Zellweger Spectrum Disorders

Mendelian MONDO:0019609 Pathograph 31 peroxisome biogenesis disorder inborn errors of metabolism

Zellweger spectrum disorders (ZSD) are a continuum of autosomal recessive peroxisome biogenesis disorders caused by biallelic pathogenic variants in any of at least 13 PEX genes, most commonly PEX1, PEX6, and PEX12. Defective peroxisome assembly produces multi-system metabolic failure characterized by plasma accumulation of very long-chain fatty acids (VLCFA), branched-chain fatty acids, and bile acid intermediates, together with deficiency of ether phospholipids (plasmalogens). The clinical spectrum spans severe neonatal Zellweger syndrome (cerebro-hepato-renal syndrome) at one end, intermediate neonatal adrenoleukodystrophy (NALD), and the milder infantile Refsum disease (IRD) at the other; severity correlates with residual peroxisomal function. Affected individuals typically present with profound hypotonia, seizures, characteristic craniofacial features, hepatic dysfunction, and variable progressive neurological, ophthalmologic, and auditory impairment.

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1
Inheritance
4
Pathophys.
17
Phenotypes
31
Pathograph
3
Genes
3
Medical Actions
3
Subtypes
1
References
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
All Zellweger spectrum disorders are inherited as autosomal recessive traits, requiring biallelic pathogenic variants in a single PEX gene.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:14527301 SUPPORT Human Clinical
"The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal recessive complementation groups (CGs)."
This review directly supports autosomal recessive inheritance of peroxisome biogenesis disorders, the parent class containing ZSD.
◆

Subtypes

3
Zellweger Syndrome (cerebro-hepato-renal syndrome)
The most severe phenotype, presenting in the neonatal period with profound hypotonia, intractable seizures, characteristic craniofacial dysmorphism, severe liver disease, and renal cortical cysts. Most affected infants die in the first year of life.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress."
GeneReviews supports the severe-end (classic Zellweger) phenotype with profound impairment and first-year mortality.
Neonatal Adrenoleukodystrophy
Intermediate-severity phenotype with neonatal hypotonia, developmental delay, progressive leukodystrophy, adrenocortical dysfunction, and longer survival into childhood than classic Zellweger syndrome.
Show evidence (1 reference)
PMID:11769739 SUPPORT Human Clinical
"There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD)."
This reference establishes NALD as a recognized intermediate phenotype on the Zellweger continuum.
Infantile Refsum Disease
The mildest end of the spectrum, with later onset, slower progression, retinitis pigmentosa, sensorineural hearing loss, ataxia, and survival into adolescence or adulthood. Distinct from adult (PHYH-related) Refsum disease.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),..."
GeneReviews supports the milder IRD-end ZSD phenotype with progressive sensory, neurologic, hepatic, and adrenal involvement.
⚙

Pathophysiology

4
Peroxisome Biogenesis Failure
Biallelic loss-of-function variants in PEX genes (peroxins) disrupt peroxisome assembly, matrix protein import, or membrane biogenesis. The result is absent or empty "ghost" peroxisomes incapable of carrying out peroxisomal metabolism.
PEX1 hgnc:8850 PEX6 hgnc:8859 PEX12 hgnc:8854
peroxisome organization GO:0007031 ↓ DECREASED protein import into peroxisome matrix GO:0016558 ↓ DECREASED
peroxisome GO:0005777
Downstream
VLCFA and Branched-Chain Fatty Acid Accumulation Without functional peroxisomes, peroxisomal beta- and alpha-oxidation pathways fail, allowing VLCFA, phytanic acid, and pristanic acid to accumulate in plasma and tissues.
Plasmalogen and Bile Acid Intermediate Imbalance Loss of peroxisomal ether-lipid synthesis depletes plasmalogens, while blocked bile acid side-chain shortening leads to accumulation of C27 bile acid intermediates (DHCA, THCA).
Show evidence (2 references)
PMID:17055079 SUPPORT Human Clinical
"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 review directly supports PEX-gene-mediated peroxisome assembly failure as the molecular basis of ZSD.
PMID:27941306 SUPPORT In Vitro
"Peroxisome is a single-membrane-bounded ubiquitous organelle containing a hundred different enzymes that catalyze various metabolic pathways"
Fujiki's CHO cell-mutant complementation review supports the role of peroxisomes as multifunctional metabolic organelles whose biogenesis failure underlies ZSD.
VLCFA and Branched-Chain Fatty Acid Accumulation
Defective peroxisomal beta-oxidation causes pathologic elevations of saturated very long-chain fatty acids (C26:0) and the branched-chain fatty acids phytanic and pristanic acid in plasma, fibroblasts, and tissues, providing the principal biochemical diagnostic signature.
very long-chain fatty acid metabolic process GO:0000038 ↓ DECREASED fatty acid beta-oxidation GO:0006635 ↓ DECREASED fatty acid alpha-oxidation GO:0001561 ↓ DECREASED
Downstream
Multi-System Clinical Phenotype Accumulated lipid species and absent peroxisomal products contribute to neuronal migration defects, demyelination, hepatic dysfunction, renal cysts, and craniofacial abnormalities.
Very-long-chain fatty acids Impaired peroxisomal beta-oxidation is measured clinically as elevated plasma very-long-chain fatty acids.
Phytanic acid Impaired peroxisomal alpha-oxidation can elevate plasma phytanic acid.
Show evidence (2 references)
PMID:29282281 SUPPORT Model Organism
"We generated Pex19 Drosophila mutants, which recapitulate the hallmarks of PBDs, like absence of peroxisomes, reduced viability, neurodegeneration, mitochondrial abnormalities, and accumulation of VLCFAs."
Drosophila Pex19 model recapitulates VLCFA accumulation, the defining biochemical signature of ZSD.
PMID:36649687 SUPPORT Human Clinical
"PDs are characterized by abnormal elevations of very-long-chain fatty acids (VLCFA)."
Clinical case series confirms VLCFA elevation as the defining biochemical feature of peroxisomal disorders including ZSD.
Plasmalogen and Bile Acid Intermediate Imbalance
Loss of peroxisomal ether-phospholipid synthesis depletes red blood cell and tissue plasmalogens, while blocked bile acid side-chain shortening produces accumulation of dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA). Plasmalogen deficiency is implicated in CNS myelin instability.
ether lipid biosynthetic process GO:0008611 ↓ DECREASED bile acid metabolic process GO:0008206 ↓ DECREASED
Downstream
Multi-System Clinical Phenotype Plasmalogen deficiency contributes to dysmyelination and neurologic dysfunction; accumulated bile acid intermediates contribute to cholestatic liver disease.
Plasmalogens Impaired peroxisomal ether-lipid biosynthesis lowers erythrocyte and tissue plasmalogens.
C27 bile acid intermediates (DHCA, THCA) Blocked peroxisomal bile-acid side-chain shortening leads to accumulation of abnormal C27 bile-acid intermediates.
Show evidence (1 reference)
PMID:34628380 SUPPORT Human Clinical
"it is worth investigating the level of long-chain fatty acids, plasmalogen of erythrocytes, intermediate metabolites of bile acid synthesis, or carrying out genetic sequencing."
Clinical case report supports erythrocyte plasmalogen depletion and bile acid intermediate accumulation as biochemical hallmarks of ZSD.
Multi-System Clinical Phenotype
Combined toxic accumulation and product deficiency produce the characteristic Zellweger phenotype: profound hypotonia, intractable seizures, craniofacial dysmorphism, leukodystrophy, hepatic dysfunction, renal cortical cysts, and progressive sensory loss.
Downstream
Neonatal Hypotonia The severe neonatal ZSD presentation includes hypotonia as an early neuromuscular manifestation of peroxisome biogenesis failure.
Feeding Difficulties Severe neonatal ZSD often causes poor feeding, linking the multisystem neonatal phenotype to nutritional compromise.
Seizures Congenital neuronal migration defects in severe ZSD produce neonatal-onset seizures.
Characteristic Craniofacial Features Severe ZSD includes distinctive craniofacial dysmorphism as part of the congenital malformation spectrum.
Hepatomegaly Peroxisomal bile-acid and lipid metabolism failure manifests clinically as liver involvement, including hepatomegaly, in severe and milder ZSD.
Renal Cysts Severe ZSD includes renal cysts among the congenital malformations associated with peroxisome biogenesis failure.
Chondrodysplasia Punctata Severe ZSD includes bony stippling of the patellae and long bones, captured clinically as chondrodysplasia punctata.
Sensorineural Hearing Loss Progressive peroxisome dysfunction causes sensory loss that includes sensorineural hearing impairment.
Retinitis Pigmentosa Progressive peroxisome dysfunction causes retinal dystrophy, represented in the pathograph as retinal degeneration/retinitis pigmentosa.
Leukodystrophy Progressive peroxisome dysfunction causes neurologic involvement that includes leukodystrophy.
Ataxia Progressive neurologic involvement in intermediate/milder ZSD includes ataxia.
Polyneuropathy Progressive neurologic involvement in intermediate/milder ZSD includes polyneuropathy.
Developmental Delay The neurologic impact of ZSD commonly includes developmental delay, although intellect can be normal at the mildest end.
Adrenal Insufficiency Progressive peroxisome dysfunction includes adrenal insufficiency, particularly in milder ZSD presentations.
Nephrolithiasis Progressive peroxisome dysfunction can include renal oxalate stones.
Osteopenia Some individuals with ZSD have reduced bone mineral density.
Amelogenesis Imperfecta Dental enamel involvement in secondary teeth is a common ZSD manifestation.
Show evidence (2 references)
PMID:20301621 SUPPORT Human Clinical
"Affected newborns are hypotonic and feed poorly."
GeneReviews directly supports the early multi-system clinical presentation of severe ZSD.
PMID:15868469 SUPPORT Model Organism
"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."
PEX2 mouse model supports neuronal migration defects as a core neurodevelopmental consequence of peroxisome deficiency.
⬡

