Peroxisome Biogenesis Disorder

Genetic MONDO:0019234 Pathograph 41 Inborn Error of Metabolism Peroxisomal Disorder

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Inheritance

Autosomal recessive

Show evidence (2 references)

PMID:14527301 SUPPORT

"The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal recessive complementation groups (CGs)."

This reference directly states that peroxisome biogenesis disorders are autosomal recessive.

PMID:9264803 SUPPORT

"With the exception of X-bound adrenoleukodystrophy, all diseases are based on autosomally recessive type of inheritance and a majority of them are characteristic by specific neurologic symptoms."

This reference also confirms the autosomal recessive inheritance of peroxisomal diseases, including PBDs.

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Pathophysiology

Peroxisome Biogenesis Defect

Mutations in PEX genes disrupt the assembly and function of peroxisomes, leading to impaired metabolic processes.

PEX1 link PEX6 link PEX13 link PEX26 link PEX2 link PEX10 link PEX12 link PEX5 link PEX7 link

Peroxisome link

Downstream

Impaired Peroxisome Biogenesis and Import PEX-gene defects disrupt assembly and import machinery needed for functional peroxisomes.

Peroxisome-Organelle Crosstalk Disruption Loss of functional peroxisomes disrupts lipid handling and contacts with ER and mitochondria.

Microglial Dysfunction and Neuroinflammation Peroxisomal defects in CNS-resident microglia promote lipid-stress and inflammatory phenotypes.

Multisystem Involvement Global peroxisome dysfunction affects development and metabolic homeostasis across organ systems.

Show evidence (6 references)

PMID:33417206 SUPPORT

"Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs)."

This reference highlights that mutations affecting peroxisome biogenesis lead to dysfunction of peroxisomes and consequently to metabolic impairments.

PMID:28409474 SUPPORT

"More than a dozen complementation groups of animal somatic mutant cells defective in peroxisome biogenesis have been successfully isolated in Chinese hamster ovary (CHO) cells and used as a model system reflecting fatal human severe genetic disorders named peroxisome biogenesis disorders (PBD)."

Defective peroxisome biogenesis due to mutations in PEX genes supports the statement about peroxisomal disorders and impaired metabolic processes.

PMID:28320181 SUPPORT

"Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and 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 reference details how mutations in PEX10 affect peroxisomal import, aligning with the statement's assertion about disrupted peroxisome function.

+ 3 more references

Accumulation of Toxic Metabolites

The inability to break down very long-chain fatty acids (VLCFAs) and other compounds leads to their accumulation in tissues.

fatty acid beta-oxidation link very long-chain fatty acid metabolic process link

Downstream

Very Long Chain Fatty Acids (VLCFA)

Bile Acid Intermediates

Hepatic Dysfunction Accumulated bile-acid intermediates and VLCFAs contribute to liver pathology in peroxisomal disorders.

Neurological Dysfunction Accumulated peroxisomal lipid metabolites contribute to CNS lipid imbalance and neurodegeneration.

Show evidence (3 references)

PMID:19933170 PARTIAL

"Peroxisomes are vital eukaryotic organelles that participate in lipid metabolism, in particular the metabolism of very-long-chain fatty acids (VLCFA)... including impaired peroxisomal protein import, elevated VLCFA levels and growth retardation."

The reference supports the accumulation of VLCFAs as part of the pathophysiology of Peroxisome Biogenesis Disorders but does not mention bile acid intermediates or phytanic acid.

PMID:3119940 PARTIAL

"In patients with cerebro-hepato-renal (Zellweger) syndrome, the absence of peroxisomes results in an impairment of metabolic processes... These include the catabolism of very long chain (greater than C22) fatty acids... the catabolism of phytanic acid and the catabolism of pipecolic acid."

This reference supports the accumulation of VLCFAs and phytanic acid in peroxisomal disorders but does not mention bile acid intermediates.

PMID:22978395 PARTIAL

"By comparing the different peroxisomal disorders, we provide evidence suggesting that the main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA)."

This reference supports the accumulation of bile acid intermediates in peroxisomal disorders but does not mention VLCFAs or phytanic acid.

Deficiency of Essential Compounds

Impaired synthesis of plasmalogens and other essential compounds disrupts normal cellular functions.

ether lipid biosynthetic process link bile acid biosynthetic process link

Downstream

Plasmalogens

Neurological Dysfunction Plasmalogen and ether-lipid deficiency impairs CNS myelin and neuronal lipid homeostasis.

Skeletal Abnormalities Plasmalogen deficiency is linked to chondrodysplasia punctata and abnormal skeletal development.

Retinal Pigment Epithelium Dysfunction Retinal lipid remodeling reflects deficient ether-lipid and plasmalogen metabolism.

Show evidence (3 references)

PMID:36720320 SUPPORT

"The absence of plasmalogens in several organs of patients with deficiency in peroxisome biogenesis suggests that de novo synthesis of plasmalogens contributes significantly to plasmalogen homeostasis in humans."

The literature indicates that plasmalogen biosynthesis is significantly affected in patients with peroxisome biogenesis disorders, which supports the statement regarding impaired synthesis of plasmalogens disrupting normal cellular functions.

PMID:32165495 SUPPORT

"The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid beta-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction..."

This study reinforces that impaired peroxisome function, including the biosynthesis of plasmalogens, leads to a broad spectrum of cellular dysfunctions.

PMID:33417206 SUPPORT

"Peroxisomes are presented in all eukaryotic cells and play essential roles in many of lipid metabolic pathways, including beta-oxidation of fatty acids and synthesis of ether-linked glycerophospholipids, such as plasmalogens."

The abstract confirms that peroxisomes are crucial for the synthesis of plasmalogens and that their dysfunction could disrupt normal cellular functions.

Neurological Dysfunction

Accumulation of toxic metabolites and deficiency of essential compounds lead to demyelination, neuronal migration defects, and neurodegeneration.

oligodendrocyte link

central nervous system link

Downstream

Hypotonia

Developmental Delay

Seizures

Leukodystrophy

Show evidence (5 references)

PMID:15868469 SUPPORT

"Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes."

The reference specifies that a lack of functional peroxisomes leads to severe neurological dysfunction, including demyelination and defects in neuronal migration, which aligns with the statement's content.

PMID:33417206 SUPPORT

"Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs)."

This reference describes PBDs leading to significant neurodegeneration and psychomotor dysfunction, consistent with the statement on neurological dysfunction due to the disorder.

PMID:22978395 PARTIAL

"Liver pathology is a frequent finding in patients affected by a peroxisomal disorder. ... we provide evidence suggesting that the main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid..."

While this reference supports the role of toxic metabolites, it focuses on liver pathology rather than CNS-specific features like demyelination and neuronal migration defects.

+ 2 more references

Hepatic Dysfunction

Accumulation of bile acid intermediates and VLCFAs, along with oxidative stress, cause hepatomegaly, fibrosis, and liver failure.

hepatocyte link

liver link

Downstream

Hepatomegaly

Cholestasis

Thrombocytopenia Hematologic abnormalities are modeled as secondary to severe multisystem or hepatic involvement when present.

Show evidence (6 references)

PMID:12473763 SUPPORT

"Common to these three disorders are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness."

The study mentions liver disease as a common symptom of peroxisome biogenesis disorder (PBD), supporting hepatic dysfunction.

PMID:22978395 SUPPORT

"The main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA)."

This reference supports the accumulation of bile acid intermediates causing liver pathology in PBDs.

PMID:29282281 SUPPORT

"They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality"

This reference indirectly supports the statement by discussing the lethal and severe impact of PBDs, including liver dysfunction.

+ 3 more references

Skeletal Abnormalities

Plasmalogen deficiency disrupts normal bone formation, leading to rhizomelic shortening of limbs and chondrodysplasia punctata.

bones link cartilage link

Downstream

Chondrodysplasia Punctata

Craniofacial Dysmorphism Craniofacial dysmorphism is grouped with abnormal skeletal and developmental patterning in severe presentations.

Show evidence (4 references)

PMID:10904262 SUPPORT

"Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata are progressive disorders characterized by loss of multiple peroxisomal metabolic functions."

The context indicates that rhizomelic chondrodysplasia punctata (a type of peroxisome biogenesis disorder) results from peroxisomal dysfunction, supporting the connection between plasmalogen deficiency and skeletal abnormalities, including rhizomelic shortening of limbs and chondrodysplasia punctata.

PMID:10972423 SUPPORT

"The case of a Yemeni girl with isolated peroxisomal acyl-CoA:dihydroxyacetonephosphate acyltransferase (DHAPAT) deficiency is reported. She had rhizomelic chondrodysplasia punctata, microcephaly, failure to thrive, delayed motor and mental development, and spastic quadriplegia."

The document discusses a case where plasmalogen biosynthesis deficiency leads to rhizomelic chondrodysplasia punctata, supporting the statement.

PMID:8507680 SUPPORT

"The results have clearly shown an indispensable role for peroxisomes in the total process of ether lipid synthesis as evidenced by a description of the cellular topography of this process."

The paper supports the importance of peroxisomes in lipid synthesis, including plasmalogens, which are associated with diseases like rhizomelic chondrodysplasia punctata that impact bone and cartilage formation.

+ 1 more reference

Multisystem Involvement

The pervasive nature of peroxisomal dysfunction affects multiple organ systems, resulting in a wide range of clinical manifestations.

Downstream

Renal Dysfunction Renal involvement is connected through broad cerebro-hepato-renal multisystem disease rather than a single curated renal mechanism.

Hearing Loss Hearing loss is a recurrent sensory manifestation of the multisystem PBD-ZSD spectrum.

Adrenal Insufficiency Adrenal insufficiency is included as an endocrine manifestation of peroxisomal disease, with the proximal mechanism not yet separated in this graph.

Cardiomyopathy Cardiac involvement remains mechanistically unresolved in this entry.

Heart Failure Heart failure is retained as a downstream severe cardiac outcome where cardiomyopathy is present.

Show evidence (6 references)

PMID:14527301 SUPPORT

"The multisystem clinical phenotype varies widely in severity and results from disturbances in both development and metabolic homeostasis."

This statement supports the pervasive nature of peroxisomal dysfunction affecting multiple organ systems, leading to a range of clinical manifestations.

PMID:33417210 SUPPORT

"Peroxisomopathies are rare diseases due to dysfunctions of the peroxisome in which this organelle is either absent or with impaired activities. These diseases... affect the central and peripheral nervous system."

This statement aligns with the notion that peroxisomal dysfunction affects multiple organ systems.

PMID:26453805 SUPPORT

"The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders... including mitochondria and the ER."

This reference details the involvement of multiple cellular compartments and metabolic pathways, illustrating multisystem impact.

+ 3 more references

Microglial Dysfunction and Neuroinflammation

Peroxisomal defects in microglial cells induce a disease-associated microglial (DAM) signature with altered lipid metabolism, lipid droplet accumulation, and impaired autophagy, contributing to neurodegeneration.

microglial cell link

central nervous system link

Downstream

Neurological Dysfunction Microglial lipid stress and neuroinflammation contribute to CNS degeneration and neurologic manifestations.

Peroxisome-Organelle Crosstalk Disruption

Disruption of peroxisome-ER-mitochondria interactions impairs lipid trafficking and metabolic coordination, particularly affecting VLCFA and ether-lipid flux between organelles.

peroxisome link endoplasmic reticulum link mitochondrion link

Downstream

Accumulation of Toxic Metabolites Defective peroxisome-organelle lipid trafficking contributes to VLCFA and related lipid accumulation.

Deficiency of Essential Compounds ER-peroxisome lipid trafficking is required for normal ether-lipid and plasmalogen homeostasis.

Retinal Pigment Epithelium Dysfunction

In peroxisome biogenesis disorders, retinal pigment epithelium shows progressive lipid remodeling with decreased plasmalogens and increased very-long-chain lysophosphatidylcholines, leading to structural degeneration and vision loss.

retinal pigment epithelial cell link photoreceptor cell link

retina link

Downstream

Retinopathy

Impaired Peroxisome Biogenesis and Import

Mutations in PEX genes disrupt the peroxisomal protein import machinery, including PEX5/PEX7 receptors, the PEX13/PEX14 docking complex, and the PEX1-PEX6 AAA+ ATPase export complex, preventing proper assembly and function of peroxisomes.

protein import into peroxisome matrix link peroxisome organization link

peroxisome link

Downstream

Accumulation of Toxic Metabolites Failed matrix-enzyme import disables peroxisomal beta-oxidation and related catabolic pathways.

