberately left unbound, and the meaning is carried in preferred_term. The
    TreatmentActionTerm enum is rooted at NCIT:C25218 Clinical Intervention or Procedure.
    Searching NCIT through the OLS search API by label for "surveillance" and for
    "monitoring" returns two plausible candidates, NCIT:C15719 Surveillance and
    NCIT:C53607 Patient Monitoring; asking OLS for each one's hierarchical ancestors shows
    neither has NCIT:C25218 among them. C15719 sits under Observational Study and Clinical
    Study, which is a study design rather than a clinical action, and C53607 sits under
    Monitoring and Action. Neither is a legal value for this slot.
  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
    explanation: Specifies the core surveillance intervals.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACTH and cortisol levels by age one year and annually thereafter."
    explanation: >-
      Adrenal surveillance is scheduled from infancy because insufficiency develops
      progressively rather than presenting at diagnosis.
differential_diagnoses:
- name: Peroxisome biogenesis disorder 6A (Zellweger)
  description: >-
    The severe band at the same locus. Separated not by gene but by residual peroxin-10
    function, and in practice by the presence of congenital malformations and death in the
    first year.
  distinguishing_features:
  - Congenital malformations - neuronal migration defect, renal cysts, epiphyseal stippling
  - Truncating alleles on both sides rather than a retained-function missense allele
  - Death in the first year of life without developmental progress
  evidence:
  - reference: PMID:10862081
    reference_title: "Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All four PEX10-deficient Zellweger Syndrome (ZS) patients were found to have
      nonsense, frameshift, or splice site mutations that remove large portions of the
      PEX10 coding region.
    explanation: >-
      The mutational class of the severe band, contrasted in the same survey with the
      missense allele of the mild band.
  - 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.
- name: Other autosomal recessive cerebellar ataxias
  description: >-
    The clinical differential this entry is actually met in: a child or young adult with
    progressive ataxia, cerebellar atrophy and an axonal neuropathy. A peroxisomal
    biogenesis disorder is not the first consideration and is missed unless the specific
    analytes are requested.
  distinguishing_features:
  - Raised phytanic acid and raised very-long-chain fatty acid ratios
  - Absolute very-long-chain fatty acid concentrations may be normal
  - Biallelic PEX10 variants on sequencing
  evidence:
  - reference: PMID:20695019
    reference_title: "Mutations in PEX10 are a cause of autosomal recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peroxisomal biogenesis disorders should be considered in the differential diagnosis
      of autosomal recessive ataxia.
    explanation: The authors' own statement of where this entry sits in a clinical differential.
- name: Zellweger spectrum disorders of other complementation groups
  description: >-
    The other twelve ZSD-PEX genes produce overlapping phenotypes across the same severity
    range. The distinction is molecular, and it does not change management.
  distinguishing_features:
  - Different causal PEX gene on sequencing
  - Clinically and biochemically overlapping at the same point on the severity range
  evidence:
  - 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: >-
      States 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#Partial Failure of Peroxisomal Matrix Protein Import
  - biochemical#Very-long-chain fatty acid ratios
  prompt: >-
    How often is every standard peroxisomal test - plasma very-long-chain fatty acids and
    cultured-fibroblast assays - normal in a patient who nevertheless has biallelic PEX10
    variants and disease?
  rationale: >-
    Two independent observations say the standard screen can be silent at this end of the
    allelic series: the absolute very-long-chain fatty acid concentration is normal in
    several of the reported ataxic patients, and one PEX10 patient with clearly abnormal
    blood metabolites had normal results across multiple peroxisomal pathways in cultured
    fibroblasts. Neither observation comes with a denominator for false negatives, because
    both come from patients who were eventually diagnosed. Nobody has counted the patients
    in whom the screen was normal and the diagnosis was therefore never made, so the true
    sensitivity of a peroxisomal screen in unexplained recessive ataxia is unknown. That is
    the number a clinician deciding whether to sequence needs.
  evidence:
  - reference: PMID:19127411
    reference_title: "A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite the abnormal metabolites detected in blood (phytanate, bile acid
      intermediates and pipecolate), analysis of multiple peroxisomal pathways in
      fibroblasts yielded normal results.
    explanation: >-
      A PEX10 patient in whom the fibroblast assays - the reference method for a biogenesis
      disorder - were entirely normal.
  - reference: PMID:35038753
    reference_title: "How to Detect Isolated PEX10-Related Cerebellar Ataxia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA
      levels were in normal limits in several patients.
    explanation: >-
      The blood-side version of the same problem: the analyte most laboratories report was
      normal in several patients who had the disease.
- discussion_id: where_the_ataxic_form_belongs
  kind: CONTROVERSY
  attaches_to:
  - disease#
  - has_subtypes#Ataxic form
  prompt: >-
    Is the PEX10 ataxic form part of peroxisome biogenesis disorder 6B, or a third band
    distinct from both 6A and the neonatal adrenoleukodystrophy presentation?
  rationale: >-
    The literature says both things. One group describes PEX10 as causing three subtypes -
    Zellweger syndrome, neonatal adrenoleukodystrophy and an ataxic form - which reads as a
    third band alongside, not inside, the 6B concept; the existing dismech entry for
    peroxisome biogenesis disorder 6A follows that reading and carries the ataxic form as a
    differential diagnosis. Against that, a published ataxic patient is labelled peroxisome
    biogenesis disorder 6B by the authors reporting him, and the OMIM concept that
    MONDO:0013937 maps to covers the milder PEX10 phenotypes generally. This entry takes
    the second reading, because the A/B pair is a severity split with only two members and
    an ataxic form that sat outside both would have no ontology class to live in. The
    consequence is recorded rather than hidden: the ataxic form is curated here as a
    subtype, and the peroxisome biogenesis disorder 6A entry's differential row describing
    it now overlaps this entry.
  evidence:
  - reference: PMID:28320181
    reference_title: "Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders,
      namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an
      ataxic form (mild)
    explanation: The three-band reading, which treats the ataxic form as its own subtype.
  - reference: PMID:30640048
    reference_title: "Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To describe the clinical and genetic features of a Chinese peroxisome biogenesis
      disorder 6B patient with PEX10 mutations and review PEX10-related peroxisomal
      disorders.
    explanation: >-
      The competing reading, in which an ataxic patient simply is a peroxisome biogenesis
      disorder 6B patient. Recorded as refuting the three-band framing above, because the
      two cannot both be the right way to file this presentation.
  - reference: PMID:40267090
    reference_title: "Identification of novel compound heterozygous variants in the PEX10 gene in a Han-Chinese family with PEX10-related peroxisome biogenesis disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three patients had similar phenotypes of milder PBDs, which were further
      genetically determined as PBD6B.
    explanation: >-
      A second, independent group assigning milder PEX10 disease to the PBD6B label
      directly. Recorded on the same side as the sentence above: it treats PBD6B as the
      home of milder PEX10 disease generally rather than of one named presentation.
notes: >-
  Lump/split decision: DISEASE, curated as the mild band of the PEX10 allelic series at
  MONDO:0013937, and not as a has_subtypes row on peroxisome biogenesis disorder 6A. That
  follows repository precedent. Two A/B pairs are already curated as separate Disease
  entries at exactly this granularity - 4A/4B and 11A/11B - and they are the direct
  analogue of this pair. Peroxisome_Biogenesis_Disorder_1B and _2B are also separate
  entries, although their A arms are still uncurated stubs. The decision also follows the
  ontology, which gives 6A and 6B separate MONDO and OMIM identifiers. The stub is retired
  accordingly.