Pathograph

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

Phenotypes

17
Digestive 2
Feeding Difficulties Feeding difficulties HP:0011968
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Affected newborns are hypotonic and feed poorly."
GeneReviews directly supports poor feeding in affected newborns.
Hepatomegaly Hepatomegaly HP:0002240
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"liver disease that can be severe"
GeneReviews supports hepatic disease as a major organ-system phenotype of severe ZSD.
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"sensory loss (secondary to retinal dystrophy and sensorineural hearing loss)"
GeneReviews supports sensorineural hearing loss as a recognized progressive sensory phenotype of milder ZSD.
Endocrine 1
Adrenal Insufficiency Adrenal insufficiency HP:0000846
Show evidence (1 reference)
PMID:25179809 SUPPORT Human Clinical
"Primary adrenal insufficiency was found in 7/24 patients examined, with 4/7 being asymptomatic."
Clinical cohort study supports adrenal insufficiency as a frequent and often asymptomatic phenotype in ZSD.
Genitourinary 2
Renal Cysts Renal cyst HP:0000107
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"
GeneReviews supports renal cortical cysts as a characteristic congenital malformation of severe ZSD.
Nephrolithiasis Nephrolithiasis HP:0000787
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"liver dysfunction, adrenal insufficiency, and renal oxalate stones."
GeneReviews directly lists renal oxalate stones in ZSD.
Head and Neck 2
Characteristic Craniofacial Features Abnormal facial shape HP:0001999
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"They have distinctive facies"
GeneReviews supports distinctive facial features as a hallmark of severe ZSD.
Amelogenesis Imperfecta Amelogenesis imperfecta HP:0000705
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
GeneReviews supports amelogenesis imperfecta of secondary teeth.
Musculoskeletal 2
Neonatal Hypotonia Hypotonia HP:0001252
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Affected newborns are hypotonic and feed poorly."
GeneReviews directly supports neonatal hypotonia as a defining presenting feature of ZSD.
Osteopenia Osteopenia HP:0000938
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth."
GeneReviews supports osteopenia in some individuals with ZSD.
Nervous System 4
Seizures Seizure HP:0001250
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"neuronal migration defects associated with neonatal-onset seizures"
GeneReviews supports neonatal-onset seizures as a characteristic congenital malformation phenotype of severe ZSD.
Leukodystrophy Leukodystrophy HP:0002415
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)"
GeneReviews supports leukodystrophy as a major progressive neurologic phenotype of milder ZSD.
Developmental Delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"While hypotonia and developmental delays are typical, intellect can be normal."
GeneReviews supports developmental delay as a typical neurodevelopmental phenotype across the ZSD spectrum.
Ataxia Ataxia HP:0001251
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)"
GeneReviews directly lists ataxia in intermediate/milder ZSD.
Other 3
Retinitis Pigmentosa Retinal degeneration HP:0000546
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"sensory loss (secondary to retinal dystrophy and sensorineural hearing loss)"
GeneReviews supports retinal dystrophy as a key sensory phenotype in milder ZSD.
Chondrodysplasia Punctata Epiphyseal stippling HP:0010655
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"renal cysts, and bony stippling"
GeneReviews supports chondrodysplasia punctata (epiphyseal stippling) as a characteristic congenital skeletal malformation of severe ZSD.
Polyneuropathy Polyneuropathy HP:0001271
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)"
GeneReviews directly lists polyneuropathy in intermediate/milder ZSD.
🧬