Deficiency of Essential Compounds Failed peroxisomal assembly and import impair ether-lipid, plasmalogen, and bile-acid synthetic steps.

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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

Blood 1

Thrombocytopenia OCCASIONAL Thrombocytopenia (HP:0001873)

Low platelet count

Show evidence (2 references)

PMID:27941306 NO_EVIDENCE

"Peroxisome is a single-membrane-bounded ubiquitous organelle containing a hundred different enzymes that catalyze various metabolic pathways such as beta-oxidation of very long-chain fatty acids and synthesis of plasmalogens."

The provided literature does not mention thrombocytopenia or any hematologic symptoms in relation to Peroxisome Biogenesis Disorders.

PMID:31884631 NO_EVIDENCE

"Peroxisomal disorders are a group of inherited metabolic diseases, which can be incompatible with life in the postnatal period or allow survival into adulthood. Retinopathy is a recurrent feature in both the severely and mildly affected patients, which can be accompanied with other..."

This reference discusses peroxisomal disorders but does not mention thrombocytopenia or other hematologic conditions.

Cardiovascular 2

Cardiomyopathy OCCASIONAL Cardiomyopathy (HP:0001638)

Sequelae: Heart Failure

Show evidence (2 references)

PMID:25465824 PARTIAL

"CI in MIDs includes cardiomyopathy, arrhythmias, heart failure, pulmonary hypertension, dilation of the aortic root, pericardial effusion, coronary heart disease, autonomous nervous system dysfunction, congenital heart defects, or sudden cardiac death."

The literature confirms that cardiomyopathy and heart failure are associated with mitochondrial disorders (MIDs), which are a type of metabolic disorder. However, it does not specifically mention peroxisome biogenesis disorders (PBDs) in this context.

PMID:36870438 NO_EVIDENCE

"Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure."

This reference provides an overview of pediatric cardiomyopathies but does not specifically mention peroxisome biogenesis disorders (PBDs) as a cause.

Heart Failure FREQUENT Congestive heart failure (HP:0001635)

Digestive 2

Hepatomegaly FREQUENT Hepatomegaly (HP:0002240)

Show evidence (3 references)

PMID:31005404 PARTIAL

"Inherited metabolic diseases account for about one third of pediatric patients with hepatomegaly, acute liver failure, cirrhosis or cholestasis."

The reference states that inherited metabolic diseases, which include peroxisome biogenesis disorders, account for a substantial portion of pediatric hepatomegaly cases but does not specify the frequency as 'frequent.'

PMID:22978395 PARTIAL

"Liver pathology is a frequent finding in patients affected by a peroxisomal disorder."

The reference mentions liver pathology as frequent but does not specifically state hepatomegaly.

PMID:26615381 NO_EVIDENCE

"Zellweger syndrome (ZS) is a peroxisomal disorder with a multiple congenital anomalies, characterized by stereotypical facies, profound hypotonia, organ involvement including cerebral, retinal, hepatic, and renal."

The reference discusses organ involvement including hepatic involvement but does not specify hepatomegaly as frequent.

Cholestasis FREQUENT Cholestasis (HP:0001396)

Due to bile acid biosynthetic block and hepatic lipid handling deficits

Ear 1

Hearing Loss FREQUENT Hearing impairment (HP:0000365)

Show evidence (3 references)

PMID:34534157 SUPPORT

"The majority of PBD-ZSD patients in this study presented with moderately-severe to severe hearing loss and relatively slow rates of longitudinal changes in hearing sensitivity."

This study characterizes hearing loss as a common phenotype in patients with Peroxisome Biogenesis Disorder within the Zellweger Spectrum.

PMID:36291074 SUPPORT

"Peroxisome biogenesis disorders (due to PEX gene mutations) are associated with symptoms that range in severity and can lead to early childhood death, but a common feature is hearing impairment."

This study also confirms hearing impairment as a frequent phenotype in Peroxisome Biogenesis Disorders, further supporting the statement.

PMID:33417209 SUPPORT

"Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic variations. This syndrome is one of the less severe forms of peroxisome biogenesis disorders."

Heimler syndrome, a less severe form of peroxisome biogenesis disorders, frequently presents with sensorineural hearing loss, further supporting the frequent association of hearing loss with these disorders.

Endocrine 1

Adrenal Insufficiency FREQUENT Adrenal insufficiency (HP:0000846)

Due to adrenal gland dysfunction

Show evidence (2 references)

PMID:36649687 SUPPORT

"Primary adrenal insufficiency is common in patients with PD. Based on our data, patients with the compound heterozygous PEX1 pathogenic variants of exon 13 (c.2097dupT and c.2528G>A) tend to have adrenal insufficiency."

The study indicates that primary adrenal insufficiency is frequent in patients with peroxisomal disorders, specifically those with PEX1 pathogenic variants.

PMID:25179809 SUPPORT

"Primary adrenal insufficiency was found in 7/24 patients examined, with 4/7 being asymptomatic. Systematic evaluation of adrenal function, through a Synacthen test, should be included in the clinical management of these patients."

The study highlights a high prevalence of primary adrenal insufficiency in patients with Zellweger spectrum disorders, which are a type of peroxisome biogenesis disorder.

Eye 1

Retinopathy FREQUENT Retinopathy (HP:0000488)

Show evidence (4 references)

PMID:31884631 SUPPORT

"Retinopathy is a recurrent feature in both the severely and mildly affected patients, which can be accompanied with other ophthalmological pathologies."

The study states that retinopathy is a recurrent feature in patients with peroxisomal disorders, supporting the statement that visual phenotypes, specifically retinopathy, are frequent.

PMID:12473763 SUPPORT

"Common to these three disorders are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness."

The study indicates that retinopathy is common in peroxisome biogenesis disorders like Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, supporting the frequent occurrence of retinopathy as a visual phenotype.

PMID:35227579 SUPPORT

"Retinal degeneration with or without optic atrophy is the most frequent phenotype, followed by oculomotor problems, involvement of the cornea and lens, and refractive errors."

The study states that retinal degeneration is the most frequent ocular phenotype observed in inherited metabolic disorders, which includes peroxisome biogenesis disorders, thereby supporting the frequent occurrence of retinopathy.

+ 1 more reference

Genitourinary 1

Renal Dysfunction OCCASIONAL Chronic kidney disease (HP:0012622)

Variable kidney dysfunction across the spectrum

Musculoskeletal 1

Hypotonia VERY_FREQUENT Hypotonia (HP:0001252)

Show evidence (4 references)

PMID:7685145 SUPPORT

"These disorders should be considered in the differential diagnosis of the infant with hypotonia and psychomotor delay (especially if accompanied by facial dysmorphisms, hepatomegaly, cataracts and/or retinitis, calcific stippling, short limbs, or combinations of these features), in the..."

The reference mentions hypotonia as a significant clinical feature in peroxisomal disorders.

PMID:28320181 PARTIAL

"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."

While the reference primarily discusses cerebellar involvement, it indirectly supports the statement by implicating neurological systems in PEX10-related peroxisome biogenesis disorders.

PMID:13129589 SUPPORT

"The floppy infant syndrome is a well-recognized entity for pediatricians and neonatologists. The condition refers to an infant with generalized hypotonia presenting at birth or in early life."

The reference directly supports the very frequent occurrence of hypotonia in infants with peroxisomal disorders.

+ 1 more reference

Nervous System 3

Developmental Delay VERY_FREQUENT Global developmental delay (HP:0001263)

Show evidence (5 references)

PMID:7685145 SUPPORT

"Because peroxisomes are involved in the metabolism of lipids critical to the functioning of the nervous system, many of the peroxisomal disorders manifest with significant degrees of progressive psychomotor dysfunction."

The literature indicates that peroxisomal disorders, which include Peroxisome Biogenesis Disorders (PBDs), frequently present with progressive psychomotor dysfunction, supporting the statement that developmental delay is a very frequent neurologic phenotype.

PMID:36293220 SUPPORT

"The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease."

Although this does not explicitly mention developmental delay, the overall description implies a frequent occurrence of neurologic dysfunction, which is often tied to developmental delays.

PMID:11769739 SUPPORT

"Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy."

The article describes neurologic deficits appearing early in life, which aligns with developmental delays being a very frequent phenotype.

+ 2 more references

Seizures FREQUENT Seizure (HP:0001250)

Common in severe forms, particularly neonatal Zellweger syndrome

Leukodystrophy FREQUENT Leukodystrophy (HP:0002415)

White matter degeneration due to myelin lipid dependency on peroxisomal function

Other 2

Craniofacial Dysmorphism OCCASIONAL

Show evidence (2 references)

PMID:23671347 SUPPORT

"Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities."

Distinctive facial stigmata can be considered a form of craniofacial dysmorphism, supporting the statement.

PMID:1710072 PARTIAL

"Zellweger syndrome, the most lethal of the three peroxisomal biogenesis disorders, causes infantile hypotonia, seizures, and death within the first year."

While the text does not explicitly mention craniofacial dysmorphism, the severity of symptoms and multisystem involvement suggest potential craniofacial manifestations.

Chondrodysplasia Punctata OCCASIONAL

Stippling of epiphyses on X-rays

Show evidence (3 references)

PMID:10904262 SUPPORT

Rhizomelic chondrodysplasia punctata is a type of peroxisome biogenesis disorder, supporting the statement that chondrodysplasia punctata falls under the category of musculoskeletal issues associated with peroxisome biogenesis disorders.

PMID:24030027 SUPPORT

"We present a 2-month-old male affected by Zellweger syndrome, a rare peroxisomal disorder. The diagnosis was supported by clinical and radiological findings and established by biochemical tests. The characteristic radiological features included anomalous ossification (epiphyseal stippling)."

This study supports the statement by indicating that epiphyseal stippling (chondrodysplasia punctata) is a characteristic feature in Zellweger syndrome, a type of peroxisome biogenesis disorder.

PMID:17671048 SUPPORT

"Classic rhizomelic chondrodysplasia punctata is a rare, autosomal, recessively inherited disorder that is characterized by proximal shortening of the limbs, punctuate calcifications of the epiphyses, cataracts, developmental delay, and early lethality."

Rhizomelic chondrodysplasia punctata is characterized by punctuate calcifications of the epiphyses, supporting the statement that this condition is associated with peroxisome biogenesis disorders and involves stippling of epiphyses.

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Genetic Associations

PEX1 (Pathogenic Variants)

Show evidence (2 references)

PMID:33955040 SUPPORT

"Zellweger syndrome (ZS) is the foremost common and severe phenotype within the heterogeneous ZSD. However, missense mutations encode proteins with residual functions, which are associated with phenotypes that are milder than ZS. Mutations in the PEX1 gene are among the most prevalent."

The statement is supported as it mentions that mutations in the PEX1 gene are among the most prevalent causes of Zellweger syndrome, which is a type of PBD.

CGGV:assertion_a345ba65-9dcd-43dd-a1c2-1778c1a921ea-2023-09-06T160000.000Z SUPPORT Other

ClinGen classifies the PEX1-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX6 (Pathogenic Variants)

Show evidence (6 references)

PMID:17055079 SUPPORT

"Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD)."

This statement indicates that mutations in PEX genes, including PEX6, are foundational to the development of peroxisome biogenesis disorders.

PMID:15858711 SUPPORT

"Matsumoto and colleagues recently identified PEX26 as the gene responsible for complementation group 8 of the peroxisome biogenesis disorders... Here, we identify new PEX26 disease alleles, localize the PEX6-binding domain to the N-terminal half of the protein (aa 29-174), and show that, at the..."

This paper discusses PEX26 in detail but also underscores the critical function of PEX6 in peroxisome biogenesis.

PMID:36980088 SUPPORT

"Genetic testing revealed a mutation of the PEX6 (Peroxisomal Biogenesis Factor 6) gene, and the metabolic profile was consistent with the diagnosis."

This case report directly links pathogenic variants in PEX6 to a specific case of peroxisome biogenesis disorder.