  Within the entry, the ataxic form and the neonatal adrenoleukodystrophy presentation are
  curated as two has_subtypes rows rather than as one undifferentiated mild band. They are
  not equally evidenced and the entry should not be read as if they were. The ataxic form
  has a real literature: fourteen patients from nine families, several independent case
  series, and a paper that labels its patient peroxisome biogenesis disorder 6B in so many
  words. The neonatal adrenoleukodystrophy presentation at this locus rests on one patient
  in the 2000 genotype-phenotype survey, and everything else recorded for it here - retinal
  dystrophy, liver dysfunction - comes from the spectrum-wide GeneReviews description of
  intermediate and milder ZSD rather than from any PEX10 source. Those two phenotypes are
  scoped to that subtype and their evidence items are graded accordingly.

  Neither has_subtypes row carries a 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. No MONDO class
  exists for a PEX10 ataxic form.

  Whether the ataxic form belongs inside 6B at all is genuinely contested in the sources,
  and is recorded as a CONTROVERSY discussion rather than settled silently. Note the
  practical consequence for the KB: the peroxisome biogenesis disorder 6A entry carries a
  differential row for the PEX10 ataxic form, written on the reading that it is a third
  band. That row and this entry now describe the same patients.

  Ataxia is bound to HP:0001251, for which "Cerebellar ataxia" is HPO's own exact synonym.
  Searching HPO through the OLS search API for "cerebellar ataxia" returns fourteen hits
  and no class carrying that string as its primary label: HP:0001251 Ataxia holds it as a
  synonym, and the nearest labelled alternatives are the course-qualified HP:0002073
  Progressive cerebellar ataxia and HP:0002470 Nonprogressive cerebellar ataxia.
  HP:0002073 was considered and not taken, on the repository's convention of carrying
  course on the clinical_course slot rather than inside the term. The course itself is not
  in doubt and the binding asserts it: two of the cited series describe the ataxia as
  progressive or slowly progressive, and both sentences are quoted on the phenotype record.

  Cognitive impairment is common and not obligatory: present in nine of fourteen reported
  patients, and explicitly absent in the two of normal intelligence who founded the
  presentation. A reader using normal intelligence to exclude the diagnosis would be wrong.

  Two limitations are worth naming. No animal model is curated: no PEX10-specific model is
  reported in the sources cited here. And no treatment in this entry has an outcome reported
  in a PEX10 patient. Cholic acid has an FDA approval and a reported hepatic and biochemical
  benefit, but both are for the Zellweger spectrum as a class; the only PEX10-specific
  treatment sentence in the literature cited here says the drug and the phytanic acid
  restriction "were started" and gives no follow-up. Every treatment evidence item that
  bears on efficacy is therefore INDIRECT - the three on cholic acid and the one on dietary
  phytanic acid restriction - and nothing in the entry claims an effect on the cerebellar disease
  that defines this band. The items on symptomatic management and on surveillance carry no
  directness, because they describe what is done rather than what it achieves.

📚

References & Deep Research