Genetic Associations

3
PEX1 (Autosomal recessive causal pathogenic variant; PEX1 is the most common cause of ZSD. Specific PEX1 variants in exon 13 are associated with primary adrenal insufficiency.)
Gene: PEX1 hgnc:8850
Show evidence (1 reference)
PMID:36649687 SUPPORT Human Clinical
"all the 3 patients with PBD and adrenal insufficiency who were on steroid supplementation had the compound heterozygous pathogenic variant in exon 13 of PEX1"
Clinical case series supports a specific PEX1 compound-heterozygous genotype as causal for ZSD with adrenal insufficiency.
PEX6 (Autosomal recessive causal pathogenic variant; PEX6 variants are a recognized cause of Zellweger syndrome, often associated with severe phenotypes when leading to truncation.)
Gene: PEX6 hgnc:8859
Show evidence (1 reference)
PMID:10408779 SUPPORT Human Clinical
"Most of the mutations led to premature termination or large deletions of the PEX6 protein and resulted in the most severe peroxisome biogenesis disorder phenotype of Zellweger syndrome."
Direct sequencing study supports PEX6 truncating mutations as causal for the most severe Zellweger phenotype.
PEX12 (Autosomal recessive causal pathogenic variant in the ZSD spectrum.)
Gene: PEX12 hgnc:8854
Show evidence (1 reference)
PMID:17055079 SUPPORT Human Clinical
"DNA testing is possible for all of the disorders, but is more challenging for the ZSS since 12 PEX genes are known to be associated with this spectrum of PBD."
Steinberg review supports the multi-gene PEX-based architecture of the ZSD/ZSS spectrum, in which PEX12 is one of the recognized causal genes.
💊

Medical Actions

3
Supportive Care
Action: supportive care MAXO:0000950
There is no curative therapy for Zellweger spectrum disorders. Care is multidisciplinary and supportive, addressing seizures, feeding, hepatic dysfunction, hearing, and vision.
Target Phenotypes: Feeding difficulties HP:0011968 Sensorineural hearing impairment HP:0000407 Retinal degeneration HP:0000546 Seizure HP:0001250 Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation"
GeneReviews supports symptomatic/supportive management as the standard of care across the ZSD spectrum.
Adrenal Replacement Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: hydrocortisone CHEBI:17650
Patients with documented primary adrenal insufficiency with ZSD receive glucocorticoid (and sometimes mineralocorticoid) replacement.
Target Phenotypes: Adrenal insufficiency HP:0000846
Show evidence (2 references)
PMID:25179809 SUPPORT Human Clinical
"It is important to detect impaired adrenal function because it has treatment implications."
Clinical cohort study supports systematic adrenal-function screening and replacement therapy as a treatment-relevant intervention in ZSD.
PMID:36649687 SUPPORT Human Clinical
"Three patients were on daily hydrocortisone replacement, and 1 patient was on stress-dose hydrocortisone only as needed."
Peroxisomal-disorder case series directly documents hydrocortisone replacement in patients with adrenal insufficiency.
Cholic Acid Supplementation
Action: Pharmacotherapy NCIT:C15986
Agent: cholic acid CHEBI:16359
Oral cholic acid supplementation is used as part of symptomatic management for ZSD, where peroxisomal bile acid synthesis is disrupted and C27 bile acid intermediates accumulate.
Mechanism Target:
MODULATES Plasmalogen and Bile Acid Intermediate Imbalance — Cholic acid supplementation is linked to the bile-acid-intermediate branch of peroxisomal metabolic dysfunction.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"supplementation of fat-soluble vitamins, and cholic acid supplementation"
GeneReviews lists cholic acid supplementation in ZSD management.
Show evidence (1 reference)
PMID:20301621 SUPPORT Human Clinical
"supplementation of fat-soluble vitamins, and cholic acid supplementation"
GeneReviews directly supports cholic acid supplementation as a treatment used in the symptomatic management of ZSD.
🔬

Biochemical Markers

4
Very-long-chain fatty acids (Increased)
Context: Elevated plasma VLCFA (C26:0) is the principal biochemical screening test for Zellweger spectrum disorders.
Pathograph Readouts
Readout Of VLCFA and Branched-Chain Fatty Acid Accumulation Positive Diagnostic
Increased plasma VLCFA directly reports the peroxisomal VLCFA beta-oxidation block.
Show evidence (1 reference)
PMID:36649687 SUPPORT Human Clinical
"PDs are characterized by abnormal elevations of very-long-chain fatty acids (VLCFA)."
Supports VLCFA elevation as the defining biochemical abnormality across peroxisomal disorders including ZSD.
Phytanic acid (Increased)
Context: Phytanic acid accumulates due to impaired peroxisomal alpha-oxidation.
Pathograph Readouts
Readout Of VLCFA and Branched-Chain Fatty Acid Accumulation Positive Diagnostic
Elevated phytanic acid reports impaired peroxisomal branched-chain fatty acid catabolism within the same lipid-metabolism failure branch.
Show evidence (1 reference)
PMID:3119940 SUPPORT Human Clinical
"plasma phytanic acid concentrations may be elevated."
Biochemical diagnostic review supports elevated phytanic acid as a Zellweger biochemical abnormality.
Plasmalogens (Decreased)
Context: Erythrocyte plasmalogens are reduced because peroxisomal ether-lipid synthesis is impaired.
Pathograph Readouts
Readout Of Plasmalogen and Bile Acid Intermediate Imbalance Negative Diagnostic
Decreased red blood cell plasmalogens report failure of peroxisomal ether-lipid synthesis.
Show evidence (1 reference)
PMID:36914043 SUPPORT Human Clinical
"Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders (PBD) because plasmalogen synthesis requires functional peroxisomes."
Clinical laboratory study supports reduced plasmalogens as a classic biochemical feature of peroxisome biogenesis disorders.
C27 bile acid intermediates (DHCA, THCA) (Increased)
Context: Dihydroxycholestanoic and trihydroxycholestanoic acids accumulate because peroxisomal side-chain shortening of cholesterol-derived bile acid precursors is blocked.
Pathograph Readouts
Readout Of Plasmalogen and Bile Acid Intermediate Imbalance Positive Diagnostic
Increased C27 bile acid intermediates report impaired peroxisomal bile acid side-chain shortening.
Show evidence (1 reference)
PMID:3119940 SUPPORT Human Clinical
"abnormal C27-bile acids, very long chain fatty acids, dicarboxylic acids and pipecolic acid accumulate in the plasma of the patients."
Biochemical diagnostic review supports C27 bile acid accumulation as a plasma abnormality in classic Zellweger syndrome.
{ }