+ 3 more references

PEX13 (Pathogenic Variants)

Show evidence (1 reference)

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

ClinGen classifies the PEX13-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX26 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_bf6af95e-6696-420c-8731-d2e37ca6e692-2020-02-07T170000.000Z SUPPORT Other

ClinGen classifies the PEX26-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX2 (Pathogenic Variants)

Show evidence (1 reference)

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

ClinGen classifies the PEX2-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX10 (Pathogenic Variants)

Show evidence (1 reference)

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

ClinGen classifies the PEX10-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX12 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_124c97b0-92ed-4921-a0b9-2ff33135139d-2019-12-06T170000.000Z SUPPORT Other

ClinGen classifies the PEX12-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX5 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_b49d9cfd-0e51-4219-84bb-76b4c9b99fa9-2020-01-17T170000.000Z SUPPORT Other

ClinGen classifies the PEX5-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX7 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_d0796d69-b304-4670-b4a2-8785ff6fd161-2020-02-14T170000.000Z SUPPORT Other

ClinGen classifies the PEX7-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

Other PEX Genes (Pathogenic Variants)

Show evidence (4 references)

PMID:10904262 SUPPORT

"Recent studies have identified the PEX genes that are mutated in 11 of the 12 known complementation groups of PBD patients."

This reference indicates that pathogenic variants in other PEX genes are associated with Peroxisome Biogenesis Disorder (PBD).

PMID:32399598 SUPPORT

"For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum."

Although this reference primarily discusses Perrault syndrome, it confirms that variants in PEX genes such as PEX6 are associated with peroxisomal biogenesis disorders.

PMID:34804114 SUPPORT

"Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum."

This reference highlights PEX26 gene variants contributing to peroxisomal disorders which fall under the broader category of peroxisome biogenesis disorders.

+ 1 more reference

PEX11B (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_93eacb33-b099-485d-bf8a-782479dc0a3b-2020-01-17T170000.000Z SUPPORT Other

ClinGen classifies the PEX11B-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX14 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_846efcc3-5456-4db3-9bc2-e441acb768cd-2019-09-20T160000.000Z SUPPORT Other

ClinGen classifies the PEX14-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX16 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_7506d938-efb4-416c-aafd-221251d00e6e-2020-01-13T170000.000Z SUPPORT Other

ClinGen classifies the PEX16-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX19 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_fa073c77-0623-4e82-b5b2-9fcd0eb0dc6e-2023-04-27T160000.000Z SUPPORT Other

ClinGen classifies the PEX19-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

PEX3 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_d53df483-c31a-4672-8a11-04d33d6df336-2019-11-01T160000.000Z SUPPORT Other

ClinGen classifies the PEX3-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.

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Treatments

Symptomatic Management

Action: physical therapy MAXO:0000011

Supportive care addressing specific symptoms such as physical therapy for hypotonia and seizure management.

Mechanism Target:

MODULATES Neurological Dysfunction — Symptomatic therapy targets neurologic manifestations such as hypotonia and seizures without correcting the upstream peroxisome defect.

Show evidence (2 references)

PMID:11060787 PARTIAL

"Treatment of PBD patients has generally involved only supportive care and symptomatic therapy."

The statement about supportive care and symptomatic therapy is accurate but does not explicitly mention physical therapy for hypotonia and seizure management.

PMID:38409970 PARTIAL

"Despite an absence of treatment options, prompt diagnosis of Zellweger syndrome is important for providing appropriate symptomatic care, definitive genetic testing and prenatal counselling."

The statement supports symptomatic care but does not detail specific treatments such as physical therapy for hypotonia or seizure management.

Nutritional Support

Action: dietary intervention MAXO:0000088

Specialized diet and supplements to manage biochemical abnormalities.

Mechanism Target:

MODULATES Accumulation of Toxic Metabolites — Dietary modification and supplementation are intended to reduce or manage toxic metabolite burden.

MODULATES Deficiency of Essential Compounds — Supplementation can address deficient products downstream of impaired peroxisomal metabolism.

Show evidence (3 references)

PMID:11060787 SUPPORT

"A number of experimental therapies have been evaluated to determine whether or not correction of biochemical abnormalities through dietary supplementation and/or modification is of clinical benefit to PBD patients."

This snippet indicates that dietary supplementation and/or modification has been evaluated to manage biochemical abnormalities in PBD patients, supporting the statement that specialized diet and supplements can be a treatment strategy.

PMID:18758655 SUPPORT

"The most important measures used to manage the intoxication present in many inborn errors of intermediate metabolism were presented (restriction of substrate build-up by means of diet or enzymatic inhibition, removal of toxic products, stimulation of residual enzyme activity, replacement of the..."

This reference discusses the use of diet as a measure to manage biochemical abnormalities in metabolic disorders, including peroxisomal diseases, which supports the statement.

PMID:16819396 NO_EVIDENCE

"Bile-acid therapy using oral cholic acid has proven effective in most of these bile acid synthetic defects making early diagnosis crucial to optimum clinical prognosis."

While this reference discusses a specific bile-acid therapy, it does not provide evidence about dietary or supplemental approaches for managing biochemical abnormalities in PBDs.

Liver Transplant

Action: organ transplantation MAXO:0010039

Considered in severe cases with significant liver dysfunction.

Mechanism Target:

BYPASSES Hepatic Dysfunction — Liver transplantation replaces failing hepatic function but does not correct systemic PEX-gene biogenesis defects.

Show evidence (3 references)

PMID:35331403 SUPPORT

"Most of these disorders are currently treated by liver transplantation as standard of care."

The reference indicates that liver transplantation is the standard of care for congenital inherited hepatic disorders, which includes peroxisomal disorders like Peroxisome Biogenesis Disorder (PBD), supporting that liver transplant is considered in severe cases with significant liver dysfunction.

PMID:26615381 PARTIAL

"ZS should be considered in the list of differential diagnosis in infants with stereotypical phenotype, neurodevelopmental delay, and severe hypotonia in association with liver and other organs involvement."

While this reference confirms liver involvement in Peroxisome Biogenesis Disorders such as Zellweger Syndrome, it does not specifically mention liver transplantation as a treatment.

PMID:22974902 PARTIAL

"When none of the liver parenchyma is spared, or kidney insufficiency is marked, the only potentially curable treatment is liver transplantation (LT)."

This reference supports the use of liver transplantation in severe liver conditions, though it does not directly mention Peroxisome Biogenesis Disorder.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Providing information and support to families regarding inheritance and implications.

Show evidence (2 references)

PMID:14619605 SUPPORT

"Genetic counseling has developed as a discipline in response to the need to educate patients, families and professionals about genetic mechanisms and their application in health care. ... Genetic counseling is a process of medical education based upon empathy, patient autonomy and..."

The literature describes genetic counseling as a discipline developed to educate patients, families, and professionals about genetic mechanisms and their application in healthcare, which supports the statement about providing information and support to families regarding inheritance and implications.

PMID:30237433 SUPPORT

"Furthermore, it is also important to identify pre-symptomatic patients by family analysis of probands by providing appropriate disease information and genetic counseling, which will also lead to early intervention."

The literature discusses the importance of providing disease information and genetic counseling to families, supporting the statement about providing information and support to families regarding inheritance and implications in the context of peroxisomal diseases.

🌍

Environmental Factors

Not Applicable

Show evidence (2 references)

PMID:26305119 NO_EVIDENCE

"In recent years, peroxisomes have emerged as important intracellular hubs for redox-, lipid-, inflammatory-, and nucleic acid-mediated signaling pathways. In this review, we focus on how nature and nurture modulate peroxisome biogenesis and function in mammalian cells."

The literature discusses the interplay of genetic, epigenetic, and environmental factors in peroxisome biogenesis and function but does not describe peroxisome biogenesis disorders as purely environmental.

PMID:30656921 NO_EVIDENCE

"The disturbance of the peroxisome structure due to mutations in different PEX and non-PEX genes coding functional peroxisomal proteins is the pathogenic basis of the peroxisomal disorders."

The literature explains that peroxisome biogenesis disorders are due to genetic mutations, not environmental factors.

🔬

Biochemical Markers

Very Long Chain Fatty Acids (VLCFA) (Elevated)

Context: Diagnostic marker

Show evidence (5 references)

PMID:8729109 PARTIAL

"Abnormally high levels of very long-chain fatty acids (VLCFA) are a feature in nine of the fifteen peroxisomal disorders that have been identified so far."

This reference indicates that elevated VLCFA levels are a feature in nine peroxisomal disorders but does not specify peroxisome biogenesis disorders (PBD) exclusively.

PMID:14527301 NO_EVIDENCE

"The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal recessive complementation groups (CGs)."

The abstract does not mention VLCFA levels in the context of PBD diagnosis.

PMID:37567036 SUPPORT

"Multiple dicarboxylic acylcarnitines were significantly elevated in PBD patients including medium to long chain (C8-DC to C18-DC) species as well as previously undescribed elevations of malonylcarnitine (C3-DC) and very long chain dicarboxylic acylcarnitines (C20-DC and C22-DC)."

This study identifies elevated levels of very long chain dicarboxylic acylcarnitines (a type of VLCFA) in patients with PBD.

+ 2 more references

Plasmalogens (Decreased)

Context: Diagnostic marker

Show evidence (5 references)

PMID:36914043 SUPPORT

"Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders (PBD) because plasmalogen synthesis requires functional peroxisomes."

The literature clearly states that decreased levels of plasmalogens are a characteristic feature of peroxisome biogenesis disorders.

PMID:12473763 SUPPORT

"A poor correlation with age at death was found for de novo plasmalogen synthesis, C26:0/C22:0 ratio, and phytanic acid alpha-oxidation."

The study mentions that impaired plasmalogen synthesis is one of the biochemical markers analyzed in PBD patients.

PMID:3460088 SUPPORT

"The results presented here support the view that there are two DHAP acyltransferases in animal cells and that the peroxisome is essential for the biosynthesis of plasmalogens."

The literature shows that peroxisomes play an essential role in plasmalogen biosynthesis, indicating that their dysfunction leads to decreased plasmalogen levels.

+ 2 more references

Bile Acid Intermediates (Elevated)

Context: Diagnostic marker

Show evidence (3 references)

PMID:37802748 SUPPORT

"Early postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs."

“The study states that disease-specific bile acids (BAs) can be measured as markers for peroxisome biogenesis disorders (PBDs) via a dried blood spot-based screening method.”

PMID:3119940 SUPPORT

"In classic Zellweger syndrome abnormal C27-bile acids, very long chain fatty acids, dicarboxylic acids and pipecolic acid accumulate in the plasma of the patients."

The study mentions the accumulation of C27-bile acids (a type of bile acid intermediate) in the plasma of patients with Zellweger syndrome, a type of peroxisome biogenesis disorder.

PMID:3119940 SUPPORT

"In patients with cerebro-hepato-renal (Zellweger) syndrome, the absence of peroxisomes results in an impairment of metabolic processes in which peroxisomes are normally involved. These include the catabolism of very long chain (greater than C22) fatty acids, the biosynthesis of..."

The study supports the concept that certain biochemical markers, including bile acid intermediates, are elevated due to the metabolic process impairments in peroxisome biogenesis disorders.