Source YAML

click to show 
name: Zellweger Spectrum Disorders
creation_date: "2026-05-13T00:00:00Z"
updated_date: "2026-05-21T10:52:42Z"
category: Mendelian
description: >-
  Zellweger spectrum disorders (ZSD) are a continuum of autosomal recessive
  peroxisome biogenesis disorders caused by biallelic pathogenic variants in
  any of at least 13 PEX genes, most commonly PEX1, PEX6, and PEX12. Defective
  peroxisome assembly produces multi-system metabolic failure characterized by
  plasma accumulation of very long-chain fatty acids (VLCFA), branched-chain
  fatty acids, and bile acid intermediates, together with deficiency of ether
  phospholipids (plasmalogens). The clinical spectrum spans severe neonatal
  Zellweger syndrome (cerebro-hepato-renal syndrome) at one end, intermediate
  neonatal adrenoleukodystrophy (NALD), and the milder infantile Refsum
  disease (IRD) at the other; severity correlates with residual peroxisomal
  function. Affected individuals typically present with profound hypotonia,
  seizures, characteristic craniofacial features, hepatic dysfunction, and
  variable progressive neurological, ophthalmologic, and auditory impairment.
disease_term:
  preferred_term: Zellweger spectrum disorders
  term:
    id: MONDO:0019609
    label: Zellweger spectrum disorders
synonyms:
- Peroxisome biogenesis disorder, Zellweger spectrum
- ZSD
- PBD-ZSS
parents:
- peroxisome biogenesis disorder
- inborn errors of metabolism
has_subtypes:
- name: Zellweger Syndrome
  display_name: Zellweger Syndrome (cerebro-hepato-renal syndrome)
  description: >-
    The most severe phenotype, presenting in the neonatal period with profound
    hypotonia, intractable seizures, characteristic craniofacial dysmorphism,
    severe liver disease, and renal cortical cysts. Most affected infants die
    in the first year of life.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infants with severe ZSD are significantly impaired and typically die
      during the first year of life, usually having made no developmental
      progress.
    explanation: >-
      GeneReviews supports the severe-end (classic Zellweger) phenotype with
      profound impairment and first-year mortality.
- name: NALD
  display_name: Neonatal Adrenoleukodystrophy
  description: >-
    Intermediate-severity phenotype with neonatal hypotonia, developmental
    delay, progressive leukodystrophy, adrenocortical dysfunction, and longer
    survival into childhood than classic Zellweger syndrome.
  evidence:
  - reference: PMID:11769739
    reference_title: Late onset white matter disease in peroxisome biogenesis disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is phenotypic and genetic overlap among the PBD known as
      Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal
      adrenoleukodystrophy (NALD).
    explanation: >-
      This reference establishes NALD as a recognized intermediate
      phenotype on the Zellweger continuum.
- name: IRD
  display_name: Infantile Refsum Disease
  description: >-
    The mildest end of the spectrum, with later onset, slower progression,
    retinitis pigmentosa, sensorineural hearing loss, ataxia, and survival
    into adolescence or adulthood. Distinct from adult (PHYH-related) Refsum
    disease.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with intermediate/milder ZSD do not have congenital
      malformations, but rather progressive peroxisome dysfunction variably
      manifest as sensory loss (secondary to retinal dystrophy and
      sensorineural hearing loss), neurologic involvement (ataxia,
      polyneuropathy, and leukodystrophy), liver dysfunction, adrenal
      insufficiency, and renal oxalate stones.
    explanation: >-
      GeneReviews supports the milder IRD-end ZSD phenotype with progressive
      sensory, neurologic, hepatic, and adrenal involvement.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All Zellweger spectrum disorders are inherited as autosomal recessive
    traits, requiring biallelic pathogenic variants in a single PEX gene.
  evidence:
  - reference: PMID:14527301
    reference_title: Peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal
      recessive complementation groups (CGs).
    explanation: >-
      This review directly supports autosomal recessive inheritance of
      peroxisome biogenesis disorders, the parent class containing ZSD.
pathophysiology:
- name: Peroxisome Biogenesis Failure
  description: >-
    Biallelic loss-of-function variants in PEX genes (peroxins) disrupt
    peroxisome assembly, matrix protein import, or membrane biogenesis. The
    result is absent or empty "ghost" peroxisomes incapable of carrying out
    peroxisomal metabolism.
  genes:
  - preferred_term: PEX1
    term:
      id: hgnc:8850
      label: PEX1
  - preferred_term: PEX6
    term:
      id: hgnc:8859
      label: PEX6
  - preferred_term: PEX12
    term:
      id: hgnc:8854
      label: PEX12
  biological_processes:
  - preferred_term: peroxisome organization
    term:
      id: GO:0007031
      label: peroxisome organization
    modifier: DECREASED
  - preferred_term: protein import into peroxisome matrix
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
    modifier: DECREASED
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  evidence:
  - reference: PMID:17055079
    reference_title: Peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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 review directly supports PEX-gene-mediated peroxisome assembly
      failure as the molecular basis of ZSD.
  - reference: PMID:27941306
    reference_title: Peroxisome biogenesis and human peroxisome-deficiency disorders.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Peroxisome is a single-membrane-bounded ubiquitous organelle containing
      a hundred different enzymes that catalyze various metabolic pathways
    explanation: >-
      Fujiki's CHO cell-mutant complementation review supports the role of
      peroxisomes as multifunctional metabolic organelles whose biogenesis
      failure underlies ZSD.
  downstream:
  - target: VLCFA and Branched-Chain Fatty Acid Accumulation
    description: >-
      Without functional peroxisomes, peroxisomal beta- and alpha-oxidation
      pathways fail, allowing VLCFA, phytanic acid, and pristanic acid to
      accumulate in plasma and tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3119940
      reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the absence of peroxisomes results in an impairment of metabolic
        processes in which peroxisomes are normally involved
      explanation: >-
        The diagnostic review links absent peroxisomes to impaired peroxisomal
        fatty-acid catabolism upstream of VLCFA and branched-chain fatty-acid
        accumulation.
  - target: Plasmalogen and Bile Acid Intermediate Imbalance
    description: >-
      Loss of peroxisomal ether-lipid synthesis depletes plasmalogens, while
      blocked bile acid side-chain shortening leads to accumulation of
      C27 bile acid intermediates (DHCA, THCA).
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3119940
      reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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 review ties absent peroxisomes to impaired ether-phospholipid and
        bile-acid metabolism, the upstream basis for plasmalogen depletion and
        C27 bile-acid intermediate accumulation.
- name: VLCFA and Branched-Chain Fatty Acid Accumulation
  description: >-
    Defective peroxisomal beta-oxidation causes pathologic elevations of
    saturated very long-chain fatty acids (C26:0) and the branched-chain
    fatty acids phytanic and pristanic acid in plasma, fibroblasts, and
    tissues, providing the principal biochemical diagnostic signature.
  biological_processes:
  - preferred_term: very long-chain fatty acid metabolic process
    term:
      id: GO:0000038
      label: very long-chain fatty acid metabolic process
    modifier: DECREASED
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: fatty acid alpha-oxidation