{ }

Source YAML

click to show

name: Peroxisome Biogenesis Disorder
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-05-09T15:04:05Z'
category: Genetic
parents:
- Inborn Error of Metabolism
- Peroxisomal Disorder
prevalence:
- population: Global
  percentage: Very Rare
  evidence:
  - reference: PMID:8914632
    reference_title: "Incidence of peroxisomal disorders in Japan."
    supports: SUPPORT
    snippet: The incidence of peroxisome-deficient disorders was estimated to be approximately 1 in 800,000 births which is far less than that in the USA.
    explanation: The literature quantifies peroxisome-deficient disorders as occurring approximately 1 in 800,000 births globally, supporting the claim that the prevalence is very rare.
  - reference: PMID:34628380
    reference_title: "IMPAIRMENT OF PEROXISOME BIOGENESIS IN THE SPECTRUM OF ZELLWEGER SYNDROME (CLINICAL CASE)."
    supports: SUPPORT
    snippet: The incidence of rare diseases is approximately two cases per 10,000 people.
    explanation: The literature states that the incidence of rare diseases is approximately two cases per 10,000 people, which aligns with the statement that Peroxisome Biogenesis Disorders are very rare globally.
inheritance:
- name: Autosomal recessive
  evidence:
  - reference: PMID:14527301
    reference_title: "Peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal recessive complementation groups (CGs).
    explanation: This reference directly states that peroxisome biogenesis disorders are autosomal recessive.
  - reference: PMID:9264803
    reference_title: "[Peroxisomal hereditary diseases]."
    supports: SUPPORT
    snippet: With the exception of X-bound adrenoleukodystrophy, all diseases are based on autosomally recessive type of inheritance and a majority of them are characteristic by specific neurologic symptoms.
    explanation: This reference also confirms the autosomal recessive inheritance of peroxisomal diseases, including PBDs.
pathophysiology:
- name: Peroxisome Biogenesis Defect
  description: Mutations in PEX genes disrupt the assembly and function of
    peroxisomes, leading to impaired metabolic processes.
  genes:
  - preferred_term: PEX1
    term:
      id: hgnc:8850
      label: PEX1
  - preferred_term: PEX6
    term:
      id: hgnc:8859
      label: PEX6
  - preferred_term: PEX13
    term:
      id: hgnc:8855
      label: PEX13
  - preferred_term: PEX26
    term:
      id: hgnc:22965
      label: PEX26
  - preferred_term: PEX2
    term:
      id: hgnc:9717
      label: PEX2
  - preferred_term: PEX10
    term:
      id: hgnc:8851
      label: PEX10
  - preferred_term: PEX12
    term:
      id: hgnc:8854
      label: PEX12
  - preferred_term: PEX5
    term:
      id: hgnc:9719
      label: PEX5
  - preferred_term: PEX7
    term:
      id: hgnc:8860
      label: PEX7
  cellular_components:
  - preferred_term: Peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  evidence:
  - reference: PMID:33417206
    reference_title: "Peroxisome Biogenesis Disorders."
    supports: SUPPORT
    snippet: Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs).
    explanation: This reference highlights that mutations affecting peroxisome biogenesis lead to dysfunction of peroxisomes and consequently to metabolic impairments.
  - reference: PMID:28409474
    reference_title: "Generation of Peroxisome-Deficient Somatic Animal Cell Mutants."
    supports: SUPPORT
    snippet: More than a dozen complementation groups of animal somatic mutant cells defective in peroxisome biogenesis have been successfully isolated in Chinese hamster ovary (CHO) cells and used as a model system reflecting fatal human severe genetic disorders named peroxisome biogenesis disorders (PBD).
    explanation: Defective peroxisome biogenesis due to mutations in PEX genes supports the statement about peroxisomal disorders and impaired metabolic processes.
  - 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
    snippet: Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and 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 reference details how mutations in PEX10 affect peroxisomal import, aligning with the statement's assertion about disrupted peroxisome function.
  - reference: PMID:36249295
    reference_title: "PEX6 Mutations in Peroxisomal Biogenesis Disorders: An Usher Syndrome Mimic."
    supports: SUPPORT
    snippet: Peroxisomal biogenesis disorders (PBDs) represent a spectrum of conditions that result in vision loss, sensorineural hearing loss, neurologic dysfunction, and other abnormalities resulting from aberrant peroxisomal function caused by mutations in PEX genes.
    explanation: The study confirms that mutations in PEX genes disrupt peroxisomal functions, leading to various metabolic and physiological impairments.
  - reference: PMID:34804114
    reference_title: "Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency."
    supports: SUPPORT
    snippet: Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum.
    explanation: PEX26 mutations, which lead to peroxisomal biogenesis disorders, confirm the link between PEX gene defects and impaired peroxisomal function.
  - reference: PMID:9458170
    reference_title: "Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis."
    supports: SUPPORT
    snippet: Neurological dysfunction is a prominent feature of most peroxisomal disorders. Enormous progress in defining their gene defects has been achieved. The genes and gene products, peroxins (PEX), in five of the complementation groups have been defined.
    explanation: This reference illustrates the role of PEX genes in peroxisomal disorders, supporting the claim of their involvement in cellular and metabolic disruption.
  downstream:
  - target: Impaired Peroxisome Biogenesis and Import
    causal_link_type: DIRECT
    description: PEX-gene defects disrupt assembly and import machinery needed for functional peroxisomes.
  - target: Peroxisome-Organelle Crosstalk Disruption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Loss of functional peroxisomes disrupts lipid handling and contacts with ER and mitochondria.
  - target: Microglial Dysfunction and Neuroinflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Peroxisomal defects in CNS-resident microglia promote lipid-stress and inflammatory phenotypes.
  - target: Multisystem Involvement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Global peroxisome dysfunction affects development and metabolic homeostasis across organ systems.
- name: Accumulation of Toxic Metabolites
  description: The inability to break down very long-chain fatty acids (VLCFAs) and other compounds leads to their accumulation in tissues.
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  - preferred_term: very long-chain fatty acid metabolic process
    term:
      id: GO:0000038
      label: very long-chain fatty acid metabolic process
  chemical_entities:
  - preferred_term: VLCFAs
  - preferred_term: Bile Acid Intermediates
  - preferred_term: Phytanic Acid
    term:
      id: CHEBI:16285
      label: phytanic acid
  evidence:
  - reference: PMID:19933170
    reference_title: "Drosophila models of peroxisomal biogenesis disorder: peroxins are required for spermatogenesis and very-long-chain fatty acid metabolism."
    supports: PARTIAL
    snippet: Peroxisomes are vital eukaryotic organelles that participate in lipid metabolism, in particular the metabolism of very-long-chain fatty acids (VLCFA)... including impaired peroxisomal protein import, elevated VLCFA levels and growth retardation.
    explanation: The reference supports the accumulation of VLCFAs as part of the pathophysiology of Peroxisome Biogenesis Disorders but does not mention bile acid intermediates or phytanic acid.
  - reference: PMID:3119940
    reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
    supports: PARTIAL
    snippet: In patients with cerebro-hepato-renal (Zellweger) syndrome, the absence of peroxisomes results in an impairment of metabolic processes... These include the catabolism of very long chain (greater than C22) fatty acids... the catabolism of phytanic acid and the catabolism of pipecolic acid.
    explanation: This reference supports the accumulation of VLCFAs and phytanic acid in peroxisomal disorders but does not mention bile acid intermediates.
  - reference: PMID:22978395
    reference_title: "Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites."
    supports: PARTIAL
    snippet: By comparing the different peroxisomal disorders, we provide evidence suggesting that the main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA).
    explanation: This reference supports the accumulation of bile acid intermediates in peroxisomal disorders but does not mention VLCFAs or phytanic acid.
  downstream:
  - target: Very Long Chain Fatty Acids (VLCFA)
    causal_link_type: DIRECT
  - target: Bile Acid Intermediates
    causal_link_type: DIRECT
  - target: Hepatic Dysfunction
    causal_link_type: DIRECT
    description: Accumulated bile-acid intermediates and VLCFAs contribute to liver pathology in peroxisomal disorders.
  - target: Neurological Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Accumulated peroxisomal lipid metabolites contribute to CNS lipid imbalance and neurodegeneration.
- name: Deficiency of Essential Compounds
  description: Impaired synthesis of plasmalogens and other essential compounds disrupts normal cellular functions.
  biological_processes:
  - preferred_term: ether lipid biosynthetic process
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
  - preferred_term: bile acid biosynthetic process
    term:
      id: GO:0006699
      label: bile acid biosynthetic process
  chemical_entities:
  - preferred_term: Plasmalogen
  - preferred_term: Docosahexaenoic acid
    term:
      id: CHEBI:36005
      label: docosahexaenoic acid
  evidence:
  - reference: PMID:36720320
    reference_title: "Regulation of plasmalogen biosynthesis in mammalian cells and tissues."
    supports: SUPPORT
    snippet: The absence of plasmalogens in several organs of patients with deficiency in peroxisome biogenesis suggests that de novo synthesis of plasmalogens contributes significantly to plasmalogen homeostasis in humans.
    explanation: The literature indicates that plasmalogen biosynthesis is significantly affected in patients with peroxisome biogenesis disorders, which supports the statement regarding impaired synthesis of plasmalogens disrupting normal cellular functions.
  - reference: PMID:32165495
    reference_title: "A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway."
    supports: SUPPORT
    snippet: The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid beta-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown.
    explanation: This study reinforces that impaired peroxisome function, including the biosynthesis of plasmalogens, leads to a broad spectrum of cellular dysfunctions.
  - reference: PMID:33417206
    reference_title: "Peroxisome Biogenesis Disorders."
    supports: SUPPORT
    snippet: Peroxisomes are presented in all eukaryotic cells and play essential roles in many of lipid metabolic pathways, including beta-oxidation of fatty acids and synthesis of ether-linked glycerophospholipids, such as plasmalogens.
    explanation: The abstract confirms that peroxisomes are crucial for the synthesis of plasmalogens and that their dysfunction could disrupt normal cellular functions.
  downstream:
  - target: Plasmalogens
    causal_link_type: DIRECT
  - target: Neurological Dysfunction
    causal_link_type: DIRECT
    description: Plasmalogen and ether-lipid deficiency impairs CNS myelin and neuronal lipid homeostasis.
  - target: Skeletal Abnormalities
    causal_link_type: DIRECT
    description: Plasmalogen deficiency is linked to chondrodysplasia punctata and abnormal skeletal development.
  - target: Retinal Pigment Epithelium Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Retinal lipid remodeling reflects deficient ether-lipid and plasmalogen metabolism.
- name: Neurological Dysfunction
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  description: Accumulation of toxic metabolites and deficiency of essential compounds lead to demyelination, neuronal migration defects, and neurodegeneration.
  evidence:
  - reference: PMID:15868469
    reference_title: "Peroxisome biogenesis disorders: the role of peroxisomes and metabolic dysfunction in developing brain."
    supports: SUPPORT
    snippet: Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes.
    explanation: The reference specifies that a lack of functional peroxisomes leads to severe neurological dysfunction, including demyelination and defects in neuronal migration, which aligns with the statement's content.
  - reference: PMID:33417206
    reference_title: "Peroxisome Biogenesis Disorders."
    supports: SUPPORT
    snippet: Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs).
    explanation: This reference describes PBDs leading to significant neurodegeneration and psychomotor dysfunction, consistent with the statement on neurological dysfunction due to the disorder.
  - reference: PMID:22978395
    reference_title: "Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites."
    supports: PARTIAL
    snippet: Liver pathology is a frequent finding in patients affected by a peroxisomal disorder. ... we provide evidence suggesting that the main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA).
    explanation: While this reference supports the role of toxic metabolites, it focuses on liver pathology rather than CNS-specific features like demyelination and neuronal migration defects.
  - reference: PMID:7685145
    reference_title: "Peroxisomal disorders. Neurodevelopmental and biochemical aspects."
    supports: SUPPORT
    snippet: Because peroxisomes are involved in the metabolism of lipids critical to the functioning of the nervous system, many of the peroxisomal disorders manifest with significant degrees of progressive psychomotor dysfunction.
    explanation: The reference acknowledges the impact on the nervous system and describes psychomotor dysfunction, supporting the idea of neurological dysfunction.
  - reference: PMID:30739266
    reference_title: "Peroxisomal dysfunction in neurodegenerative diseases."
    supports: PARTIAL
    snippet: The importance of functional peroxisomes for cellular metabolism is demonstrated by the marked brain and systemic organ abnormalities occuring in peroxisome biogenesis disorders and peroxisomal enzyme deficiencies
    explanation: This reference highlights general brain abnormalities due to peroxisomal dysfunction but does not specifically describe demyelination and neuronal migration defects. Partial support is given as it indicates a broad CNS impact.
  downstream:
  - target: Hypotonia
    causal_link_type: DIRECT
  - target: Developmental Delay
    causal_link_type: DIRECT
  - target: Seizures
    causal_link_type: DIRECT
  - target: Leukodystrophy
    causal_link_type: DIRECT
- name: Hepatic Dysfunction
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  description: Accumulation of bile acid intermediates and VLCFAs, along with oxidative stress, cause hepatomegaly, fibrosis, and liver failure.
  evidence:
  - reference: PMID:12473763
    reference_title: "Biochemical markers predicting survival in peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: Common to these three disorders are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness.
    explanation: The study mentions liver disease as a common symptom of peroxisome biogenesis disorder (PBD), supporting hepatic dysfunction.
  - reference: PMID:22978395
    reference_title: "Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites."
    supports: SUPPORT
    snippet: The main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA).
    explanation: This reference supports the accumulation of bile acid intermediates causing liver pathology in PBDs.
  - reference: PMID:29282281
    reference_title: "Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants."
    supports: SUPPORT
    snippet: They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality
    explanation: This reference indirectly supports the statement by discussing the lethal and severe impact of PBDs, including liver dysfunction.
  - reference: PMID:8184191
    reference_title: "[Liver pathologies due to peroxisome disorders]."
    supports: SUPPORT
    snippet: Zellweger disease or cerebro-hepato-renal syndrome is characterized clinically by... liver damage leading to cirrhosis.
    explanation: This confirms hepatic dysfunction including fibrosis in PBDs.
  - reference: PMID:8729109
    reference_title: "Very long-chain fatty acids in diagnosis, pathogenesis, and therapy of peroxisomal disorders."
    supports: SUPPORT
    snippet: Abnormally high levels of very long-chain fatty acids (VLCFA) are a feature in nine of the fifteen peroxisomal disorders that have been identified so far.
    explanation: Supports the accumulation of VLCFAs as part of the pathophysiology.
  - reference: PMID:17682975
    reference_title: "Inborn errors of bile acid metabolism."
    supports: SUPPORT
    snippet: Nine recognized inborn errors of bile acid metabolism have been identified that lead to enzyme deficiencies and impaired bile acid synthesis in infants, children, and adults.
    explanation: This reference supports the accumulation of bile acid intermediates, contributing to hepatic dysfunction.
  downstream:
  - target: Hepatomegaly
    causal_link_type: DIRECT
  - target: Cholestasis
    causal_link_type: DIRECT
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hematologic abnormalities are modeled as secondary to severe multisystem or hepatic involvement when present.
- name: Skeletal Abnormalities
  locations:
  - preferred_term: bones
    term:
      id: UBERON:0001474
      label: bone element
  - preferred_term: cartilage
    term:
      id: UBERON:0002418
      label: cartilage tissue
  description: Plasmalogen deficiency disrupts normal bone formation, leading to rhizomelic shortening of limbs and chondrodysplasia punctata.
  evidence:
  - reference: PMID:10904262
    reference_title: "Peroxisome biogenesis disorders: genetics and cell biology."
    supports: SUPPORT
    snippet: Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata are progressive disorders characterized by loss of multiple peroxisomal metabolic functions.
    explanation: The context indicates that rhizomelic chondrodysplasia punctata (a type of peroxisome biogenesis disorder) results from peroxisomal dysfunction, supporting the connection between plasmalogen deficiency and skeletal abnormalities, including rhizomelic shortening of limbs and chondrodysplasia punctata.
  - reference: PMID:10972423
    reference_title: "Abnormal myelin formation in rhizomelic chondrodysplasia punctata type 2 (DHAPAT-deficiency)."
    supports: SUPPORT
    snippet: The case of a Yemeni girl with isolated peroxisomal acyl-CoA:dihydroxyacetonephosphate acyltransferase (DHAPAT) deficiency is reported. She had rhizomelic chondrodysplasia punctata, microcephaly, failure to thrive, delayed motor and mental development, and spastic quadriplegia.
    explanation: The document discusses a case where plasmalogen biosynthesis deficiency leads to rhizomelic chondrodysplasia punctata, supporting the statement.
  - reference: PMID:8507680
    reference_title: "Ether lipid synthesis and its deficiency in peroxisomal disorders."
    supports: SUPPORT
    snippet: The results have clearly shown an indispensable role for peroxisomes in the total process of ether lipid synthesis as evidenced by a description of the cellular topography of this process.
    explanation: The paper supports the importance of peroxisomes in lipid synthesis, including plasmalogens, which are associated with diseases like rhizomelic chondrodysplasia punctata that impact bone and cartilage formation.
  - reference: PMID:24172221
    reference_title: "The neurology of rhizomelic chondrodysplasia punctata."
    supports: SUPPORT
    snippet: Rhizomelic chondrodysplasia punctata (RCDP); a peroxisomal disorder clinically characterized by skeletal abnormalities, congenital cataracts, severe growth and developmental impairments and immobility of joints. Defective plasmalogen biosynthesis is the main biochemical feature.
    explanation: This clearly supports the notion that defective plasmalogen biosynthesis leads to skeletal abnormalities characteristic of rhizomelic chondrodysplasia punctata, including rhizomelic shortening of limbs and chondrodysplasia punctata.
  downstream:
  - target: Chondrodysplasia Punctata
    causal_link_type: DIRECT
  - target: Craniofacial Dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial dysmorphism is grouped with abnormal skeletal and developmental patterning in severe presentations.
- name: Multisystem Involvement
  description: The pervasive nature of peroxisomal dysfunction affects multiple organ systems, resulting in a wide range of clinical manifestations.
  evidence:
  - reference: PMID:14527301
    reference_title: "Peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: The multisystem clinical phenotype varies widely in severity and results from disturbances in both development and metabolic homeostasis.
    explanation: This statement supports the pervasive nature of peroxisomal dysfunction affecting multiple organ systems, leading to a range of clinical manifestations.
  - reference: PMID:33417210
    reference_title: "Potential Involvement of Peroxisome in Multiple Sclerosis and Alzheimer's Disease : Peroxisome and Neurodegeneration."
    supports: SUPPORT
    snippet: Peroxisomopathies are rare diseases due to dysfunctions of the peroxisome in which this organelle is either absent or with impaired activities. These diseases... affect the central and peripheral nervous system.
    explanation: This statement aligns with the notion that peroxisomal dysfunction affects multiple organ systems.
  - reference: PMID:26453805
    reference_title: "Hepatic dysfunction in peroxisomal disorders."
    supports: SUPPORT
    snippet: The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders... including mitochondria and the ER.
    explanation: This reference details the involvement of multiple cellular compartments and metabolic pathways, illustrating multisystem impact.
  - reference: PMID:1710072
    reference_title: "The peroxisome and the eye."
    supports: SUPPORT
    snippet: Several childhood multisystem disorders with prominent ophthalmological manifestations have been ascribed to the malfunction of the peroxisome, a subcellular organelle.
    explanation: It categorizes peroxisomal disorders as multisystem with significant implications in different organ systems, particularly the eyes.
  - reference: PMID:15868469
    reference_title: "Peroxisome biogenesis disorders: the role of peroxisomes and metabolic dysfunction in developing brain."
    supports: SUPPORT
    snippet: Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes.
    explanation: This echoes the impact on multiple organ systems but emphasizes the neurological dysfunctions.
  - reference: PMID:21397417
    reference_title: "Peroxisomal disorders with infantile seizures."
    supports: SUPPORT
    snippet: Peroxisomal disorders (PDs) are heterogeneous groups of diseases and affect many organs with varying degrees of involvement.
    explanation: This source supports the statement by highlighting the multi-organ involvement in peroxisomal disorders.
  downstream:
  - target: Renal Dysfunction
    causal_link_type: UNKNOWN
    description: Renal involvement is connected through broad cerebro-hepato-renal multisystem disease rather than a single curated renal mechanism.
  - target: Hearing Loss
    causal_link_type: UNKNOWN
    description: Hearing loss is a recurrent sensory manifestation of the multisystem PBD-ZSD spectrum.
  - target: Adrenal Insufficiency
    causal_link_type: UNKNOWN
    description: Adrenal insufficiency is included as an endocrine manifestation of peroxisomal disease, with the proximal mechanism not yet separated in this graph.
  - target: Cardiomyopathy
    causal_link_type: UNKNOWN
    description: Cardiac involvement remains mechanistically unresolved in this entry.
  - target: Heart Failure
    causal_link_type: UNKNOWN
    description: Heart failure is retained as a downstream severe cardiac outcome where cardiomyopathy is present.
- name: Microglial Dysfunction and Neuroinflammation
  description: Peroxisomal defects in microglial cells induce a disease-associated microglial (DAM) signature with altered lipid metabolism, lipid droplet accumulation, and impaired autophagy, contributing to neurodegeneration.
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  notes: Recent research highlights that microglial peroxisomal defects force cells into a pathological phenotype that may be a key contributor to CNS pathogenesis in peroxisomal disorders.
  downstream:
  - target: Neurological Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Microglial lipid stress and neuroinflammation contribute to CNS degeneration and neurologic manifestations.
- name: Peroxisome-Organelle Crosstalk Disruption
  description: Disruption of peroxisome-ER-mitochondria interactions impairs lipid trafficking and metabolic coordination, particularly affecting VLCFA and ether-lipid flux between organelles.
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  notes: ACBD5 tethers peroxisomes to ER via VAPs, facilitating lipid flux; disruption perturbs VLCFA and ether-lipid trafficking.
  downstream:
  - target: Accumulation of Toxic Metabolites
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective peroxisome-organelle lipid trafficking contributes to VLCFA and related lipid accumulation.
  - target: Deficiency of Essential Compounds
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: ER-peroxisome lipid trafficking is required for normal ether-lipid and plasmalogen homeostasis.
- name: Retinal Pigment Epithelium Dysfunction
  description: In peroxisome biogenesis disorders, retinal pigment epithelium shows progressive lipid remodeling with decreased plasmalogens and increased very-long-chain lysophosphatidylcholines, leading to structural degeneration and vision loss.
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  notes: RPE lipid changes precede structural changes and show dorsal-to-ventral progression in animal models. Both RPE and photoreceptors are affected by peroxisomal dysfunction.
  downstream:
  - target: Retinopathy
    causal_link_type: DIRECT
- name: Impaired Peroxisome Biogenesis and Import
  description: Mutations in PEX genes disrupt the peroxisomal protein import machinery, including PEX5/PEX7 receptors, the PEX13/PEX14 docking complex, and the PEX1-PEX6 AAA+ ATPase export complex, preventing proper assembly and function of peroxisomes.
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  biological_processes:
  - preferred_term: protein import into peroxisome matrix
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
  - preferred_term: peroxisome organization
    term:
      id: GO:0007031
      label: peroxisome organization
  notes: The import cycle involves PTS1/PTS2 cargo binding, docking, translocation, ubiquitination of PEX5, and AAA+ ATPase-mediated extraction for recycling.
  downstream:
  - target: Accumulation of Toxic Metabolites
    causal_link_type: DIRECT
    description: Failed matrix-enzyme import disables peroxisomal beta-oxidation and related catabolic pathways.
  - target: Deficiency of Essential Compounds
    causal_link_type: DIRECT
    description: Failed peroxisomal assembly and import impair ether-lipid, plasmalogen, and bile-acid synthetic steps.
phenotypes:
- category: Neurologic
  name: Hypotonia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:7685145
    reference_title: "Peroxisomal disorders. Neurodevelopmental and biochemical aspects."
    supports: SUPPORT
    snippet: These disorders should be considered in the differential diagnosis of the infant with hypotonia and psychomotor delay (especially if accompanied by facial dysmorphisms, hepatomegaly, cataracts and/or retinitis, calcific stippling, short limbs, or combinations of these features), in the school-aged child with progressive neurologic dysfunction, and in adults with slowly progressive motor dysfunction.
    explanation: The reference mentions hypotonia as a significant clinical feature in peroxisomal disorders.
  - 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: PARTIAL
    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: While the reference primarily discusses cerebellar involvement, it indirectly supports the statement by implicating neurological systems in PEX10-related peroxisome biogenesis disorders.
  - reference: PMID:13129589
    reference_title: "The floppy infant: contribution of genetic and metabolic disorders."
    supports: SUPPORT
    snippet: The floppy infant syndrome is a well-recognized entity for pediatricians and neonatologists. The condition refers to an infant with generalized hypotonia presenting at birth or in early life.
    explanation: The reference directly supports the very frequent occurrence of hypotonia in infants with peroxisomal disorders.
  - reference: PMID:38409970
    reference_title: "Zellweger Syndrome: A Case Report."
    supports: SUPPORT
    snippet: Common clinical presentations include hypotonia, seizure, hepatomegaly, craniofacial dysmorphism and early death.
    explanation: Hypotonia is listed as one of the common clinical presentations in Zellweger syndrome, a type of peroxisome biogenesis disorder.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
- category: Neurologic
  name: Developmental Delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:7685145