    term:
      id: GO:0001561
      label: fatty acid alpha-oxidation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: very-long-chain fatty acids
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
    modifier: INCREASED
  - preferred_term: branched-chain fatty acids
    term:
      id: CHEBI:35819
      label: branched-chain fatty acid
    modifier: INCREASED
  - preferred_term: phytanic acid
    term:
      id: CHEBI:16285
      label: phytanic acid
    modifier: INCREASED
  - preferred_term: pristanic acid
    term:
      id: CHEBI:51340
      label: pristanic acid
    modifier: INCREASED
  evidence:
  - reference: PMID:29282281
    reference_title: Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We generated Pex19 Drosophila mutants, which recapitulate the hallmarks
      of PBDs, like absence of peroxisomes, reduced viability,
      neurodegeneration, mitochondrial abnormalities, and accumulation of
      VLCFAs.
    explanation: >-
      Drosophila Pex19 model recapitulates VLCFA accumulation, the defining
      biochemical signature of ZSD.
  - reference: PMID:36649687
    reference_title: "Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PDs are characterized by abnormal elevations of very-long-chain fatty
      acids (VLCFA).
    explanation: >-
      Clinical case series confirms VLCFA elevation as the defining
      biochemical feature of peroxisomal disorders including ZSD.
  downstream:
  - target: Multi-System Clinical Phenotype
    description: >-
      Accumulated lipid species and absent peroxisomal products contribute to
      neuronal migration defects, demyelination, hepatic dysfunction, renal
      cysts, and craniofacial abnormalities.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - lipotoxicity and mitochondrial damage
    - neurodegeneration
    evidence:
    - reference: PMID:29282281
      reference_title: Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We generated Pex19 Drosophila mutants, which recapitulate the hallmarks
        of PBDs, like absence of peroxisomes, reduced viability,
        neurodegeneration, mitochondrial abnormalities, and accumulation of
        VLCFAs.
      explanation: >-
        The peroxisome-deficient model links VLCFA accumulation with
        neurodegeneration and mitochondrial abnormalities, supporting an
        indirect route from lipid accumulation to the clinical phenotype.
  - target: Very-long-chain fatty acids
    description: >-
      Impaired peroxisomal beta-oxidation is measured clinically as elevated
      plasma very-long-chain fatty acids.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36649687
      reference_title: "Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PDs are characterized by abnormal elevations of very-long-chain fatty
        acids (VLCFA).
      explanation: >-
        The clinical series supports elevated VLCFA as a direct biochemical
        readout of peroxisomal fatty-acid oxidation failure.
  - target: Phytanic acid
    description: >-
      Impaired peroxisomal alpha-oxidation can elevate plasma phytanic acid.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3119940
      reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        plasma phytanic acid concentrations may be elevated.
      explanation: >-
        The diagnostic review supports phytanic acid elevation as a biochemical
        readout of the branched-chain fatty-acid catabolism defect.
- name: Plasmalogen and Bile Acid Intermediate Imbalance
  description: >-
    Loss of peroxisomal ether-phospholipid synthesis depletes red blood cell
    and tissue plasmalogens, while blocked bile acid side-chain shortening
    produces accumulation of dihydroxycholestanoic acid (DHCA) and
    trihydroxycholestanoic acid (THCA). Plasmalogen deficiency is implicated
    in CNS myelin instability.
  biological_processes:
  - preferred_term: ether lipid biosynthetic process
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
    modifier: DECREASED
  - preferred_term: bile acid metabolic process
    term:
      id: GO:0008206
      label: bile acid metabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: plasmalogens
    term:
      id: CHEBI:64611
      label: ether lipid
    modifier: DECREASED
  - preferred_term: C27 bile acid intermediates
    term:
      id: CHEBI:3098
      label: bile acid
    modifier: INCREASED
  evidence:
  - reference: PMID:34628380
    reference_title: "IMPAIRMENT OF PEROXISOME BIOGENESIS IN THE SPECTRUM OF ZELLWEGER SYNDROME (CLINICAL CASE)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it is worth investigating the level of long-chain fatty acids,
      plasmalogen of erythrocytes, intermediate metabolites of bile acid
      synthesis, or carrying out genetic sequencing.
    explanation: >-
      Clinical case report supports erythrocyte plasmalogen depletion and
      bile acid intermediate accumulation as biochemical hallmarks of ZSD.
  downstream:
  - target: Multi-System Clinical Phenotype
    description: >-
      Plasmalogen deficiency contributes to dysmyelination and neurologic
      dysfunction; accumulated bile acid intermediates contribute to
      cholestatic liver disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - plasmalogen deficiency
    - bile acid intermediate accumulation
    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
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Markedly reduced plasmalogens are a classic feature of peroxisome
        biogenesis disorders (PBD) because plasmalogen synthesis requires
        functional peroxisomes.
      explanation: >-
        The clinical laboratory study links peroxisome biogenesis disorders to
        plasmalogen deficiency, a known contributor to neurologic dysfunction.
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        progressive peroxisome dysfunction variably manifest as sensory loss
        (secondary to retinal dystrophy and sensorineural hearing loss),
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy),
        liver dysfunction, adrenal insufficiency, and renal oxalate stones.
      explanation: >-
        GeneReviews supports progressive peroxisome dysfunction as the clinical
        context for neurologic, sensory, hepatic, adrenal, and renal disease.
  - target: Plasmalogens
    description: >-
      Impaired peroxisomal ether-lipid biosynthesis lowers erythrocyte and
      tissue plasmalogens.
    causal_link_type: DIRECT
    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
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Markedly reduced plasmalogens are a classic feature of peroxisome
        biogenesis disorders (PBD) because plasmalogen synthesis requires
        functional peroxisomes.
      explanation: >-
        This directly supports reduced plasmalogens as a readout of impaired
        peroxisome-dependent ether-lipid synthesis.
  - target: C27 bile acid intermediates (DHCA, THCA)
    description: >-
      Blocked peroxisomal bile-acid side-chain shortening leads to accumulation
      of abnormal C27 bile-acid intermediates.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3119940
      reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      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 diagnostic review supports C27 bile-acid accumulation as a direct
        readout of peroxisomal bile-acid metabolism failure.
- name: Multi-System Clinical Phenotype
  description: >-
    Combined toxic accumulation and product deficiency produce the
    characteristic Zellweger phenotype: profound hypotonia, intractable
    seizures, craniofacial dysmorphism, leukodystrophy, hepatic dysfunction,
    renal cortical cysts, and progressive sensory loss.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected newborns are hypotonic and feed poorly.
    explanation: >-
      GeneReviews directly supports the early multi-system clinical
      presentation of severe ZSD.
  - reference: PMID:15868469
    reference_title: "Peroxisome biogenesis disorders: the role of peroxisomes and metabolic dysfunction in developing brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    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: >-
      PEX2 mouse model supports neuronal migration defects as a core
      neurodevelopmental consequence of peroxisome deficiency.
  downstream:
  - target: Neonatal Hypotonia
    description: >-
      The severe neonatal ZSD presentation includes hypotonia as an early
      neuromuscular manifestation of peroxisome biogenesis failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected newborns are hypotonic and feed poorly.
      explanation: GeneReviews directly links severe neonatal ZSD with hypotonia.
  - target: Feeding Difficulties
    description: >-
      Severe neonatal ZSD often causes poor feeding, linking the multisystem
      neonatal phenotype to nutritional compromise.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected newborns are hypotonic and feed poorly.
      explanation: GeneReviews directly lists poor feeding in affected newborns.
  - target: Seizures
    description: >-
      Congenital neuronal migration defects in severe ZSD produce
      neonatal-onset seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        neuronal migration defects associated with neonatal-onset seizures
      explanation: GeneReviews links neuronal migration defects with neonatal seizures.
  - target: Characteristic Craniofacial Features
    description: >-
      Severe ZSD includes distinctive craniofacial dysmorphism as part of the
      congenital malformation spectrum.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        They have distinctive facies
      explanation: GeneReviews directly supports distinctive facies in severe ZSD.
  - target: Hepatomegaly
    description: >-
      Peroxisomal bile-acid and lipid metabolism failure manifests clinically
      as liver involvement, including hepatomegaly, in severe and milder ZSD.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        liver disease that can be severe
      explanation: GeneReviews supports severe liver disease as part of ZSD.
  - target: Renal Cysts
    description: >-
      Severe ZSD includes renal cysts among the congenital malformations
      associated with peroxisome biogenesis failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        neuronal migration defects associated with neonatal-onset seizures,
        renal cysts, and bony stippling
      explanation: GeneReviews lists renal cysts among severe ZSD malformations.
  - target: Chondrodysplasia Punctata
    description: >-
      Severe ZSD includes bony stippling of the patellae and long bones,
      captured clinically as chondrodysplasia punctata.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        renal cysts, and bony stippling
      explanation: GeneReviews lists bony stippling as part of severe ZSD.
  - target: Sensorineural Hearing Loss
    description: >-
      Progressive peroxisome dysfunction causes sensory loss that includes
      sensorineural hearing impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        sensory loss (secondary to retinal dystrophy and sensorineural hearing
        loss)
      explanation: GeneReviews links ZSD sensory loss to sensorineural hearing loss.
  - target: Retinitis Pigmentosa
    description: >-
      Progressive peroxisome dysfunction causes retinal dystrophy, represented
      in the pathograph as retinal degeneration/retinitis pigmentosa.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        sensory loss (secondary to retinal dystrophy and sensorineural hearing
        loss)
      explanation: GeneReviews links progressive sensory loss to retinal dystrophy.
  - target: Leukodystrophy
    description: >-
      Progressive peroxisome dysfunction causes neurologic involvement that
      includes leukodystrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)
      explanation: GeneReviews directly lists leukodystrophy in milder ZSD.
  - target: Ataxia
    description: >-
      Progressive neurologic involvement in intermediate/milder ZSD includes
      ataxia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)
      explanation: GeneReviews directly lists ataxia in milder ZSD.
  - target: Polyneuropathy
    description: >-
      Progressive neurologic involvement in intermediate/milder ZSD includes
      polyneuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)
      explanation: GeneReviews directly lists polyneuropathy in milder ZSD.
  - target: Developmental Delay
    description: >-
      The neurologic impact of ZSD commonly includes developmental delay,
      although intellect can be normal at the mildest end.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While hypotonia and developmental delays are typical, intellect can be
        normal.
      explanation: GeneReviews supports developmental delay across the ZSD spectrum.
  - target: Adrenal Insufficiency
    description: >-
      Progressive peroxisome dysfunction includes adrenal insufficiency,
      particularly in milder ZSD presentations.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        liver dysfunction, adrenal insufficiency, and renal oxalate stones.
      explanation: GeneReviews lists adrenal insufficiency among ZSD manifestations.
  - target: Nephrolithiasis
    description: >-
      Progressive peroxisome dysfunction can include renal oxalate stones.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        liver dysfunction, adrenal insufficiency, and renal oxalate stones.
      explanation: GeneReviews lists renal oxalate stones in intermediate/milder ZSD.
  - target: Osteopenia
    description: >-
      Some individuals with ZSD have reduced bone mineral density.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Some have osteopenia; almost all have ameleogenesis imperfecta in the
        secondary teeth.
      explanation: GeneReviews supports osteopenia in a subset of individuals.
  - target: Amelogenesis Imperfecta
    description: >-
      Dental enamel involvement in secondary teeth is a common ZSD
      manifestation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Some have osteopenia; almost all have ameleogenesis imperfecta in the
        secondary teeth.
      explanation: GeneReviews supports amelogenesis imperfecta in secondary teeth.
phenotypes:
- name: Neonatal Hypotonia
  category: Neurologic
  diagnostic: true
  description: >-
    Profound generalized hypotonia is one of the earliest and most consistent
    presenting features of severe Zellweger spectrum disorders.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected newborns are hypotonic and feed poorly.
    explanation: >-
      GeneReviews directly supports neonatal hypotonia as a defining
      presenting feature of ZSD.
- name: Feeding Difficulties
  category: Gastrointestinal
  description: >-
    Poor feeding is an early neonatal manifestation that often contributes to
    nutritional compromise and the need for supportive feeding care.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected newborns are hypotonic and feed poorly.
    explanation: >-
      GeneReviews directly supports poor feeding in affected newborns.
- name: Seizures
  category: Neurologic
  description: >-
    Neonatal-onset seizures, often intractable, are characteristic of
    classic Zellweger syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neuronal migration defects associated with neonatal-onset seizures
    explanation: >-
      GeneReviews supports neonatal-onset seizures as a characteristic
      congenital malformation phenotype of severe ZSD.
- name: Hepatomegaly
  category: Hepatic
  description: >-
    Hepatomegaly is a specific hepatic manifestation within the severe liver
    disease seen in Zellweger spectrum disorders.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      liver disease that can be severe
    explanation: >-
      GeneReviews supports hepatic disease as a major organ-system phenotype
      of severe ZSD.
- name: Sensorineural Hearing Loss
  category: Auditory
  description: >-