    reference_title: "Peroxisomal disorders. Neurodevelopmental and biochemical aspects."
    supports: SUPPORT
    snippet: Because peroxisomes are involved in the metabolism of lipids critical to the functioning of the nervous system, many of the peroxisomal disorders manifest with significant degrees of progressive psychomotor dysfunction.
    explanation: The literature indicates that peroxisomal disorders, which include Peroxisome Biogenesis Disorders (PBDs), frequently present with progressive psychomotor dysfunction, supporting the statement that developmental delay is a very frequent neurologic phenotype.
  - reference: PMID:36293220
    reference_title: "Diagnostic Odyssey in an Adult Patient with Ophthalmologic Abnormalities and Hearing Loss: Contribution of RNA-Seq to the Diagnosis of a PEX1 Deficiency."
    supports: SUPPORT
    snippet: The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease.
    explanation: Although this does not explicitly mention developmental delay, the overall description implies a frequent occurrence of neurologic dysfunction, which is often tied to developmental delays.
  - reference: PMID:11769739
    reference_title: "Late onset white matter disease in peroxisome biogenesis disorder."
    supports: SUPPORT
    snippet: Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy.
    explanation: The article describes neurologic deficits appearing early in life, which aligns with developmental delays being a very frequent phenotype.
  - reference: PMID:38409970
    reference_title: "Zellweger Syndrome: A Case Report."
    supports: SUPPORT
    snippet: Zellweger syndrome is an autosomal recessive disease within the spectrum of peroxisome biogenesis disorder manifesting in the neonatal period with profound dysfunction of the central nervous system, liver and kidney.
    explanation: The mention of the neonatal onset of CNS dysfunction supports the frequent presence of developmental delays.
  - reference: PMID:24172221
    reference_title: "The neurology of rhizomelic chondrodysplasia punctata."
    supports: SUPPORT
    snippet: Neurodevelopmental deficits and age-related occurrence of seizures are characteristic of RCDP and are related to the rest-activity in plasmalogen biosynthesis.
    explanation: RCDP is a type of peroxisomal disorder, and its characteristic neurodevelopmental deficits support the statement about developmental delay being a common phenotype in PBDs.
  phenotype_term:
    preferred_term: Developmental Delay
    term:
      id: HP:0001263
      label: Global developmental delay
- category: Neurologic
  name: Seizures
  frequency: FREQUENT
  notes: Common in severe forms, particularly neonatal Zellweger syndrome
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
- category: Neurologic
  name: Leukodystrophy
  frequency: FREQUENT
  notes: White matter degeneration due to myelin lipid dependency on peroxisomal function
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
- category: Hepatobiliary
  name: Hepatomegaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:31005404
    reference_title: "Clinical and biochemical footprints of inherited metabolic diseases. II. Metabolic liver diseases."
    supports: PARTIAL
    snippet: Inherited metabolic diseases account for about one third of pediatric patients with hepatomegaly, acute liver failure, cirrhosis or cholestasis.
    explanation: The reference states that inherited metabolic diseases, which include peroxisome biogenesis disorders, account for a substantial portion of pediatric hepatomegaly cases but does not specify the frequency as 'frequent.'
  - reference: PMID:22978395
    reference_title: "Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites."
    supports: PARTIAL
    snippet: Liver pathology is a frequent finding in patients affected by a peroxisomal disorder.
    explanation: The reference mentions liver pathology as frequent but does not specifically state hepatomegaly.
  - reference: PMID:26615381
    reference_title: "Early Onset Hepatocellular Disease in an Infant with Zellweger Syndrome."
    supports: NO_EVIDENCE
    snippet: Zellweger syndrome (ZS) is a peroxisomal disorder with a multiple congenital anomalies, characterized by stereotypical facies, profound hypotonia, organ involvement including cerebral, retinal, hepatic, and renal.
    explanation: The reference discusses organ involvement including hepatic involvement but does not specify hepatomegaly as frequent.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- category: Hepatobiliary
  name: Cholestasis
  frequency: FREQUENT
  notes: Due to bile acid biosynthetic block and hepatic lipid handling deficits
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
- category: Renal
  name: Renal Dysfunction
  frequency: OCCASIONAL
  notes: Variable kidney dysfunction across the spectrum
  phenotype_term:
    preferred_term: Abnormal renal physiology
    term:
      id: HP:0012622
      label: Chronic kidney disease
- category: Visual
  name: Retinopathy
  frequency: FREQUENT
  evidence:
  - reference: PMID:31884631
    reference_title: "Peroxisomal Disorders and Retinal Degeneration."
    supports: SUPPORT
    snippet: Retinopathy is a recurrent feature in both the severely and mildly affected patients, which can be accompanied with other ophthalmological pathologies.
    explanation: The study states that retinopathy is a recurrent feature in patients with peroxisomal disorders, supporting the statement that visual phenotypes, specifically retinopathy, are frequent.
  - reference: PMID:12473763
    reference_title: "Biochemical markers predicting survival in peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: Common to these three disorders are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness.
    explanation: The study indicates that retinopathy is common in peroxisome biogenesis disorders like Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, supporting the frequent occurrence of retinopathy as a visual phenotype.
  - reference: PMID:35227579
    reference_title: "Clinical and biochemical footprints of inherited metabolic disorders. VII. Ocular phenotypes."
    supports: SUPPORT
    snippet: Retinal degeneration with or without optic atrophy is the most frequent phenotype, followed by oculomotor problems, involvement of the cornea and lens, and refractive errors.
    explanation: The study states that retinal degeneration is the most frequent ocular phenotype observed in inherited metabolic disorders, which includes peroxisome biogenesis disorders, thereby supporting the frequent occurrence of retinopathy.
  - reference: PMID:31254513
    reference_title: "A longitudinal study of retinopathy in the PEX1-Gly844Asp mouse model for mild Zellweger Spectrum Disorder."
    supports: SUPPORT
    snippet: Retinopathy leading to blindness is one of the major untreatable handicaps faced by patients with ZSD but is not well characterized, and the requirement for peroxisomes in retinal health is unknown.
    explanation: The study highlights that retinopathy leading to blindness is a significant issue in patients with Zellweger Spectrum Disorder, a type of peroxisome biogenesis disorder, supporting the frequency of retinopathy as a visual phenotype.
  phenotype_term:
    preferred_term: Retinopathy
    term:
      id: HP:0000488
      label: Retinopathy
- category: Auditory
  name: Hearing Loss
  frequency: FREQUENT
  evidence:
  - reference: PMID:34534157
    reference_title: "A Retrospective Study of Hearing Loss in Patients Diagnosed with Peroxisome Biogenesis Disorders in the Zellweger Spectrum."
    supports: SUPPORT
    snippet: The majority of PBD-ZSD patients in this study presented with moderately-severe to severe hearing loss and relatively slow rates of longitudinal changes in hearing sensitivity.
    explanation: This study characterizes hearing loss as a common phenotype in patients with Peroxisome Biogenesis Disorder within the Zellweger Spectrum.
  - reference: PMID:36291074
    reference_title: "The Effect of a Pex3 Mutation on Hearing and Lipid Content of the Inner Ear."
    supports: SUPPORT
    snippet: Peroxisome biogenesis disorders (due to PEX gene mutations) are associated with symptoms that range in severity and can lead to early childhood death, but a common feature is hearing impairment.
    explanation: This study also confirms hearing impairment as a frequent phenotype in Peroxisome Biogenesis Disorders, further supporting the statement.
  - reference: PMID:33417209
    reference_title: "Heimler Syndrome."
    supports: SUPPORT
    snippet: Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic variations. This syndrome is one of the less severe forms of peroxisome biogenesis disorders.
    explanation: Heimler syndrome, a less severe form of peroxisome biogenesis disorders, frequently presents with sensorineural hearing loss, further supporting the frequent association of hearing loss with these disorders.
  phenotype_term:
    preferred_term: Hearing Loss
    term:
      id: HP:0000365
      label: Hearing impairment
- category: Craniofacial
  name: Craniofacial Dysmorphism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23671347
    reference_title: "Child neurology: Zellweger syndrome."
    supports: SUPPORT
    snippet: Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities.
    explanation: Distinctive facial stigmata can be considered a form of craniofacial dysmorphism, supporting the statement.
  - reference: PMID:1710072
    reference_title: "The peroxisome and the eye."
    supports: PARTIAL
    snippet: Zellweger syndrome, the most lethal of the three peroxisomal biogenesis disorders, causes infantile hypotonia, seizures, and death within the first year.
    explanation: While the text does not explicitly mention craniofacial dysmorphism, the severity of symptoms and multisystem involvement suggest potential craniofacial manifestations.
- category: Endocrine
  frequency: FREQUENT
  name: Adrenal Insufficiency
  notes: Due to adrenal gland dysfunction
  evidence:
  - reference: PMID:36649687
    reference_title: "Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series."
    supports: SUPPORT
    snippet: Primary adrenal insufficiency is common in patients with PD. Based on our data, patients with the compound heterozygous PEX1 pathogenic variants of exon 13 (c.2097dupT and c.2528G>A) tend to have adrenal insufficiency.
    explanation: The study indicates that primary adrenal insufficiency is frequent in patients with peroxisomal disorders, specifically those with PEX1 pathogenic variants.
  - reference: PMID:25179809
    reference_title: "High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders."
    supports: SUPPORT
    snippet: Primary adrenal insufficiency was found in 7/24 patients examined, with 4/7 being asymptomatic. Systematic evaluation of adrenal function, through a Synacthen test, should be included in the clinical management of these patients.
    explanation: The study highlights a high prevalence of primary adrenal insufficiency in patients with Zellweger spectrum disorders, which are a type of peroxisome biogenesis disorder.
  phenotype_term:
    preferred_term: Adrenal Insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Chondrodysplasia Punctata
  notes: Stippling of epiphyses on X-rays
  evidence:
  - reference: PMID:10904262
    reference_title: "Peroxisome biogenesis disorders: genetics and cell biology."
    supports: SUPPORT
    snippet: Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata are progressive disorders characterized by loss of multiple peroxisomal metabolic functions.
    explanation: Rhizomelic chondrodysplasia punctata is a type of peroxisome biogenesis disorder, supporting the statement that chondrodysplasia punctata falls under the category of musculoskeletal issues associated with peroxisome biogenesis disorders.
  - reference: PMID:24030027
    reference_title: "Zellweger syndrome: prenatal and postnatal growth failure with epiphyseal stippling."
    supports: SUPPORT
    snippet: We present a 2-month-old male affected by Zellweger syndrome, a rare peroxisomal disorder. The diagnosis was supported by clinical and radiological findings and established by biochemical tests. The characteristic radiological features included anomalous ossification (epiphyseal stippling).
    explanation: This study supports the statement by indicating that epiphyseal stippling (chondrodysplasia punctata) is a characteristic feature in Zellweger syndrome, a type of peroxisome biogenesis disorder.
  - reference: PMID:17671048
    reference_title: "Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature."
    supports: SUPPORT
    snippet: Classic rhizomelic chondrodysplasia punctata is a rare, autosomal, recessively inherited disorder that is characterized by proximal shortening of the limbs, punctuate calcifications of the epiphyses, cataracts, developmental delay, and early lethality.
    explanation: Rhizomelic chondrodysplasia punctata is characterized by punctuate calcifications of the epiphyses, supporting the statement that this condition is associated with peroxisome biogenesis disorders and involves stippling of epiphyses.
- category: Hematologic
  frequency: OCCASIONAL
  name: Thrombocytopenia
  notes: Low platelet count
  evidence:
  - reference: PMID:27941306
    reference_title: "Peroxisome biogenesis and human peroxisome-deficiency disorders."
    supports: NO_EVIDENCE
    snippet: Peroxisome is a single-membrane-bounded ubiquitous organelle containing a hundred different enzymes that catalyze various metabolic pathways such as beta-oxidation of very long-chain fatty acids and synthesis of plasmalogens.
    explanation: The provided literature does not mention thrombocytopenia or any hematologic symptoms in relation to Peroxisome Biogenesis Disorders.
  - reference: PMID:31884631
    reference_title: "Peroxisomal Disorders and Retinal Degeneration."
    supports: NO_EVIDENCE
    snippet: Peroxisomal disorders are a group of inherited metabolic diseases, which can be incompatible with life in the postnatal period or allow survival into adulthood. Retinopathy is a recurrent feature in both the severely and mildly affected patients, which can be accompanied with other ophthalmological pathologies.
    explanation: This reference discusses peroxisomal disorders but does not mention thrombocytopenia or other hematologic conditions.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
- category: Cardiac
  frequency: OCCASIONAL
  name: Cardiomyopathy
  sequelae:
  - target: Heart Failure
  evidence:
  - reference: PMID:25465824
    reference_title: "Cardiac manifestations of primary mitochondrial disorders."
    supports: PARTIAL
    snippet: CI in MIDs includes cardiomyopathy, arrhythmias, heart failure, pulmonary hypertension, dilation of the aortic root, pericardial effusion, coronary heart disease, autonomous nervous system dysfunction, congenital heart defects, or sudden cardiac death.
    explanation: The literature confirms that cardiomyopathy and heart failure are associated with mitochondrial disorders (MIDs), which are a type of metabolic disorder. However, it does not specifically mention peroxisome biogenesis disorders (PBDs) in this context.
  - reference: PMID:36870438
    reference_title: "Cardiomyopathies in children: An overview."
    supports: NO_EVIDENCE
    snippet: Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure.
    explanation: This reference provides an overview of pediatric cardiomyopathies but does not specifically mention peroxisome biogenesis disorders (PBDs) as a cause.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
- category: Cardiovascular
  name: Heart Failure
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Heart Failure
    term:
      id: HP:0001635
      label: Congestive heart failure
biochemical:
- name: Very Long Chain Fatty Acids (VLCFA)
  presence: Elevated
  context: Diagnostic marker
  evidence:
  - reference: PMID:8729109
    reference_title: "Very long-chain fatty acids in diagnosis, pathogenesis, and therapy of peroxisomal disorders."
    supports: PARTIAL
    snippet: Abnormally high levels of very long-chain fatty acids (VLCFA) are a feature in nine of the fifteen peroxisomal disorders that have been identified so far.
    explanation: This reference indicates that elevated VLCFA levels are a feature in nine peroxisomal disorders but does not specify peroxisome biogenesis disorders (PBD) exclusively.
  - reference: PMID:14527301
    reference_title: "Peroxisome biogenesis disorders."
    supports: NO_EVIDENCE
    snippet: The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal recessive complementation groups (CGs).
    explanation: The abstract does not mention VLCFA levels in the context of PBD diagnosis.
  - reference: PMID:37567036
    reference_title: "Dicarboxylic acylcarnitine biomarkers in peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: Multiple dicarboxylic acylcarnitines were significantly elevated in PBD patients including medium to long chain (C8-DC to C18-DC) species as well as previously undescribed elevations of malonylcarnitine (C3-DC) and very long chain dicarboxylic acylcarnitines (C20-DC and C22-DC).
    explanation: This study identifies elevated levels of very long chain dicarboxylic acylcarnitines (a type of VLCFA) in patients with PBD.
  - reference: PMID:19933170
    reference_title: "Drosophila models of peroxisomal biogenesis disorder: peroxins are required for spermatogenesis and very-long-chain fatty acid metabolism."
    supports: SUPPORT
    snippet: Peroxisomes are vital eukaryotic organelles that participate in lipid metabolism, in particular the metabolism of very-long-chain fatty acids (VLCFA).
    explanation: This reference supports that elevated VLCFA levels are relevant in peroxisomal disorders which include peroxisome biogenesis disorders.
  - reference: PMID:8914632
    reference_title: "Incidence of peroxisomal disorders in Japan."
    supports: PARTIAL
    snippet: Very long chain fatty acid analysis in the serum sphingomyelin was introduced since 1987 and was useful for the first screening of peroxisomal disorders.
    explanation: Although this reference states that VLCFA analysis is useful for peroxisomal disorders, it is not specific to PBD.
- name: Plasmalogens
  presence: Decreased
  context: Diagnostic marker
  evidence:
  - reference: PMID:36914043
    reference_title: "Quantitative analysis of ethanolamine plasmalogen species in red blood cells using liquid chromatography tandem mass spectrometry for diagnosing peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders (PBD) because plasmalogen synthesis requires functional peroxisomes.
    explanation: The literature clearly states that decreased levels of plasmalogens are a characteristic feature of peroxisome biogenesis disorders.
  - reference: PMID:12473763
    reference_title: "Biochemical markers predicting survival in peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: A poor correlation with age at death was found for de novo plasmalogen synthesis, C26:0/C22:0 ratio, and phytanic acid alpha-oxidation.
    explanation: The study mentions that impaired plasmalogen synthesis is one of the biochemical markers analyzed in PBD patients.
  - reference: PMID:3460088
    reference_title: "Isolation of animal cell mutants deficient in plasmalogen biosynthesis and peroxisome assembly."
    supports: SUPPORT
    snippet: The results presented here support the view that there are two DHAP acyltransferases in animal cells and that the peroxisome is essential for the biosynthesis of plasmalogens.
    explanation: The literature shows that peroxisomes play an essential role in plasmalogen biosynthesis, indicating that their dysfunction leads to decreased plasmalogen levels.
  - reference: PMID:7957386
    reference_title: "Clinical and biochemical characteristics of peroxisomal disorders: an update."
    supports: SUPPORT
    snippet: Rhizomelic chondrodysplasia punctata, its recently identified variant form and glutaryl-CoA oxidase deficiency will show no abnormalities and must be identified by other means.
    explanation: The mention of specific conditions excluded from typical diagnostic methods indirectly reaffirms that decreased plasmalogen levels are a diagnostic marker for most PBDs.
  - reference: PMID:33417206
    reference_title: "Peroxisome Biogenesis Disorders."
    supports: SUPPORT
    snippet: Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs).
    explanation: The statement supports the role of peroxisomes in normal cellular function, and by extension, indicates that their dysfunction would likely lead to decreased plasmalogen synthesis.
- name: Bile Acid Intermediates
  presence: Elevated
  context: Diagnostic marker
  evidence:
  - reference: PMID:37802748
    reference_title: "Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites."
    supports: SUPPORT
    snippet: Early postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs.
    explanation: “The study states that disease-specific bile acids (BAs) can be measured as markers for peroxisome biogenesis disorders (PBDs) via a dried blood spot-based screening method.”
  - reference: PMID:3119940
    reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
    supports: SUPPORT
    snippet: In classic Zellweger syndrome abnormal C27-bile acids, very long chain fatty acids, dicarboxylic acids and pipecolic acid accumulate in the plasma of the patients.
    explanation: The study mentions the accumulation of C27-bile acids (a type of bile acid intermediate) in the plasma of patients with Zellweger syndrome, a type of peroxisome biogenesis disorder.
  - reference: PMID:3119940
    reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
    supports: SUPPORT
    snippet: In patients with cerebro-hepato-renal (Zellweger) syndrome, the absence of peroxisomes results in an impairment of metabolic processes in which peroxisomes are normally involved. These include the catabolism of very long chain (greater than C22) fatty acids, the biosynthesis of ether-phospholipids and of bile acids, the catabolism of phytanic acid and the catabolism of pipecolic acid.
    explanation: The study supports the concept that certain biochemical markers, including bile acid intermediates, are elevated due to the metabolic process impairments in peroxisome biogenesis disorders.
genetic:
- name: PEX1
  gene_term:
    preferred_term: PEX1
    term:
      id: hgnc:8850
      label: PEX1
  association: Pathogenic Variants
  evidence:
  - reference: PMID:33955040
    reference_title: "Compound heterozygous p. Arg949Trp and p. Gly970Ala mutations deteriorated the function of PEX1p: A study on PEX1 in a patient with Zellweger syndrome."
    supports: SUPPORT
    snippet: Zellweger syndrome (ZS) is the foremost common and severe phenotype within the heterogeneous ZSD. However, missense mutations encode proteins with residual functions, which are associated with phenotypes that are milder than ZS. Mutations in the PEX1 gene are among the most prevalent.
    explanation: The statement is supported as it mentions that mutations in the PEX1 gene are among the most prevalent causes of Zellweger syndrome, which is a type of PBD.
  - reference: CGGV:assertion_a345ba65-9dcd-43dd-a1c2-1778c1a921ea-2023-09-06T160000.000Z
    reference_title: "PEX1 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX1 | HGNC:8850 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX1-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PEX6
  gene_term:
    preferred_term: PEX6
    term:
      id: hgnc:8859
      label: PEX6
  association: Pathogenic Variants
  evidence:
  - reference: PMID:17055079
    reference_title: "Peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD).
    explanation: This statement indicates that mutations in PEX genes, including PEX6, are foundational to the development of peroxisome biogenesis disorders.
  - reference: PMID:15858711
    reference_title: "Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis."
    supports: SUPPORT
    snippet: Matsumoto and colleagues recently identified PEX26 as the gene responsible for complementation group 8 of the peroxisome biogenesis disorders... Here, we identify new PEX26 disease alleles, localize the PEX6-binding domain to the N-terminal half of the protein (aa 29-174), and show that, at the cellular level, PEX26 deficiency impairs peroxisomal import of both PTS1- and PTS2-targeted matrix proteins.
    explanation: This paper discusses PEX26 in detail but also underscores the critical function of PEX6 in peroxisome biogenesis.
  - reference: PMID:36980088
    reference_title: "PEX6 Mutation in a Child with Infantile Refsum Disease-A Case Report and Literature Review."
    supports: SUPPORT
    snippet: Genetic testing revealed a mutation of the PEX6 (Peroxisomal Biogenesis Factor 6) gene, and the metabolic profile was consistent with the diagnosis.
    explanation: This case report directly links pathogenic variants in PEX6 to a specific case of peroxisome biogenesis disorder.
  - reference: PMID:33955040
    reference_title: "Compound heterozygous p. Arg949Trp and p. Gly970Ala mutations deteriorated the function of PEX1p: A study on PEX1 in a patient with Zellweger syndrome."
    supports: SUPPORT
    snippet: Autosomal recessive disorder of the Zellweger spectrum (ZSD) is a major subset of peroxisome biogenesis disorders (PBDs) that can be caused by mutations in any of the 14 PEX genes. ... Mutations in the PEX1 gene are among the most prevalent. PEX1 and PEX6 proteins, belonging to the AAA family of ATPases, form a hexameric complex, which is associated with peroxisome membranes and essential for peroxisome biology.
    explanation: This paper confirms that mutations in PEX6, similar to those in PEX1, are linked to peroxisome biogenesis disorders.
  - reference: PMID:10408779
    reference_title: "Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: The PEX6 (peroxisome assembly factor-2, PAF-2) gene... restores peroxisome assembly in fibroblasts from peroxisome biogenesis disorder patients belonging to complementation group C (group 4 in the United States).
    explanation: This research clarifies the structure and mutations of PEX6, noting its role in peroxisome biogenesis disorders.
  - reference: CGGV:assertion_54df6fb2-b692-4ece-a525-ae0cfe243826-2019-09-06T160000.000Z
    reference_title: "PEX6 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX6 | HGNC:8859 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX6-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PEX13
  gene_term:
    preferred_term: PEX13
    term:
      id: hgnc:8855
      label: PEX13
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_0c662669-4eb8-45e3-8540-c394ea40c1b2-2019-10-04T160000.000Z
    reference_title: "PEX13 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX13 | HGNC:8855 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX13-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
  notes: PEX13 is part of the docking complex for peroxisomal protein import
- name: PEX26
  gene_term:
    preferred_term: PEX26
    term:
      id: hgnc:22965
      label: PEX26
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_bf6af95e-6696-420c-8731-d2e37ca6e692-2020-02-07T170000.000Z
    reference_title: "PEX26 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX26 | HGNC:22965 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX26-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
  notes: PEX26 anchors the PEX1-PEX6 AAA+ ATPase complex to the peroxisomal membrane
- name: PEX2
  gene_term:
    preferred_term: PEX2
    term:
      id: hgnc:9717
      label: PEX2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_17bf1c4a-1775-40c6-a499-774c93827343-2020-02-07T170000.000Z
    reference_title: "PEX2 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX2 | HGNC:9717 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX2-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
  notes: Part of the RING E3 ubiquitin ligase complex involved in PEX5 ubiquitination
- name: PEX10
  gene_term:
    preferred_term: PEX10
    term:
      id: hgnc:8851
      label: PEX10
  association: Pathogenic Variants
  evidence:
  - 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 classifies the PEX10-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
  notes: Part of the RING E3 ubiquitin ligase complex involved in peroxisomal matrix protein import
- name: PEX12
  gene_term:
    preferred_term: PEX12
    term:
      id: hgnc:8854
      label: PEX12
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_124c97b0-92ed-4921-a0b9-2ff33135139d-2019-12-06T170000.000Z
    reference_title: "PEX12 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX12 | HGNC:8854 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX12-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
  notes: Part of the RING E3 ubiquitin ligase complex
- name: PEX5
  gene_term:
    preferred_term: PEX5
    term:
      id: hgnc:9719
      label: PEX5
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_b49d9cfd-0e51-4219-84bb-76b4c9b99fa9-2020-01-17T170000.000Z
    reference_title: "PEX5 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX5 | HGNC:9719 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX5-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
  notes: PTS1 receptor for peroxisomal protein import
- name: PEX7
  gene_term:
    preferred_term: PEX7
    term:
      id: hgnc:8860
      label: PEX7
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_d0796d69-b304-4670-b4a2-8785ff6fd161-2020-02-14T170000.000Z
    reference_title: "PEX7 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX7 | HGNC:8860 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX7-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