    Progressive sensorineural hearing loss is a frequent feature, particularly
    in the milder NALD and IRD forms.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sensory loss (secondary to retinal dystrophy and sensorineural hearing
      loss)
    explanation: >-
      GeneReviews supports sensorineural hearing loss as a recognized
      progressive sensory phenotype of milder ZSD.
- name: Retinitis Pigmentosa
  category: Ophthalmologic
  description: >-
    Progressive retinal degeneration with retinitis pigmentosa is a hallmark
    of the milder NALD and IRD phenotypes.
  phenotype_term:
    preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sensory loss (secondary to retinal dystrophy and sensorineural hearing
      loss)
    explanation: >-
      GeneReviews supports retinal dystrophy as a key sensory phenotype in
      milder ZSD.
- name: Characteristic Craniofacial Features
  category: Craniofacial
  description: >-
    Craniofacial features including high forehead, large fontanelles, flat
    occiput, and broad nasal bridge are characteristic of classic Zellweger
    syndrome.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They have distinctive facies
    explanation: >-
      GeneReviews supports distinctive facial features as a hallmark of
      severe ZSD.
- name: Adrenal Insufficiency
  category: Endocrine
  description: >-
    Primary adrenal insufficiency is common in ZSD, frequently asymptomatic
    in milder forms, and associated with specific PEX1 variants.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:25179809
    reference_title: High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary adrenal insufficiency was found in 7/24 patients examined,
      with 4/7 being asymptomatic.
    explanation: >-
      Clinical cohort study supports adrenal insufficiency as a frequent
      and often asymptomatic phenotype in ZSD.
- name: Renal Cysts
  category: Renal
  description: >-
    Renal cortical cysts are a near-universal congenital malformation of severe
    Zellweger syndrome.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neuronal migration defects associated with neonatal-onset seizures,
      renal cysts, and bony stippling
    explanation: >-
      GeneReviews supports renal cortical cysts as a characteristic congenital
      malformation of severe ZSD.
- name: Chondrodysplasia Punctata
  category: Skeletal
  description: >-
    Punctate epiphyseal calcifications (chondrodysplasia punctata) of the
    patellae and long bones are a characteristic congenital skeletal feature
    of severe Zellweger syndrome.
  phenotype_term:
    preferred_term: Chondrodysplasia punctata
    term:
      id: HP:0010655
      label: Epiphyseal stippling
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      renal cysts, and bony stippling
    explanation: >-
      GeneReviews supports chondrodysplasia punctata (epiphyseal stippling) as
      a characteristic congenital skeletal malformation of severe ZSD.
- name: Leukodystrophy
  category: Neurologic
  description: >-
    Progressive white matter disease (leukodystrophy) is a major neurologic
    feature of the intermediate (NALD) and milder (IRD) ZSD phenotypes.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)
    explanation: >-
      GeneReviews supports leukodystrophy as a major progressive neurologic
      phenotype of milder ZSD.
- name: Developmental Delay
  category: Neurodevelopmental
  description: >-
    Global developmental delay is a typical feature across the Zellweger
    spectrum, although intellect can be normal in the mildest cases.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While hypotonia and developmental delays are typical, intellect can be
      normal.
    explanation: >-
      GeneReviews supports developmental delay as a typical neurodevelopmental
      phenotype across the ZSD spectrum.
- name: Ataxia
  category: Neurologic
  description: >-
    Ataxia occurs in intermediate and milder ZSD as part of progressive
    neurologic involvement.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)
    explanation: GeneReviews directly lists ataxia in intermediate/milder ZSD.
- name: Polyneuropathy
  category: Neurologic
  description: >-
    Polyneuropathy occurs in intermediate and milder ZSD as part of progressive
    neurologic involvement.
  phenotype_term:
    preferred_term: Polyneuropathy
    term:
      id: HP:0001271
      label: Polyneuropathy
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurologic involvement (ataxia, polyneuropathy, and leukodystrophy)
    explanation: GeneReviews directly lists polyneuropathy in intermediate/milder ZSD.
- name: Nephrolithiasis
  category: Renal
  description: >-
    Renal oxalate stones occur in intermediate and milder ZSD and require
    renal surveillance and supportive management.
  phenotype_term:
    preferred_term: Renal oxalate stones
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      liver dysfunction, adrenal insufficiency, and renal oxalate stones.
    explanation: GeneReviews directly lists renal oxalate stones in ZSD.
- name: Osteopenia
  category: Skeletal
  description: >-
    Reduced bone mineral density is reported in a subset of individuals with
    ZSD.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some have osteopenia; almost all have ameleogenesis imperfecta in the
      secondary teeth.
    explanation: GeneReviews supports osteopenia in some individuals with ZSD.
- name: Amelogenesis Imperfecta
  category: Dental
  description: >-
    Dental enamel dysplasia of the secondary teeth is a common manifestation in
    ZSD survivors.
  phenotype_term:
    preferred_term: Amelogenesis imperfecta
    term:
      id: HP:0000705
      label: Amelogenesis imperfecta
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some have osteopenia; almost all have ameleogenesis imperfecta in the
      secondary teeth.
    explanation: GeneReviews supports amelogenesis imperfecta of secondary teeth.
biochemical:
- name: Very-long-chain fatty acids
  presence: Increased
  context: >-
    Elevated plasma VLCFA (C26:0) is the principal biochemical screening test
    for Zellweger spectrum disorders.
  readouts:
  - target: VLCFA and Branched-Chain Fatty Acid Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased plasma VLCFA directly reports the peroxisomal VLCFA
      beta-oxidation block.
  biomarker_term:
    preferred_term: very long-chain fatty acid
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
  evidence:
  - reference: PMID:36649687
    reference_title: "Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PDs are characterized by abnormal elevations of very-long-chain fatty
      acids (VLCFA).
    explanation: >-
      Supports VLCFA elevation as the defining biochemical abnormality
      across peroxisomal disorders including ZSD.
- name: Phytanic acid
  presence: Increased
  context: >-
    Phytanic acid accumulates due to impaired peroxisomal alpha-oxidation.
  readouts:
  - target: VLCFA and Branched-Chain Fatty Acid Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated phytanic acid reports impaired peroxisomal branched-chain fatty
      acid catabolism within the same lipid-metabolism failure branch.
  biomarker_term:
    preferred_term: phytanic acid
    term:
      id: CHEBI:16285
      label: phytanic acid
  evidence:
  - reference: PMID:3119940
    reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      plasma phytanic acid concentrations may be elevated.
    explanation: >-
      Biochemical diagnostic review supports elevated phytanic acid as a
      Zellweger biochemical abnormality.
- name: Plasmalogens
  presence: Decreased
  context: >-
    Erythrocyte plasmalogens are reduced because peroxisomal ether-lipid
    synthesis is impaired.
  readouts:
  - target: Plasmalogen and Bile Acid Intermediate Imbalance
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Decreased red blood cell plasmalogens report failure of peroxisomal
      ether-lipid synthesis.
  biomarker_term:
    preferred_term: plasmalogens
    term:
      id: CHEBI:64611
      label: ether lipid
  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
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Markedly reduced plasmalogens are a classic feature of peroxisome
      biogenesis disorders (PBD) because plasmalogen synthesis requires
      functional peroxisomes.
    explanation: >-
      Clinical laboratory study supports reduced plasmalogens as a classic
      biochemical feature of peroxisome biogenesis disorders.
- name: C27 bile acid intermediates (DHCA, THCA)
  presence: Increased
  context: >-
    Dihydroxycholestanoic and trihydroxycholestanoic acids accumulate because
    peroxisomal side-chain shortening of cholesterol-derived bile acid
    precursors is blocked.
  readouts:
  - target: Plasmalogen and Bile Acid Intermediate Imbalance
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased C27 bile acid intermediates report impaired peroxisomal bile
      acid side-chain shortening.
  biomarker_term:
    preferred_term: C27 bile acid intermediates
    term:
      id: CHEBI:3098
      label: bile acid
  evidence:
  - reference: PMID:3119940
    reference_title: "Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal C27-bile acids, very long chain fatty acids, dicarboxylic
      acids and pipecolic acid accumulate in the plasma of the patients.
    explanation: >-
      Biochemical diagnostic review supports C27 bile acid accumulation as a
      plasma abnormality in classic Zellweger syndrome.
genetic:
- name: PEX1
  gene_term:
    preferred_term: PEX1
    term:
      id: hgnc:8850
      label: PEX1
  association: >-
    Autosomal recessive causal pathogenic variant; PEX1 is the most common
    cause of ZSD. Specific PEX1 variants in exon 13 are associated with
    primary adrenal insufficiency.
  evidence:
  - reference: PMID:36649687
    reference_title: "Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all the 3 patients with PBD and adrenal insufficiency who were on
      steroid supplementation had the compound heterozygous pathogenic
      variant in exon 13 of PEX1
    explanation: >-
      Clinical case series supports a specific PEX1 compound-heterozygous
      genotype as causal for ZSD with adrenal insufficiency.
- name: PEX6
  gene_term:
    preferred_term: PEX6
    term:
      id: hgnc:8859
      label: PEX6
  association: >-
    Autosomal recessive causal pathogenic variant; PEX6 variants are a
    recognized cause of Zellweger syndrome, often associated with severe
    phenotypes when leading to truncation.
  evidence:
  - 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
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of the mutations led to premature termination or large deletions
      of the PEX6 protein and resulted in the most severe peroxisome
      biogenesis disorder phenotype of Zellweger syndrome.
    explanation: >-
      Direct sequencing study supports PEX6 truncating mutations as causal
      for the most severe Zellweger phenotype.
- name: PEX12
  gene_term:
    preferred_term: PEX12
    term:
      id: hgnc:8854
      label: PEX12
  association: Autosomal recessive causal pathogenic variant in the ZSD spectrum.
  evidence:
  - reference: PMID:17055079
    reference_title: Peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA testing is possible for all of the disorders, but is more
      challenging for the ZSS since 12 PEX genes are known to be associated
      with this spectrum of PBD.
    explanation: >-
      Steinberg review supports the multi-gene PEX-based architecture of the
      ZSD/ZSS spectrum, in which PEX12 is one of the recognized causal genes.
diagnosis:
- name: Plasma very-long-chain fatty acid measurement
  description: >-
    Plasma VLCFA testing is the first-line biochemical screen for Zellweger
    spectrum disorders and remains the cornerstone of ZSD diagnosis.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:36649687
    reference_title: "Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PDs are characterized by abnormal elevations of very-long-chain fatty
      acids (VLCFA).
    explanation: >-
      Clinical case series supports VLCFA measurement as the defining
      biochemical diagnostic test in peroxisomal disorders.
- name: Molecular genetic testing of PEX genes
  description: >-
    Identification of biallelic pathogenic variants in one of the 13 known
    ZSD-PEX genes establishes the molecular diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of ZSD is established in a proband with the suggestive
      clinical and biochemical findings above by identification of biallelic
      pathogenic variants in one of the 13 known ZSD-PEX genes.
    explanation: >-
      GeneReviews directly supports biallelic PEX gene testing as the
      molecular diagnostic standard for ZSD.
treatments:
- name: Supportive Care
  description: >-
    There is no curative therapy for Zellweger spectrum disorders. Care is
    multidisciplinary and supportive, addressing seizures, feeding,
    hepatic dysfunction, hearing, and vision.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  - preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The focus is on symptomatic therapy and may include gastrostomy to
      provide adequate calories, hearing aids, cataract removal, glasses to
      correct refractive errors, supplementation of fat-soluble vitamins,
      and cholic acid supplementation
    explanation: >-
      GeneReviews supports symptomatic/supportive management as the standard
      of care across the ZSD spectrum.
- name: Adrenal Replacement Therapy
  description: >-
    Patients with documented primary adrenal insufficiency with ZSD receive
    glucocorticoid (and sometimes mineralocorticoid) replacement.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: CHEBI:17650
        label: cortisol
  target_phenotypes:
  - preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:25179809
    reference_title: High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is important to detect impaired adrenal function because it has
      treatment implications.
    explanation: >-
      Clinical cohort study supports systematic adrenal-function screening
      and replacement therapy as a treatment-relevant intervention in ZSD.
  - reference: PMID:36649687
    reference_title: "Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were on daily hydrocortisone replacement, and 1 patient
      was on stress-dose hydrocortisone only as needed.
    explanation: >-
      Peroxisomal-disorder case series directly documents hydrocortisone
      replacement in patients with adrenal insufficiency.
- name: Cholic Acid Supplementation
  description: >-
    Oral cholic acid supplementation is used as part of symptomatic management
    for ZSD, where peroxisomal bile acid synthesis is disrupted and C27 bile
    acid intermediates accumulate.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  target_mechanisms:
  - target: Plasmalogen and Bile Acid Intermediate Imbalance
    treatment_effect: MODULATES
    description: >-
      Cholic acid supplementation is linked to the bile-acid-intermediate branch
      of peroxisomal metabolic dysfunction.
    evidence:
    - reference: PMID:20301621
      reference_title: Zellweger Spectrum Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        supplementation of fat-soluble vitamins, and cholic acid supplementation
      explanation: GeneReviews lists cholic acid supplementation in ZSD management.
  evidence:
  - reference: PMID:20301621
    reference_title: Zellweger Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      supplementation of fat-soluble vitamins, and cholic acid supplementation
    explanation: >-
      GeneReviews directly supports cholic acid supplementation as a
      treatment used in the symptomatic management of ZSD.
datasets: []
references:
- reference: PMID:20301621
  title: Zellweger Spectrum Disorder.
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301621
Zellweger Spectrum Disorder.
No top-level findings curated for this source.