  notes: PTS2 receptor for peroxisomal protein import
- name: Other PEX Genes
  association: Pathogenic Variants
  notes: Approximately 14 PEX genes are known to cause peroxisome biogenesis disorders when mutated
  evidence:
  - reference: PMID:10904262
    reference_title: "Peroxisome biogenesis disorders: genetics and cell biology."
    supports: SUPPORT
    snippet: Recent studies have identified the PEX genes that are mutated in 11 of the 12 known complementation groups of PBD patients.
    explanation: This reference indicates that pathogenic variants in other PEX genes are associated with Peroxisome Biogenesis Disorder (PBD).
  - reference: PMID:32399598
    reference_title: "Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM)."
    supports: SUPPORT
    snippet: For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum.
    explanation: Although this reference primarily discusses Perrault syndrome, it confirms that variants in PEX genes such as PEX6 are associated with peroxisomal biogenesis disorders.
  - reference: PMID:34804114
    reference_title: "Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency."
    supports: SUPPORT
    snippet: Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum.
    explanation: This reference highlights PEX26 gene variants contributing to peroxisomal disorders which fall under the broader category of peroxisome biogenesis disorders.
  - reference: PMID:29070486
    reference_title: "The functions of PEX genes in peroxisome biogenesis and pathogenicity in phytopathogenic fungi."
    supports: SUPPORT
    snippet: The biogenesis of peroxisomes requires a category of proteins named peroxins, which are encoded by the PEX genes.
    explanation: The reference supports that PEX genes are crucial for peroxisome biogenesis, implying that pathogenic variants can lead to related disorders.
- name: PEX11B
  gene_term:
    preferred_term: PEX11B
    term:
      id: hgnc:8853
      label: PEX11B
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_93eacb33-b099-485d-bf8a-782479dc0a3b-2020-01-17T170000.000Z
    reference_title: "PEX11B / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX11B | HGNC:8853 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX11B-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PEX14
  gene_term:
    preferred_term: PEX14
    term:
      id: hgnc:8856
      label: PEX14
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_846efcc3-5456-4db3-9bc2-e441acb768cd-2019-09-20T160000.000Z
    reference_title: "PEX14 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX14 | HGNC:8856 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX14-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PEX16
  gene_term:
    preferred_term: PEX16
    term:
      id: hgnc:8857
      label: PEX16
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_7506d938-efb4-416c-aafd-221251d00e6e-2020-01-13T170000.000Z
    reference_title: "PEX16 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX16 | HGNC:8857 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX16-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PEX19
  gene_term:
    preferred_term: PEX19
    term:
      id: hgnc:9713
      label: PEX19
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_fa073c77-0623-4e82-b5b2-9fcd0eb0dc6e-2023-04-27T160000.000Z
    reference_title: "PEX19 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX19 | HGNC:9713 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX19-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PEX3
  gene_term:
    preferred_term: PEX3
    term:
      id: hgnc:8858
      label: PEX3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_d53df483-c31a-4672-8a11-04d33d6df336-2019-11-01T160000.000Z
    reference_title: "PEX3 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX3 | HGNC:8858 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the PEX3-peroxisome biogenesis disorder gene-disease relationship as definitive with autosomal recessive inheritance.
environmental:
- name: Not Applicable
  evidence:
  - reference: PMID:26305119
    reference_title: "Peroxisome biogenesis in mammalian cells: The impact of genes and environment."
    supports: NO_EVIDENCE
    snippet: In recent years, peroxisomes have emerged as important intracellular hubs for redox-, lipid-, inflammatory-, and nucleic acid-mediated signaling pathways. In this review, we focus on how nature and nurture modulate peroxisome biogenesis and function in mammalian cells.
    explanation: The literature discusses the interplay of genetic, epigenetic, and environmental factors in peroxisome biogenesis and function but does not describe peroxisome biogenesis disorders as purely environmental.
  - reference: PMID:30656921
    reference_title: "[Peroxisomal disorders]."
    supports: NO_EVIDENCE
    snippet: The disturbance of the peroxisome structure due to mutations in different PEX and non-PEX genes coding functional peroxisomal proteins is the pathogenic basis of the peroxisomal disorders.
    explanation: The literature explains that peroxisome biogenesis disorders are due to genetic mutations, not environmental factors.
treatments:
- name: Symptomatic Management
  description: Supportive care addressing specific symptoms such as physical therapy for hypotonia and seizure management.
  evidence:
  - reference: PMID:11060787
    reference_title: "Therapeutic developments in peroxisome biogenesis disorders."
    supports: PARTIAL
    snippet: Treatment of PBD patients has generally involved only supportive care and symptomatic therapy.
    explanation: The statement about supportive care and symptomatic therapy is accurate but does not explicitly mention physical therapy for hypotonia and seizure management.
  - reference: PMID:38409970
    reference_title: "Zellweger Syndrome: A Case Report."
    supports: PARTIAL
    snippet: Despite an absence of treatment options, prompt diagnosis of Zellweger syndrome is important for providing appropriate symptomatic care, definitive genetic testing and prenatal counselling.
    explanation: The statement supports symptomatic care but does not detail specific treatments such as physical therapy for hypotonia or seizure management.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_mechanisms:
  - target: Neurological Dysfunction
    treatment_effect: MODULATES
    description: Symptomatic therapy targets neurologic manifestations such as hypotonia and seizures without correcting the upstream peroxisome defect.
- name: Nutritional Support
  description: Specialized diet and supplements to manage biochemical abnormalities.
  evidence:
  - reference: PMID:11060787
    reference_title: "Therapeutic developments in peroxisome biogenesis disorders."
    supports: SUPPORT
    snippet: A number of experimental therapies have been evaluated to determine whether or not correction of biochemical abnormalities through dietary supplementation and/or modification is of clinical benefit to PBD patients.
    explanation: This snippet indicates that dietary supplementation and/or modification has been evaluated to manage biochemical abnormalities in PBD patients, supporting the statement that specialized diet and supplements can be a treatment strategy.
  - reference: PMID:18758655
    reference_title: "Treatment of inborn errors of metabolism."
    supports: SUPPORT
    snippet: The most important measures used to manage the intoxication present in many inborn errors of intermediate metabolism were presented (restriction of substrate build-up by means of diet or enzymatic inhibition, removal of toxic products, stimulation of residual enzyme activity, replacement of the deficient product).
    explanation: This reference discusses the use of diet as a measure to manage biochemical abnormalities in metabolic disorders, including peroxisomal diseases, which supports the statement.
  - reference: PMID:16819396
    reference_title: "Defects in bile acid biosynthesis--diagnosis and treatment."
    supports: NO_EVIDENCE
    snippet: Bile-acid therapy using oral cholic acid has proven effective in most of these bile acid synthetic defects making early diagnosis crucial to optimum clinical prognosis.
    explanation: While this reference discusses a specific bile-acid therapy, it does not provide evidence about dietary or supplemental approaches for managing biochemical abnormalities in PBDs.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Accumulation of Toxic Metabolites
    treatment_effect: MODULATES
    description: Dietary modification and supplementation are intended to reduce or manage toxic metabolite burden.
  - target: Deficiency of Essential Compounds
    treatment_effect: MODULATES
    description: Supplementation can address deficient products downstream of impaired peroxisomal metabolism.
- name: Liver Transplant
  description: Considered in severe cases with significant liver dysfunction.
  evidence:
  - reference: PMID:35331403
    reference_title: "Cell therapy in congenital inherited hepatic disorders."
    supports: SUPPORT
    snippet: Most of these disorders are currently treated by liver transplantation as standard of care.
    explanation: The reference indicates that liver transplantation is the standard of care for congenital inherited hepatic disorders, which includes peroxisomal disorders like Peroxisome Biogenesis Disorder (PBD), supporting that liver transplant is considered in severe cases with significant liver dysfunction.
  - reference: PMID:26615381
    reference_title: "Early Onset Hepatocellular Disease in an Infant with Zellweger Syndrome."
    supports: PARTIAL
    snippet: ZS should be considered in the list of differential diagnosis in infants with stereotypical phenotype, neurodevelopmental delay, and severe hypotonia in association with liver and other organs involvement.
    explanation: While this reference confirms liver involvement in Peroxisome Biogenesis Disorders such as Zellweger Syndrome, it does not specifically mention liver transplantation as a treatment.
  - reference: PMID:22974902
    reference_title: "Liver transplantation for massive hepatomegaly due to polycystic liver disease: an extreme case."
    supports: PARTIAL
    snippet: When none of the liver parenchyma is spared, or kidney insufficiency is marked, the only potentially curable treatment is liver transplantation (LT).
    explanation: This reference supports the use of liver transplantation in severe liver conditions, though it does not directly mention Peroxisome Biogenesis Disorder.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  target_mechanisms:
  - target: Hepatic Dysfunction
    treatment_effect: BYPASSES
    description: Liver transplantation replaces failing hepatic function but does not correct systemic PEX-gene biogenesis defects.
- name: Genetic Counseling
  description: Providing information and support to families regarding inheritance and implications.
  evidence:
  - reference: PMID:14619605
    reference_title: "Genetic counseling."
    supports: SUPPORT
    snippet: Genetic counseling has developed as a discipline in response to the need to educate patients, families and professionals about genetic mechanisms and their application in health care. ... Genetic counseling is a process of medical education based upon empathy, patient autonomy and confidentiality in an atmosphere of empathy, support and understanding.
    explanation: The literature describes genetic counseling as a discipline developed to educate patients, families, and professionals about genetic mechanisms and their application in healthcare, which supports the statement about providing information and support to families regarding inheritance and implications.
  - reference: PMID:30237433
    reference_title: "Expanding the concept of peroxisomal diseases and efficient diagnostic system in Japan."
    supports: SUPPORT
    snippet: Furthermore, it is also important to identify pre-symptomatic patients by family analysis of probands by providing appropriate disease information and genetic counseling, which will also lead to early intervention.
    explanation: The literature discusses the importance of providing disease information and genetic counseling to families, supporting the statement about providing information and support to families regarding inheritance and implications in the context of peroxisomal diseases.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
review_notes: This is a multisystem disorder affecting multiple organ systems due to defective peroxisome function. The phenotypes can be quite variable, but neurologic and hepatic manifestations are most prominent. Enhanced with recent research (2023-2025) highlighting microglial DAM signatures, peroxisome-organelle crosstalk, retinal pigment epithelium dysfunction, and detailed PEX gene import machinery. Added biological process annotations for fatty acid metabolism, ether lipid biosynthesis, and peroxisome organization. Expanded genetic variants to include specific PEX genes (PEX2, PEX5, PEX7, PEX10, PEX12, PEX13, PEX26) with functional notes. Added phenotypes including seizures, leukodystrophy, cholestasis, and renal dysfunction.
disease_term:
  preferred_term: peroxisome biogenesis disorder
  term:
    id: MONDO:0019234
    label: peroxisome biogenesis disorder
references:
- reference: DOI:10.1002/mgg3.2315
  title: 'Severe Zellweger spectrum disorder due to a novel missense variant in the <i>PEX13</i> gene: A case report and the literature review'
  findings: []
- reference: DOI:10.1007/s00418-023-02259-5
  title: 'The peroxisome: an update on mysteries 3.0'
  findings: []
- reference: DOI:10.1038/s43856-024-00605-9
  title: Lipidomic biomarkers in plasma correlate with disease severity in adrenoleukodystrophy
  findings: []
- reference: DOI:10.1101/2024.09.05.611330
  title: Geographic characterization of RPE structure and lipid changes in the PEX1-p.Gly844Asp mouse model for Zellweger spectrum disorder
  findings: []
- reference: DOI:10.1186/s12887-024-05246-4
  title: 'Normal very long-chain fatty acids level in a patient with peroxisome biogenesis disorders: a case report'
  findings: []
- reference: DOI:10.1242/jcs.236943
  title: Recent insights into peroxisome biogenesis and associated diseases
  findings: []
- reference: DOI:10.3389/fnmol.2023.1170313
  title: Peroxisomal defects in microglial cells induce a disease-associated microglial signature
  findings: []
- reference: DOI:10.3389/fnmol.2025.1642590
  title: Peroxisomes as emerging clinical targets in neuroinflammatory diseases
  findings: []
- reference: DOI:10.3390/cells14020147
  title: Modelling Peroxisomal Disorders in Zebrafish
  findings: []

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References & Deep Research

References

DOI:10.1002/mgg3.2315

Severe Zellweger spectrum disorder due to a novel missense variant in the <i>PEX13</i> gene: A case report and the literature review